Cd37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof

In general, the present invention discloses compositions and their use in methods of treating B cell related disorders, and more particularly, provides both humanized small modular immunopharmaceutical molecules (SMIPs) directed against CD37 as well as therapies with synergistic combinations with the use of CD37 specific binding molecules in combination with bifunctional chemotherapeutics for use in the treatment or prevention of autoimmune, inflammatory diseases or diseases associated with B cell hyperproliferation.

Description of the State of the Art [0002] Typically, the human immune system protects the body from invading foreign substances and pathogens. One of the elements of the immune system are B lymphocytes, also called B cells, which produce antibodies that protect the body by binding to foreign substances or pathogens, and in some cases mediates their destruction. However, in some cases, the immune system functions improperly, resulting in disease progression. For example, there are many cancers, autoimmune diseases and inflammatory diseases in which uncontrolled B cell proliferation occurs.

[0003] B cells can be identified based on the identification of molecules found on the surface of cells, such as CD37. CD37 is a highly glycosylated 40-52 kDa protein that belongs to the tetraspanin family of transmembrane antigens found on the surface of cells. These proteins are highly expressed on the surface of normal, B-cell-producing antibodies, but do not occur on precursor B cells or on plasma cells. In addition to normal B cells, almost all cancers from B-lymphocytes are positive for CD37 expression, including chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL) and hairy cell leukemia (Moore et al., J. Pathol 152: 13 ( 1987), Merson and Brochier, Immunol. Lett. 19: 269 (1988) and Faure et al., Am. J. Dermatopathol 12: 122 (1990)).

[0004] Several immunotherapy specific for CD37 has been developed. An IgG1 mouse monoclonal antibody specific for CD37 called MB-1 was labeled with an I-isotope¹³¹ and tested in clinical trials for the treatment of NHL (see Press et al., J. Clin., Oncol. 7: 1027 (1989); Bernstein et al., Cancer Res (Suppl) 50: 1017 (1990); Press et al. Front, Radiat. Ther. Oncol. 24: 204 (1990), Press et al., Adv. Exp. Med. Biol. 303: 91 (1991) and Brown et al., Nucl. Med. Biol. 24: 657 (1997) )). The MB-1 antibody has no Fc-terminal end effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC). The MB-1 antibody deprived of these functions does not inhibit tumor growth in vivo in a xenogeneic model (Buchsbaum et al., Cancer Res. 52: 6476 (1992)). In addition, mice were administered an immunoconjugate in which adriamycin is attached to G28-1, another mouse monoclonal antibody directed against CD37. The immunoconjugate has been shown to be internalized with adriamycin, and adriamycin is released within

Cell (see Braslawsky et al., Cancer immune \ Immunother 33: 367 (1991)). The constructed fusion protein, called a small modular immunopharmaceutical product (SMIP ™) and directed against CD37, is currently being tested on a group of patients (see, e.g., Publications of Patent Application US 2003/0133939 and 2007/0059306).

[0005] In spite of extensive research into antibody-based therapies, there is still a need in the art for providing alternative or improved compositions and methods useful in treating disorders or diseases associated with B cells.

[0006] The present invention provides CD37-specific binding molecules that contain amino acid sequences as set forth in SEQ. ID NO. 253.

[0007] In some embodiments, CD37-specific binding molecules essentially consist of the amino acid sequence set forth in SEQ. ID NO. 253.

[0008] In some embodiments, the CD37 specific binding molecule comprises an amino acid sequence that is set forth in SEQ. ID NO. 253.

[0009] According to a related aspect, the present invention also provides an isolated nucleic acid molecule that comprises a nucleotide sequence coding for humanized, specifically CD37-binding molecules of the invention.

[0010] In another similar aspect, the invention provides a vector comprising a single nucleic acid molecule that encodes a humanized, specifically CD37 binding molecule of the present invention.

[0011] In another similar aspect, the invention provides a host cell that comprises the above-described vector.

[0012] The invention also provides a composition that comprises humanized, specifically CD37-binding molecules of the present invention and a pharmaceutically acceptable carrier. [0013] In another aspect, the invention provides the use of compounds of the invention in a method of reducing B cell number or in treating diseases associated with abnormal B cell activity, which method comprises administering to a subject in need thereof an effective amount of a humanized, CD37 specific binding molecule of the present invention. invention.

[0014] In some embodiments, the disease associated with abnormal B cell activity is B-cell lymphoma, B-cell leukemia, multiple myeloma, a disease characterized by the production of antibodies against its own antigens, or a disease characterized by abnormal T-cell stimulation associated with the B cell pathway.

[0015] In some embodiments, a disease characterized by the production of antibodies directed against self antigens is idiopathic myopathy with inflammation, rheumatoid arthritis, myasthenia gravis, Graves' disease, type I diabetes, multiple sclerosis, autoimmune disease, dermatomyositis, polymyositis or polymyositis. Waldenstrom's macroglobulinemia.

[0016] In some embodiments, the disease associated with abnormal B-cell activity is chronic lymphocytic leukemia (CLL).

BRIEF DESCRIPTION OF THE FIGURES [0017]

Figure 1 shows the comparison of the amino acid sequence of the mouse G28.1 heavy and light chain variable region, CAS-024 sequence and consensus sequence.

Figures 2A-2D show the molecular sieve chromatograms (SEC) of the CAS-001, CAS-002, CAS-003 and CAS-024 formulations. Peaks of interest (POIs) contain 9899% of purified SMIP molecules. CAS-024 has a very sharp and symmetrical peak (indicating homogeneity), while peaks for CAS-001, CAS-002 and CAS-003 have a descending arm (where, after integration for this arm, a value of about 35% of POIs was obtained), which indicates heterogeneous population of molecules.

Figure 3 is a graph illustrating how different specific anti-CD37 SMIP proteins compete for the parent CAS-006 molecule (chimeric anti-CD37 SMIP chMV, mVLmVH) in binding to CD37 on Ramos cells, indicating that the binding affinity for CD37 compared to the parent molecule CAS-024 (hVHhVL) is basically the same as CAS-006, while the other molecules (CAS-001, CAS-002 and CAS-003, all hVLhVH) show a reduced factor of about four-fold.

Figures 4A and 4B are graphs depicting additional competitive binding assays in competition with the CAS-006 antibody (designated SMIP-016 on these graphs). Here, hybrid SMIP mouse (CAS-014 mVHhVL and CAS-017 hVLmVH) have an affinity that is higher than CAS-006, CAS-024 has the same affinity as CAS-006, while CAS-003 (hVLhVH) shows lower binding affinity.

Figure 5A shows the competitive binding of a number of different anti-CD37 and CAS-006 antibodies (chimeric anti-CD37 SMIP molecule).

Figures 6A and 6B show that CAS-024 was statistically superior to Rituxan® in the in vivo treatment carried out on an animal lymphoma model, as shown by the survival ratio (A) and the percentage of non-tumorous animals (B).

Figure 7 shows that CAS-024 acts synergistically with the fludarabine and vincristine chemotherapies by killing the cell lymphoma cells Rec-1 cells (MCL).

Figure 8 is a bar graph showing the level of peripheral blood lymphocyte deficiency in human patients treated with anti-CD37 SMIP molecules of the present disclosure.

Figure 9 illustrates the loss of lymphocytes and the course of treatment in a patient with BJB. Patients with BJB (part of Kohorty 7) in the first cycle were treated with a dose of 3.0 mg / kg given on days 1, 3 and 5 in the first week, followed by three doses in the first cycle for three weeks. The same treatment regimen was used in the second cycle. Patients with BJB had a dramatic decrease in lymphocyte counts (within 48 hours), a reduction in palpable lymph nodes until day 4. After 4 days, the response is still maintained.

EP-2132228B1PL

Figure 10 illustrates the loss of lymphocytes and the course of treatment in a patient with GRP. Patients with GRP (part of Kohorta 4) were treated with 1.0 mg / kg given once a week for four weeks in the first cycle, and then treated two months later in the same way as part of the second cycle. Patients with GRP had a drastic decrease in lymphocyte counts (within 2 weeks), a reduction in computed lymph nodes sizes by 36%, a reduction in spleen size, an improvement in hemoglobin, and the response to treatment continued.

Figure 11 is a diagram of the CI index for the inhibitory effect of CAS-024 and bendamustine on the growth of Rec-1 cells.

Figure 12 illustrates the inhibitory effect of chlorambucil and chlorambucil alone in combination therapy with CAS-024 on the growth of SU-DHL-6 cells.

Figure 13 shows a diagram of the CI index for the inhibitory effect of CAS-024 and chlorambucil on the growth of SU-DHL-6 cells.

Figure 14A shows tumor size comparisons in tumor-bearing mice resulting from injection of DOHH2 cells and then treated with hulgG (Human IgG, R & D Systems), CAS024, bendamustine and CAS-024 in combination with bendamustine. Figure 14B shows the tumor volume of individual mice measured on day 13 (compared to day 0).

Figure 15 shows the mean tumor volumes varying over time in tumor-bearing mice resulting from injection of DOHH2 cells followed by treatment with hulgG (Human IgG, R & D Systems), CAS-024, bendamustine and CAS-024 in combination with bendamustine. Values ​​are the mean ± standard error of the mean for each day of measurement. The curves for each group are prepared until one or two mice of the group are euthanized.

Figure 16 shows the time-course survival rate of tumor-bearing mice resulting from injection of DOHH2 cells and then treated with hulgG (Human IgG, R & D Systems), CAS-024, bendamustine, and CAS-024 in combination with bendamustine.

Figure 17 shows the incidence of cancer in mice that changes after treatment with hulgG, CAS-024, bendamustine and CAS-024 in combination with bendamustine.

DETAILED DESCRIPTION [0018] In one aspect, the present invention provides a CAS-024 molecule (SEQ ID NO: 253) specifically binding CD37, which is a humanized version of CAS-006 (small modular immunopharmaceutical protein (SMIP) having a variable immunoglobulin region derived from a mouse Monoclonal antibody G28-1 directed against CD37 Unexpectedly, the CAS-024 SMIP (1) protein is expressed at levels up to about 25-fold higher than other humanized versions of CAS-006 (e.g. CAS-002, CAS-003; see Example 2 and 5), (2) is capable of binding both CD37 and CAS-006 as opposed to other humanized versions (see Examples 4 and 5) and (3) is produced as a homogeneous population of molecules compared to other versions of the humanized antibodies produced in a heterogeneous population (see Example 3).In addition, the present disclosure provides a molecule

EP-2132228B1PL

CAS-024 (SEQ ID No. 253) for CD37 binding for use in methods of reducing B cells or for treating diseases associated with abnormal B cell activity, comprising administering to the patient in need thereof an effective amount of CAS-024 of the invention.

[0019] Before discussing this disclosure in more detail, it may be helpful to understand the terms that will be used herein. The present disclosure provides additional definitions.

[0020] In the present description, any concentration range, percentage percentage range, index range or integer range is to be interpreted as a range including any integer value falling within the given range and, when appropriate, parts thereof (e.g. one tenth and one hundredth of an integer), unless otherwise stated. Furthermore, unless otherwise indicated, it should be understood that any numerical range referred to herein referring to any physical property such as a polymer subunit, size or thickness, includes any integer in the referenced range, unless otherwise indicated. As used herein, the term "about" or "consisting essentially of" means ± 20% of the indicated range, value or structure, unless otherwise indicated. It should be understood that in the present description, in the English version "a" and "an" and in the Polish version, the use of nouns in the singular refers to "one or more" of the listed elements. When using an alternative expression (e.g., "or"), one or both alternatives should be understood. As used herein, the terms "comprises" and "covers" are used interchangeably. Furthermore, it should be understood that individual compounds or groups of compounds derived from the various combinations of structures and substituents described herein are disclosed in this application to the same extent as when each compound or group of compounds are presented singly.

[0021] The term "CD37-specific binding molecule" refers to a protein, polypeptide, oligopeptide or peptide that specifically binds CD37 to Ka of at least about 10⁶

-1

M^-1 (e.g., at least about 10⁷ M^-1, 10⁸ M^-1, 10⁹ M^-1, 10¹⁰ M^-1, 10¹¹ M^-1, 10¹² M^-1or 10¹³ M^-1).

[0022] The term "CD37-specific binding domain" refers to a part or the entire domain of the CD37 specific binding molecule responsible for the specific binding of the CD37 molecule. A domain specifically binding CD37 (i.e., without any other portion of the CD37 specific binding molecule) binds CD37 to Ka of at least about 10⁶ M^-1 (e.g., at least about 10⁷ M^-1, 10⁸ M^-1, 10⁹ M^-1, 10¹⁰ M^-110¹¹ M^-1, 10¹² M^-1 or 10¹³ M^-1). The CD37 binding domain alone may be sufficient as a CD37 specific binding molecule. Exemplary CD37-specific binding domains include scFv fragments and Fab fragments that specifically bind to CD37, which can be obtained from anti-CD37 antibodies, such as monoclonal antibody G28-1.

[0023] The term "derivative", as used herein, refers to a chemically or biologically modified version of a compound that is structurally similar to the parent compound and (actually or theoretically) is a derivative thereof. In general, a "derivative" differs from the "analogue" in that the starting compound may be the starting material for the formation of a "derivative", but is not necessarily the starting material for obtaining an "analogue". The derivative may differ from the starting material chemical and physical properties. For example, the derivative may be more hydrophilic or it may be a mutant sequence with altered reactivity, e.g. a CDR having altered amino acids,

[0024] "Disorder or disease associated with B cells" refers to abnormal B cell activity or activity thereof that deviates from normal, normal or expected activity. For example, a disorder or disease associated with B cells may involve abnormal proliferation of cells that have damaged or defective DNA or other cell components. B-cell dysfunction may affect cell proliferation characterized by abnormally high levels of cell division, abnormally low levels of apoptosis, or may include both. Such diseases may be characterized for example by abnormal proliferation of one or more cells, groups of cells or the growth of tissue (s), while neoplastic or non-cancerous, a benign or malignant disorder or disease associated with B cells may also include abnormal production of antibodies, such as the production of antibodies directed against self antigens or the overproduction of more desirable antibodies when their production is at the correct level. The present invention also contemplates a variant in which abnormal B cell activity may occur in specific subpopulations or may include abnormal T cell stimulation, such as presentation of T-cells of the abnormal antigen or abnormal B-cell activity on another pathway.

[0025] "Treatment" (noun) or "treatment" (participle in participle) refers to both therapeutic treatment and prophylactic / preventative treatment. Therapeutic treatment of individual patients may improve the patient's condition in at least one symptom of the disease, delay the deterioration of the patient's state of health or progression of the disease or prevent the occurrence of additional complaints associated with the disease.

[0026] "Therapeutically effective amount (dose)" or "effective amount (dose)" of a specifically binding molecule or compound refers to that amount of a chemical that is an amount sufficient to provide an improvement in one or more symptoms of the disease being treated. When applied to individual active ingredients in monotherapy, a therapeutically effective dose refers to said component used individually. When used in combination therapy, the therapeutically effective dose refers to the amount of combined active ingredients that lead to the therapeutic effect, independently

EP-2132228B1EN on whether they are administered sequentially or simultaneously. In particular, a variant is contemplated in the invention wherein one or more specific binding molecules can be administered by the method of the invention, each at a therapeutically effective dose.

[0027] "A subject suffering from a disease associated with impaired B cell activity or a subject suspected of having such a disease is an individual whose disease or disease symptom may be caused by a disruption of B cell activity or B cell proliferative disorder, his condition may deteriorate due to impaired B cell activity or can be cured by regulating the activity of B cells. Examples of such diseases are B cell tumor diseases or B cell carcinoma (e.g., B-cell lymphoma, B-cell leukemia or multiple B-cell myeloma.) These diseases are characterized by antibodies directed against self antigens or abnormal T-cell stimulation caused by improper antigen presentation of T cells by B cells or abnormal B cell activity on another metabolic pathway.

[0028] Additional definitions are included in the following detailed description of the disclosure.

Humanized molecules specifically binding CD37 [0029] In one aspect, the invention provides humanized molecules specifically binding CD37, as defined in the claims. These molecules can be in any form that contains humanized CD37 specific domains, including a humanized anti-CD37 antibody, a Fab fragment of a humanized anti-CD37 antibody, a humanized CD37 specific single Fv chain (scFv), humanized CD37-specific SMIP protein, humanized CD37-specific SCORPION protein and other bi-or multispecific-binding proteins that contain at least one humanized CD37 binding domain. A detailed description of the SMIP proteins and methods for their preparation can be found, for example, in published U.S. Pat. No. 2003/0133939, 2003/0118592 and 2005/0136049 and WO 2005017148. Methods of producing SCORPION proteins can be found, for example, in PCT Application No. WO 2007/146968. Other examples of fusion multifunctional proteins can be found, for example, in US Patent Application Publication No. 2006/0051844 and US Patent No. 7,166,707. Some dual or multispecific binding proteins may contain CD37 specific scFv and one or more other binding domains that are not derived from immunoglobulins. . [0030] The SMIP-type protein SMIP surprisingly (1) is up to about 25-fold higher than other humanized versions of CAS-006 (e.g. CAS-002, CAS-003, see Examples 2 and 5), (2) is able to bind CD337 as well as GAZ-006 as opposed to other humanized versions (see Examples 4 and 5) and (3) is produced as a homogeneous population of molecules compared to the heterogeneous population of other humanized molecules (see Example 3). In a preferred embodiment, the present invention provides a CD37 binding protein that comprises or consists of CAS-024 (SEQ ID NO: 253). In particular, the humanized CD37 binding molecule has substantially the same affinity for CD37 as the starting chimeric molecule (CAS-006, SMIP protein with variable regions).

Immunoglobulin derived from a mouse monoclonal antibody G28-1 directed against human CD37) and in contrast to other humanized molecules, is expressed at a high level compared to other humanized molecules and / or after purification in a molecular sieve (SEC) shows a high degree of homogeneity in contrast to other humanized molecules. In addition, it was shown that the CAS-024 molecule specifically binding CD37 effectively inhibits tumor growth and prolongs tumor regression time.

[0031] The disclosure also includes a single nucleic acid molecule comprising a nucleotide sequence encoding humanized molecules specifically binding CD37 of the present invention. In one embodiment, the disclosure includes vectors that comprise these nucleic acid molecules and host cells that comprise these vectors.

[0032] The disclosure also encompasses a process for producing polypeptides as described herein, comprising growing the host cells under conditions suitable for expressing the polypeptides and optionally isolating the polypeptides from the cell culture.

COMPOSITIONS AND METHODS [0033] In one aspect, the invention provides use of a composition of the present invention in a method of reducing B cell number or in a method of treating a disease associated with impaired B cell activity, which comprises administering to a subject in need thereof (i.e. a person suffering from a disease associated with abnormal B cell activity or a person with suspected disease associated with abnormal B cell activity) of the effective amount of the humanized CD37 specific binding molecule provided in the present invention e.g. CAS-024).

[0034] Cancers associated with B cells include B cell lymphomas [such as various forms of Hodgkin's disease, Non Hodgkin's lymphoma (NHL) or central nervous system lymphomas], leukemia [such as acute lymphoblastic leukemia (ALL), chronic lymphatic leukemia ( CLL), hairy cell leukemia and chronic myelogenous leukemia] and myelomas (such as multiple myeloma). Other B-cell tumors include diseases such as small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, marginal spleen lymphoma, multiple myeloma, single myeloma, non-myeloma, hypertensive meconium-associated lymphoma (MALT) of the marginal zone of lymphatic zone, B cell lymphoma of the marginal zone, follicular lymphoma, mantle cell lymphoma,

[0035] Burkitt's lymphoma (or "B-cell tumor of Burkittta" or "Burkitt's tumor" or "malignant lymphoma, Burkitt's type") is a cancer of the lymphatic system (in

In particular B lymphocytes). It can be divided into three main clinical variants: endemic, sporadic variants associated with deficiency of the immune system.

[0036] B-cell neoplasms not of the Burkitt type include, but are not limited to, B cellular chronic lymphocytic leukemia (CLL) / SLL lymphoma, B-cell promyelocytic leukemia, acute lymphoblastic leukemia (ALL), lymphoplasmic lymphoma (incl. not only Waldenstrom's macroglobulinemia), marginal zone lymphomas (including, but not limited to B-cell lymphoma of the spleen's marginal zone, marginal zone node nodal lymphoma and extranodal B-cell lymphoma of marginal zone of the mucosa associated with lymphoid tissue (MALT type), leukemia cell leukemia, multiple myeloma / myeloma, follicular lymphoma, mantle cell lymphoma (MCL), diffuse large cell type B lymphoma, transforming lymphoma from large B lymphocytes, large cell lymphoma,endovascular B-cell lymphoma, primary cutaneous lymphoma and non-Burkitt's lymphoma and Non-Hodgkins lymphoma (NHL).

[0037] Disorders characterized by the production of autoantibodies are often considered as autoimmune diseases. Autoimmune diseases include, but are not limited to, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, multi-chondritis, psoriatic arthritis, psoriasis, dermatitis, polymyositis, dermatomyositis, and intramural muscular inflammation, myositis, toxic epidermal necrolysis, systemic sclerosis and sclerosis, CREST syndrome, reactions related to inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute respiratory distress syndrome, adult respiratory distress syndrome (ARDS), meningitis encephalitis, uveitis,

Whiskott-Aldrich syndrome and thromboangiitis obliterans, autoimmune thyroid disease (e.g. Graves-Basedow and Hashimoto's disease), Sjogren's syndrome and idiopathic myopathy with inflammation (IIM), including dermatomyositis (DM) and polymyositis ( PM). The above autoimmune diseases can also be treated with humanized CD37 binding molecules or a combination of molecules specifically binding CD37 and bifunctional chemotherapeutics. [0038] In one aspect of the disclosure, humanized molecules specifically binding CD37 are administered in a pharmaceutical composition. For the administration of a humanized molecule specifically binding CD37 to human or experimental animals, it is preferred to formulate a binding molecule in a combination comprising one or more pharmaceutically acceptable carriers.

EP-2132228B1PL

The term "pharmaceutically or pharmacologically acceptable" refers to homogeneous forms and compositions that, following administration via well-known routes of drug administration, as described below, do not induce allergic or other adverse reactions. "Pharmaceutically acceptable carriers" contain any clinically useful solvents, dispersants, coatings, antibacterial and antifungal agents, isotonic and delaying absorption agents, and the like. In addition, the compounds can form solvates with water or with ordinary organic solvents. Such solvates are also considered here.

[0039] The pharmaceutical compositions of the present invention comprising the humanized CD37-specific binding molecule used in the method of the disclosure may contain pharmaceutically acceptable carriers or additives depending on the route of administration. Examples of such carriers or additives include water, a pharmaceutically acceptable organic solvent, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextrans, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum , gum arabic, casein, gelatin, agar, diglycerine, glycerol, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin (HSA), mannitol, sorbitol, lactose, a pharmaceutically acceptable surfactant and the like. The additives used are selected from, but not limited to, the additives listed above or their combinations thereof depending on the dosage form of the present disclosure.

[0040] The formulation of the pharmaceutical composition will vary depending on the chosen route of administration (e.g., solution, emulsion). A suitable composition containing antibodies to be administered may be prepared in a physiologically acceptable vehicle or carrier. For solutions or emulsions, suitable carriers include, for example, aqueous or alcohol / aqueous solutions, emulsions or suspensions, including physiological saline and a buffered medium. Substrates for parenteral administration may contain a solution of sodium chloride, Ringer's dextrose, dextrose and sodium chloride, Ringer's lactate or hardened oils. Substrates for intravenous administration may contain various additives, preservatives, or liquid, nutrients or electrolyte replenishers.

[0041] A variety of aqueous carriers, e.g. water, buffered water, 0.4% saline, 0.3% glycine, or an aqueous suspension may contain the active ingredient in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic. Dispersing or wetting agents may be naturally occurring phosphatides, e.g. lecithin or condensation products of alkylene oxide with fatty acids, e.g. polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. heptadecetyl-eneoxycetanol or products

Condensation of ethylene oxide with partially esterified fatty acid esters and hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide products with partial esters derived from fatty acids and hexitol anhydrides, e.g. polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl, n-propyl or p-hydroxybenzoate.

[0042] The CD37 binding molecule or composition comprising the binding molecule of the invention may be lyophilized for storage and reconstituted in a suitable vehicle prior to use. This technique was effective for conventional immunoglobulins. Any suitable freeze-drying and reconstitution technique can be used. Those skilled in the art are aware that freeze-drying and reconstitution can lead to a loss of activity to varying degrees, and that for fitness purposes, the level of activity loss should be compensated.

[0043] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are given below.

[0044] The concentration of the CD37 binding molecule in these formulations can vary widely, for example from less than about 0.5%, usually or at least about 1% to even 15% or 20% by weight, and will be selected mainly on the basis of volume and viscosity fluid, etc. according to the selected method of administration. Thus, a typical pharmaceutical composition intended for parenteral administration can be made up to 1 ml of sterile buffered water and 50 mg of antibodies. A typical composition intended for infusion can be made up to 250 ml of sterile Ringer's solution and 150 mg of antibodies. The present methods for the preparation of compositions intended for parenteral administration will be known or obvious to those skilled in the art and are described in more detail, for example in Pharmaceutical Science Remington, 15th ed. , Mack Publishing Company, Easton, PA (1980). The effective dose of CD37-specific molecules (including humanized CD37 specific binding molecules) is in the range of 0.01 mg to 1000 mg per 1 kg of body weight per administration.

[0045] The pharmaceutical compositions may be administered in the form of an aqueous solution for injection, oily suspensions, colloidal solutions or sterile powders for the subsequent preparation of sterile colloidal solutions or solutions. The suspension can be formulated according to the known art using the abovementioned suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. The carrier can be a solvent or dispersing agent containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid glycol).

Polyethylene, etc.) suitable mixtures thereof, vegetable oils, Ringer's solution and isotonic sodium chloride solution, etc. Furthermore, sterile fixed oils are commonly used as a solvent or suspending medium. For this purpose, any colorless fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of the preparation for administration by injection.

[0046] In all cases, the form must be sterile and fluid to the extent that it is easy to handle with the syringe. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of a colloidal solution and by the use of surfactants. The formulation must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Protection against the action of microorganisms can be obtained by means of various agents with antibacterial and antifungal properties, e.g. paraben, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases it will be desirable to include isotonic agents in the composition, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be achieved by the use in the compositions of agents delaying the absorption of, for example, aluminum monostearate and gelatin.

[0047] In order to increase efficacy, compositions suitable for administration may be formulated with the content of agents that enhance absorption or absorption. Such enhancers include, for example, salicylate, glycocholate / linolenic acid salt, glycocholate, aprotinin, bacitracin, SDS, caprate and the like (see, e.g., Fix (J. Pharm. Sci., 85: 12821285, 1996) and Oliyai and Stella ( Ann. Rev. Pharmacol. Toxicol., 32: 521-544, 1993).

[0048] Furthermore, the hydrophilic and hydrophobic properties contemplated in the disclosure are well balanced, which increases their usefulness in vitro and in vivo, especially in vitro, while other compositions that lack the balance are much less useful. In particular, the compositions contemplated for use in the present disclosure have an adequate degree of solubility in an aqueous medium that permits absorption and makes the composition bioavailable in the body. These compositions are also fat-soluble, allowing the compounds to pass through the cell membrane to the putative site of action. Thus, the antibody compositions contemplated show the greatest efficacy when it is possible to deliver them to the site of action of the target antigen.

[0049] The binding molecule or combination compositions of this molecule can be administered orally, topically, percutaneously, parenterally, by inhalation, vaginally, rectally, by intracranial injection or any combination of the aforementioned methods of drug administration. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, receiver and infusion methods. Intravenous, intradermal, intramuscular, intramammary, intraperitoneal, intrathecal, retrobulbar

Pulmonary injection and / or surgical implantation in a specific location. In general, the compositions are substantially free of pyrogens, as well as other impurities that may be harmful when injected to the subject being treated, preferably especially when injected intravenously.

[0050] In one embodiment, the drug is administered to a tumor site or in a location where changes have occurred in the tissues requiring treatment by direct injection into the treated place or by direct sustained delivery or sustained release mechanism that allows the drug to be delivered inward. For example, biodegradable microspheres, capsules, or other configurations of biodegradable polymers capable of prolonged delivery of the composition (e.g., soluble polypeptide, antibody or small molecules) may be included in the formulations of the present disclosure and implanted in the vicinity of the cancer site. [0051] Therapeutic compositions may be given to many places of the patient's body. Multiple administration may take place simultaneously or may be spread over time. In certain cases, it is preferred to administer the therapeutic composition under continuous flow conditions. Additional therapy can be used at intervals such as hours, days, weeks or months.

[0052] According to the present disclosure, it is also contemplated to administer a binding molecule or a variant of the composition in combination with an additional therapeutic agent. Additional therapeutic agents contemplated in the present disclosure are indicated below.

[0053] An additional therapeutic agent may be a molecule bound to B cells. Other B cell-associated molecules contemplated in the present disclosure include binding molecules that bind to non-CD37 molecules on the B cell surface. B-cell-associated molecules are CD19 (CD19 antigen) B lymphocytes, also called B or Leu-12 surface antigen), CD20, CD21, CD22 (B cell receptor CD22, also called Leu-14, B-cell adhesion molecule or BL-CAM), CD23, CD40 (CD40 surface antigen, also called a superfamily member5 receptors for tumor necrosis factor, receptor CD40L or BP50), CD80 (CD80 T cell activation antigen) also called Activation Antigen B7-1, B7, B7-1 or BB1), CD86 (CD86 T cell activation antigen, also called Activation Antigen B7 -2, B70, FUN-1, or BU63), CD37 (also known as a member of the 9 receptor of the necrosis factor of the tumor), CD152 (also called a protein of 4 cytotoxic T lymphocytes or CTLA-4), L6 (a tumor-associated antigen L6, called also as a member of the 4 transmembrane family members, superfamily 1, membrane marker 1 or M3S1), CD30 (CD30 lymphocyte antigen, also called member of the tumor necrosis factor receptor, CD30L or Ki-1 receptor), CD50 (also called ICAM3) Intercellular Adhesion Molecule-3) or ICAM-R, CD54 (also called ICAM-1)Intercellular Adhesion Molecule-1) or receptor of the main rhinovirus group), Β · Η1 (ligand of the receptor that inhibits the immune response of activated T cells, B cells and cells

Also known as PD-L1, see Dong et al., "B7-H1, and third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion", Nat Med, 5: 1365-1369 (1999), CD134 (also known as a member of the tumor necrosis factor receptor OX40, OX40L receptor, ACT35 antigen or transcriptionally activated glycoprotein 1 TAX receptor), 41BB (4-1BB ligand receptor, 4-1BB antigen T cell antigen ILA ), CD153 (also referred to as a member of the 8th tumor growth factor receptor, CD30 or CD30-L ligand), CD154 (also called a member of the tumor necrosis factor superfamily, a protein associated with TNF activation, TRAP or Tp cell antigen) Toll receptors or similar.

[0054] Examples of chemotherapeutic agents contemplated as additional therapeutic agents include alkylating agents, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil); nitrosoureas (e.g., carmustine (BCNU), lomustine (CCNU) and semustine (methyl-CCNU)); ethyleneimine and methyl-melamine (e.g., triethyleneamine (TEM), triethylene thiosophosphoramide (thiotepa) and hexamethylmelamine (HMM, altretamine)); alkylsulfonates (e.g., buslfan) and triazines (e.g., dacabazine (DTIC)); antimetabolites, such as folic acid analogs (e.g., methotrexate, trimetrexate and pemetrexed (multidirectional folic acid antagonist)); pyrimidine analogs (e.g., 5-fluorouracil (5-FU), fluorodeoxyuridine, gencitabine, cytosine arabinoside, (AraC, cytarabine), 5-azacytidine and 2,2 '

2-deoxycofomycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, 2-chlorodeoxyadenosine (cladribine, 2-CdA); Type I topoisomerase inhibitors such as camptothecin (CPT), topotecan and irinotecan, natural products such as epipodophylotoxin (e.g. etoposide and teniposide) and vinca alkaloids (e.g. vinblastine, vincristine and vinorelbine); anti-cancer antibiotics such as actinomycin D doxorubicin and bleomycin; radiation-sensitizing agents such as 5-bromodeoxyuridine, 5-iodoxyuridine and bromodeoxyuridine; platinum coordination complexes such as cis-platinum and carboplatin and oxaliplatin; substituted urea, such as hydroxyurea and methylhydrazine derivatives such as N-methylhydrazine (MIH) and procarbazine.

[0055] Additional therapeutic agents contemplated in the present disclosure as useful for the treatment of autoimmune diseases are referred to as immunosuppressive agents that suppress or neutralize the immune system of the patient to be treated. Immunosuppressive agents include, for example, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, glucocorticosteroids, disease-modifying anti-rheumatic drugs (LMPCh) for the treatment of arthritis or biological response modifiers. The compositions in the description of DMARD, in addition to the treatment of RA, are also useful in the treatment of many other autoimmune diseases.

[0056] Exemplary NSAIDs were selected from the group consisting of ibuprofen, naproxen, naproxen sodium, Cox-2 inhibitors, such as Vioxx and Celebrex, and sialylated forms. Sample medicines

The analgesics are selected from the group consisting of paracetamol, oxycodone, tramadol as propoxyphene hydrochloride. Exemplary glucocorticoids were selected from the group consisting of cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone or prednisone. Exemplary biological response modifiers include molecules directed against cell surface markers (e.g., CD4, CD5, etc.), cytokine inhibitors such as TNF antagonists (e.g. etaineccept (Enbrel), adalimumab (Humira) and infliximab (Remicade)), chemokine inhibitors and adhesion molecule inhibitors. Biological response modifiers include monoclonal antibodies as well as recombinant forms of molecules. An example of a DMARD medicine is azathioprine, cyclophosphamide, cyclosporine, methotrexate, penicillamine, leflunomide, sulfasalazine, hydroxychloroquine,

[0057] It is also contemplated to administer a binding molecule and an additional therapeutic agent simultaneously in the same formulation. Alternatively, said agents are administered in a separate formulation, but at the same time, wherein "simultaneously" means administration of these agents in the interval of minutes, hours or days.

[0058] In another aspect, the additional therapeutic agent is administered prior to administration of the binding molecule. The term & quot; pre-administration & quot; refers to the administration of a further therapeutic agent in the time range of one minute, one hour or one week before treatment with the binding molecule, bifunctional chemotherapeutics, or a composition containing a combination of these therapeutic agents. It is further contemplated to administer the next therapeutic agent after administering the binder composition. By "subsequent administration" is meant administration at an interval longer than minutes, hours or weeks elapsed following treatment or administration of a binding molecule, a bifunctional chemotherapeutic agent or combination of compositions.

[0059] Further contemplated is the variant wherein administering a binding molecule in conjunction with another therapeutic agent, which is a cytokine, growth factor, or chemotherapeutic, may also include the use of a radiotherapeutic agent or radiation therapy. The radiation therapy used in combination with the antibody composition is administered at doses determined by the attending physician typical of patients treated for cancer. [0060] These compositions may be administered in a single dose or in several doses. Standard dose response studies, first on animal models, and then on clinical trials reveal optimal doses for individual disease states and patient populations.

[0061] After administration of a single therapeutic dose of the binding molecule or combination of compositions, the population of B cells is reduced by at least 20%. In one embodiment, the population of B cells is reduced by at least about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or 100%. The reduction in the number of B cells is defined as the total number of B cells below the lower limit of normal B cells obtained, e.g. 70%, 80%, 90% of the initial value for a given subject or the amount falling within the range of

EP-2132228B1PL. In addition, administration of a binding molecule or a combination of the compositions of the present invention results in the desired clinical effects in the disease or disorder being treated.

Biological parameters for improving the patient's condition suffering from RA after administration of CD37 specific and CD20-specific binding molecules include measurement of cytokine level changes determined at the protein or RNA level. The cytokines of interest include, but are not limited to, TNF-α, IL-1, interferons, Blys and APRIL. Cytokine changes may be caused by a decrease in B cell number or a reduction in the number of activated T cells. In patients suffering from RA, markers of importance for bone turnover (bone resorption or erosion) are measured before and after the administration of CD20 specific binding molecules. Important markers include, but are not limited to, alkaline phosphatase, osteocalcin, collagen breakdown fragments, hydroxyproline, tartrate-resistant acid phosphatase, and RANK ligand (RANKL). Other parameters relevant for RA improvement include measurement of C-reactive protein (CRP), Biernacki's pH (OB), rheumatoid factor, CCP antibodies (cyclic citrullinated peptide) and assessment of systemic levels of B lymphocytes and lymphocytes by flow cytometry. Specific factors can also be measured in the synovium of RA patients by assessing B cell levels in the synovium based on synovial biopsy, RANKL levels and other bone factors and cytokines defined above.

[0064] In a similar aspect, the effect of administering the drug on other diseases can be measured in accordance with standards known in the art. For example, Crohn's disease patients treated in accordance with the present invention are believed to achieve an improvement in the Crohn's disease activity index (CDAI) in the range of about 50 to about 70 units, with reentration taking place at 150 units (Simonis et al., Scand. J Gastroent 1998, 33: 283-8). A score of 150 or 200 is considered to be within the norm and a score of 450 is considered to be a serious disease number. Furthermore, it is desirable that the administration of CD37 and CD20 specific binding molecules results in a reduction in the amount of pANCA antibodies (Perinuclear Anti-Neutrophil Cytoplasmic Antibodies) and antibodies directed against Saccharomyces cerevisiae (ASCA) in people afflicted with inflammatory bowel disease.

[0065] The case of adolescent and adult patients suffering from myositis is further considered. Said patients after treatment in accordance with the present disclosure may show improvement of the basic set of evaluated parameters, such as improvement of 3 from the set of 6 measured parameters by about 20% and no more than 2 parameters from the basic set worse by about 25% (see Rider et al. Arthritis Rheum. 2004, 50: 2281-90).

[0066] Hereinafter, the case of SLE patients is considered in patients treated according to the present disclosure. These patients may achieve an improvement in the SLAM (Systemic Lupus Activity Measure) or SLE Disease Activity Index (SLE) parameter of at least 1 point (Gladman et al., J Rheumatol 1994, 21: 1468-71) ( Tan et al., Arthritis Rheum. 1982, 25: 1271-7). The SLAM> 5 or SLEDAI> 2 evaluation parameter is considered to be a clinically active disease. Response to treatment can be defined as improvement or stabilization in the range of 2 parameters of SLEDAI and SLAM assessment and 2 parameters of quality of life (general assessment according to the patient and according to Krupp Fatigue Severity Scale) (Petri et al. Arthritis Rheum. 2004, 50: 2858-68) Furthermore, the case is considered, when the reduction of the amount of antibodies directed against double-stranded DNA is observed after administration of binding molecules in SLE patients. Alternatively, the improvement can be measured using the BILAG criteria (British Isles Lupus Assessment Group Criteria).

[0067] The case of patients with multiple sclerosis is further contemplated, who after treatment according to the present disclosure may achieve an improvement in the clinical performance parameter in the EDSS (Kurtzke Expanded Disability Status scale) (Kurtzke, F., Neurology 1983, 33: 1444-52) at least by 0.5 or a delay in the severity of clinical symptoms by at least 1.0 on the EDSS scale (Rudick et al., Neurology 1997, 49: 358-63).

[0068] Further consideration is given to the case of patients suffering from IIM who after treatment according to the present disclosure may achieve a reduction of at least one of the five criteria of IIMC (Idiopathic Inflammatory Criteria Myopathy Criteria) (Miller, F., supra) . A case in which administration to IIM patients may result in a reduction of IIM-related factors selected from the group consisting of creatine kinase (CK), lactate dehydrogenase, aldolase, C-reactive protein, aspartate aminotransferase (AST), alanine aminotransferase (ALAT). , anti-nuclear antibodies (ANA), antibodies specific to inflammatory myopathy (MSA) and antibodies specific to extractable nuclear antigens. Alternatively, patients meet 3 of the 6 criteria set out in Rider et al., Arthritis Rheum.,

[0069] In some embodiments, patients suffering from B cell cancer and treatment of the present disclosure may exhibit a generally favorable response to treatment assessed based on clinical criteria well known and commonly used in the art, as described below, such as tumor size reduction, reduction the number of tumors and / or weakness of the disease symptoms

[0070] Exemplary clinical criteria are available in the NCI (National National Cancer Institute), which divides certain classes of cancer into "chronic" lymphomas and "aggressive" lymphomas in a clinical division. Chronic lymphomas include follicular cell lymphomas, divided into a series of cytological grades, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), Iymphoplasmacytoid / Waidenstrom's macroglobulinemia, marginal zone lymphoma and Hairy leukemia cells. Aggressive lymphomas include dispersed mixed and large lymphocytic lymphoma, Burkitt's lymphoma / small dispersed non-cut cell lymphoma, lymphoma, lymphoma, coat cell lymphoma and AIDS lymphomas. In some cases, the International Forecast Index (IPI) is used for aggressive and follicular lymphomas. Factors considered in IPI include age (<60 years versus> 60 years), lactate dehydrogenase (normal level compared to elevated), performance status (0 or 1 compared to 2-4) (see definition below) , stage of disease (I or II compared to III or IV) and presence of extranodal cancer (0 or 1 compared to 2-4). Patients with a risk equivalent to 2 or more have less than 50% chance of surviving for 5 years without relapse. 60 years), lactate dehydrogenase (normal level compared to elevated level), performance status (0 or 1 compared to 2-4) (see definition below), stage of disease (I or II compared to III or IV) and presence of extranodal cancer (0 or 1 compared to 2-4). Patients with a risk equivalent to 2 or more have less than 50% chance of surviving for 5 years without relapse. 60 years), lactate dehydrogenase (normal level compared to elevated level), performance status (0 or 1 compared to 2-4) (see definition below), stage of disease (I or II compared to III or IV) and presence of extranodal cancer (0 or 1 compared to 2-4). Patients with a risk equivalent to 2 or more have less than 50% chance of surviving for 5 years without relapse.

[0071] The performance status in aggressive IPI is defined as follows: Scale Description: 0 patient fully active, is able to perform without limitations all activities as before the onset of the disease, 1 - patient limited in physical activity, but treated outpatient , is able to perform light or sitting work, for example, light housework, office work, 2 - patient treated outpatient, able to perform daily life activities, but unable to work, requires care 50% of the time,

3- patient able to perform daily life activities to a limited extent, immobilized in a bed or chair, requires care over 50% of the time, 4 - the patient completely excluded from daily life activities, completely immobilized in a bed or chair, and 5- patient dead. (see The International Non-Hodgkin's Lymphoma Prognostic Factors Protect. A Predictive Model for Aggressive Non-Hodgkin's Lymphoma N. Engl. J. Med. 329: 987-94, 1993) [0072] Typically, the stage of lymphoma is clinically evaluated on the basis of the following criteria: the presence of low-grade lymphoma, its chronic course and slow growth. Diseases with intermediate and high levels are usually characterized by significantly greater aggressiveness and the presence of large extranodal tumors.

[0073] The Ann Arbor classification system is also used to assess the progression of tumors, particularly non-cultivating lymphomas. In this system, stage I, II, III, and IV NHL in adults can be classified in categories A and B depending on whether the patient has well-defined general symptoms (B) or no symptoms (A). B is assigned to patients with the following symptoms: unexplained loss of more than 10% of body weight over 6 months

Pre-diagnosis, fever with unexplained etiology at a temperature above 38 ° C and confining night sweats. The definitions characterizing individual stages are: Degree I - involvement of one group of lymph nodes or involvement of one organ or place in extranodal area, Stage II - involvement of two or more groups of nodes on the same side of the diaphragm or localization of one occupied adjacent extracranial organ or site its close group of nodes, where the lymph nodes in other regions on the same side of the diaphragm are or are not occupied. Stage III - involvement of lymph node regions on both sides of the diaphragm, which may be accompanied by localized involvement of extranodal organ or site outside the nodes, involvement of the spleen or both. Degree IV - dispersed (multifocal) involvement of one or more sites outside of the nodes, which may be accompanied by involvement of lymph nodes or individual extranodal organs or involvement of the body and distant (not local) lymph nodes. More details in The International NonHodgkin's Lymphoma Prognostic Factors Protect. A predictive model for aggressive non-Hodgkin's lymphoma, New England J. Med. (1993) 329: 987-994.

[0074] In one aspect, the therapeutic effect of the methods of the present disclosure depends on the level of the reaction, e.g. the partial response is defined as reducing the tumor to a size that is halved in size compared to the size prior to treatment. The complete answer is defined as the total eradication of the disease confirmed clinically and radiologically. In one embodiment, the patient to be treated according to the present invention exhibits at least a response to treatment.

[0075] According to the Cheson criteria, NHL evaluations developed in collaboration with the NCI (National Cancer Institute) (Cheson et al. J Clin Oncol. 1999, 17: 1244: Grillo-Lopez et al., Ann Oncol. 2000, 11: 399-408). The total response is obtained when there is complete disappearance of all detectable clinical and radiological evidence for disease and disease-related symptoms, all lymph nodes have returned to their normal size, the spleen has decreased, and the bone marrow is free of lymphoma.

[0076] An unacknowledged complete response is obtained when the patient demonstrates complete disappearance of the disease, the spleen is reduced, but the lymph nodes have decreased by more than 75%, and the bone marrow condition is undefined. An unconfirmed full answer meets and goes beyond for partial responses. The overall response is defined as a reduction of at least 50 percent of the total tumor mass.

[0077] Similar criteria have been developed for various other forms of cancer or diseases with a hyperproliferative basis. These criteria are readily available to the person skilled in the art. See, e.g., Cheson et al., Clin Adv Hematol Oncol. 2006, 4: 4-5, which describes the criteria for assessing CLL; Cheson et al., J Clin Oncol. 2003, 21: 4642-9, which describes the evaluation criteria of AML; Cheson et al., Blood 2000, 96: 3671-4, which describes criteria for myelodysplastic symptoms.

[0078] In another aspect, the therapeutic response in patients suffering from B cell cancer is manifested by a slowing of disease progression compared to untreated patients. measurement

The slowdown of disease progression or any of the above factors can be accomplished using techniques known in the art, including bone scan, CT scan, gallium scan, lymphangiogram, MRI, PET scan, ultrasound, and the like.

[0079] As an additional aspect, the disclosure includes kits that include one or more compounds or compositions useful in the methods of this disclosure packaged in a manner that facilitates their use when using the methods of the disclosure. In a simplest embodiment, such a kit comprises a compound or compositions described herein as being useful in the use of the method of the present disclosure packaged in containers, such as closed bottles or dishes with a label or labeled on the container or label that describes the use of the compound or composition when using the method of the disclosure. Preferably, the compound or composition is packaged in unit dosage form. The kit may also include devices suitable for administering the composition according to a preferred route of administration or for performing a screening test.

EXAMPLES

EXAMPLE 1

MICE PARTICIPATING BOTTOM PARTICLES [0080] From the exemplary elements shown in Tables 2-4, various proteins specifically binding CD36 can be prepared. For example, chimeric, humanized or human antibodies or SMIPs may be made. In particular, preferably the CDR regions of the light chain variable region are shown in SEQ. ID NO. 236-240 and 247-254. Preferably, the CDRs have a variable domain domain comprising the sequence of SEQ ID NO: 1. ID NO. 241245 and 247-254. In addition, preferably variable regions of the light and heavy chains can be found in SEQ. ID NO. 236-240 and SEQ. ID NO. 241-245. Preferred variable heavy and light chain regions can also be found in SEQ ID NO: 1. NR 247-254. Preferred variable domain linkers include SEQ. ID NO. 225-229, while the preferred hinge regions comprise the sequence of SEQ. ID NO. 230-235.

[0081] A particularly preferred embodiment is CAS-024 [G28 VH-1 (M99F, Y102S) -VL (T25A) scFv (SSC-P) H WCH2 WCH3], which is a recombinant 483-amino acid single chain human CD37 binding protein fusion. . The binding domain includes humanized scFv based on CDRs of the variable region of G28-1 antibody, including mutations in the heavy CDR3 and light CDR1 chains. The variable domains are joined by a 25 amino acid sequence (G4S) 5 (25 amino acids) (SEQ ID NO: 229) that is attached to the three amino acid residue of the combination (GDQ) to the amino terminus of the modified upper and core IgG1 hinge (where the first two of the three cysteines found in these hinge regions are substituted with serine). The carboxy terminus of the hinge region is linked to an effector domain containing CH2 and CH3 domains of IgG1.

EP-2132228B1PL

The CAS-024 amino acid sequence is SEQ. ID NO. 253. Figure 1 shows a comparison of the amino acid sequence of the heavy and light chain of the mouse G28.1 and CAS024 variable regions to a consensus sequence.

Table 1.

<td colspan="5">Exemplary SMIP constructs specific for CD37</td>

<td>construct</td><td>Description f</td><td>Connector</td><td>Hinge region *</td><td>Seq. amino acid nr</td>

<td>CAS-001</td><td>Vk3 VHS-51</td><td>16aa (G4S)₂(G4T) G</td><td>SSC-P</td><td>6</td>

<td>CAS-002</td><td>Vk3: VH5 JH4 CDRL1 (T25A); CDRH3 (M99F)</td><td>16aa (G4S)₂(G4T) G</td><td>SSC-P</td><td>48</td>

<td>CAS-003</td><td>Vk3: VH5 JH5a CDRL1 (T25A); CDRH3 (M99F; Y102S)</td><td>16aa (G4S)₂(G4T) G</td><td>SSC-P</td><td>52</td>

<td>CAS-007</td><td>Vk3: VH5-51 (Connector, TG SS)</td><td>16aa (G4S)₃S</td><td>SSC-P</td><td>8</td>

<td>CAS-008</td><td>Vk3: VH5 ^ 51 VH V11S</td><td>16aa (G4S) 2 (G4T) G</td><td>SSC-P</td><td>10</td>

<td>CAS-009</td><td>Vk3: VH5-51 CDRL1 (E27Q)</td><td>16aa (G4S) 2 (G4T) G</td><td>SSC-P</td><td>12</td>

<td>CAS-010</td><td>Vk3: VR5-51 CDRL1 (N28S)</td><td>16aa (G4S 2 (G4T) G</td><td>SSC-P</td><td>14</td>

<td>CAS-011</td><td>Vk3: VH5-51 CDRL1 (72.5A)</td><td>16aa (G4S) 2 (G4T) G</td><td>SSC-P</td><td>16</td>

<td>CAS-012</td><td>MVK: VH5 ^ 5a</td><td>16aa (G4S) 2 (G4A) S</td><td>SSC-P</td><td>18</td>

<td>CAS-013</td><td>Vk3: VH5 YH3 FWI</td><td>16aa (G4S) 2 (G4A) S</td><td>SSC-P</td><td>22</td>

<td>CAS-014</td><td>mVH: Vk3</td><td>22aa (G4S) 4AS</td><td>SSC-P</td><td>24</td>

<td>CAS-015</td><td>Vk3: mVH (2H7 leader)</td><td>16aa (G4S) 2 (G4A) S</td><td>SSC-P</td><td>26</td>

<td>CAS-016</td><td>mVH: Vk3</td><td>22aa (GjS) as</td><td>SCC-P</td><td>28</td>

<td>CAS-017</td><td>Vk3: mVH</td><td>16aa (G4S) 2 (G4A) S</td><td>SSC-P</td><td>thirty</td>

<td>CAS-018</td><td>Vk3: mVH</td><td>16aa (G4S) 2 (G4A) S</td><td>SCC-P</td><td>32</td>

<td>CAS-019</td><td>Vk.3: VH5 VH3 FW1</td><td>16aa (G4S) 2 (G4A) S</td><td>SCC-P</td><td>34</td>

<td>CAS-020</td><td>Vk3: VH5 VH3-13 FW1</td><td>16aa (G4S) 2 (G4A) S</td><td>SSC-P</td><td>38</td>

<td>CAS-021</td><td>Vk3: VH5 YH3-13 FW1</td><td>16aa (G4S) 2 (G4A) S</td><td>SCC-P</td><td>40</td>

<td>CAS-022</td><td>Vk3: VH5 VH3-13 V11SFWl</td><td>16aa</td><td>SSC-P</td><td>42</td>

EP-2132228B1PL

<td colspan="5">Exemplary SMIP constructs specific for CD37</td>

<td>construct</td><td>Description f</td><td>Connector</td><td>Hinge region *</td><td>Seq. amino acid nr</td>

<td></td><td></td><td>(G4S)₂(G4A) S</td><td></td><td></td>

<td>CAS-023</td><td>Vk3: VH5 VH1-13 V11S FW1</td><td>16aa (G4S)₂(G4A) S</td><td>SCC-P</td><td>44</td>

<td>CAS-024</td><td>V H V L</td><td>25aa (G4S)₅</td><td>SSC-P</td><td>253</td>

<td>CAS-060</td><td>Vk3: VH5 VH3 FW1</td><td>16aa (G4S)₂(G4A) S</td><td>SSC-P</td><td>36</td>

<td>CAS-061</td><td>Vk3: VH5 CDRL1 (T25A, E27Q)</td><td>16aa (G4S)₂(G4T) G</td><td>SSC-P</td><td>46</td>

<td>CAS-062</td><td>Vk3: CDR-H3 JH6 CDRL1 (T25A), CDRH3 (Y102V)</td><td>16aa (G4S ₂(G4T) G</td><td>SSC-P</td><td>254</td>

<td>CAS-063</td><td>Vk3: VH5 JH5b CDRL1 (T25A); CDRH3 (M99F, Y102P)</td><td>16aa (G4S ₂(G4T) G</td><td>SSC-P</td><td>266</td>

<td>CAS-064</td><td>Vk3: VH5 JH1 CDRL1 (T25A) CDRH3 (D101E; Y102H)</td><td>16aa (G4S ₂(G4T) G</td><td>SSC-P</td><td>267</td>

<td>CAS-065</td><td>Vk3: CDR-H3 TH3a CDRL1 (T25A) CDRH3 (M99F; Y102V)</td><td>16aa (G4S ₂(G4T) G</td><td>SSC-P</td><td>268</td>

<td>CAS-066</td><td>Vk3: CDR-H3 JH3b CDRL1 (T25A) CDRH3 (M99F, Y102I)</td><td>16aa (G4S ₂(G4T) G</td><td>SSC-P</td><td>269</td>

<td>CAS-067</td><td>Vk3: CDR-H3 JH2 CDRL1 (T25A) CDRH3 (M99F, Y102L)</td><td>16aa (G4S 2 (G4T) G</td><td>SSC-P</td><td>80</td>

<td>CAS-068</td><td>Vk3: VH5 JH2 CDRL1 (T25A) CDRH2 (T59N, N61A, R62Q; K65Q)</td><td>16aa (G4S) 2 (G4A) s</td><td>SSC-P</td><td>82</td>

<td>CAS-069</td><td>Vk3: VH5 JH2 CDRL1 (T25A) CDRH2 (T59N, N61A, R62Q; K65Q)</td><td>16aa (G4S) 2 (G4A) S</td><td>SSC-P</td><td>262</td>

<td>CAS-070</td><td>Vk3: VH5 JH5b CDRL1 (T25A); CDRH3 (M99F, Y102P)</td><td>20aa (G4S) 3 (G3A) S</td><td>CPPCP</td><td>84</td>

<td colspan="5">* Entries are abbreviations for the hinge region with IgG1 having mutations in only the first or first and second cysteines located in the upper region and the core region. The only exception is SEQ. ID NO. 84, which depicts the full-length amino acid sequence used in the hinge region (CPPCP, SEQ ID NO. 4: 230) (basically only the core sequence of IgG1 with proline at the end) t The numbering of the CDR mutation is based on the Kabat numbering scheme.</td>

[0082] Additional hinge regions that can potentially be used in molecules

For specific CD37 binding, such as SMIP molecules or antibodies, see the table below.

Table 2.

<td colspan="3">Exemplary hinge regions for CD37 specific binding proteins.</td>

<td>Description of the hinge region</td><td>Amino acid sequence</td><td>Seq. No.</td>

<td>ccc (p) -hIgG1</td><td>EPKSCDKTHTCPPCP</td><td>90</td>

<td>scc (p) -hIgG1</td><td>EPKSSDKTHTCPPCP</td><td>92</td>

<td>scc (s) -hIgG1</td><td>EPKSSDKTHTCPPCS</td><td>94</td>

<td>csc (p) -hIgG1</td><td>EPKSCDKTHTSPPCP</td><td>102</td>

<td>csc (s) -hIgG1</td><td>EPKSCDKTHTSPPCS</td><td>104</td>

<td>ccs (p) -hIgG1</td><td>EPKSCDKTHTCPPSP</td><td>255</td>

<td>ccs (s) -hIgG1</td><td>EPKSCDKTHTCPPSS</td><td>256</td>

<td>ssc (p) -hIgG1</td><td>EPKSSDKIHISPPCP</td><td>106</td>

<td>ssc (s) -hIgG1</td><td>EPKSSDKIHISPPCS</td><td>108</td>

<td>scs (p) -hIgG1</td><td>EPKSSDKTHTCPPSP</td><td>257</td>

<td>scs (s) -hIgG1</td><td>EPKSSDKTHTCPPSS</td><td>96</td>

<td>css (p) -hIgG1</td><td>EPKSCDKTHTSPPSP</td><td>110</td>

<td>css (s) -hIgG1</td><td>EPKSCDKTHTSPPSS</td><td>112</td>

<td>sss (p) -hIgG1</td><td>EPKSSDKTHTSPPSP</td><td>98</td>

<td>sss (s) -hIgG1</td><td>EPKSSDKTHTSPPSS</td><td>100</td>

<td>hIgA1</td><td>VPSTFPTPSPSTPPTPSPS</td><td>115</td>

<td>hIgA2</td><td>VPPPPP</td><td>116</td>

<td>hIgG3</td><td>ELKrPLGDTIHTCPRCPEPKSCDTPPPCPRCPEPKS CDTPPPCPRCPEPKSCDIPPPCPRCP</td><td>118</td>

<td>hIgG3 (ccc)</td><td>EPKSCDIPPPCPRCP</td><td>258</td>

<td>hIgG3 (scc)</td><td>EPKSSDTPPPCPRCP</td><td>120</td>

<td>hIgG3 (csc)</td><td>EPKSCDTPPPSPRCP</td><td>126</td>

<td>hIgG3 (ccs)</td><td>EPKSCDTPPPCPRSP</td><td>259</td>

<td>hIgG3 (ssc)</td><td>EPKSCDTPPPSPRCP</td><td>260</td>

<td>hIgG3 (scs)</td><td>EPKSCDTPPPCPRSP</td><td>261</td>

<td>hIgG3 (css)</td><td>EPKSCDTPPPSPRSP</td><td>122</td>

<td>hIgG3 (sss)</td><td>EPKSSDTPPPSPRSP</td><td>124</td>

<td>hIgD</td><td>ESPRAQASSVPIAQPQAEGSLAKA, nAFATTRNTC RGGEEKKKEKEKEEQEERETK TP</td><td>127</td>

[0083] Additional framework regions that can potentially be used in CD37 specific binding molecules, such as SMIP molecules or antibodies, can be found in the table below.

EP-2132228B1PL

Table 3A.

<td colspan="3">Human heavy chain backbone regions for proteins specifically binding CD37.</td>

<td>Region V</td><td>Element of the construct - VH regions of human origin</td><td>Seq. No.</td>

<td></td><td>FR1</td><td></td>

<td>VH1</td><td>QVQLVQSGAEVKKPGASVKVSCKASGYTFT</td><td>140</td>

<td>VH1</td><td>QVQLVQSGAEVKKPGSSVKVSCKASGGTFS</td><td>141</td>

<td>VH1</td><td>EVQLVQSGAEVKKPGATVKISCKVSGYTFT</td><td>143</td>

<td>VH5</td><td>EVQLVQSGAEVKKPGESLKISCKGSGYSFI</td><td>144</td>

<td>VH5</td><td>EVQLVQSGAEVKKPGESLRISCKGSGYSF T</td><td>145</td>

<td>VH7</td><td>QVQLVQSGSELKKPGASVKVSCKASGYTFT</td><td>146</td>

<td></td><td>FR2</td><td></td>

<td>VH1</td><td>WVRQAPGQGLEWMG</td><td>147</td>

<td>VH1</td><td>WVQQAPGKGLEWMG</td><td>150</td>

<td>VH5</td><td>WVRQMPGKGLEWMG</td><td>151</td>

<td></td><td>FR3</td><td></td>

<td>VH1</td><td>RVTMTIDTSTSTAYMELRSLRSDDIAVYYCAR</td><td>154</td>

<td>VH1</td><td>RVTITADESTSTAYMELSSLRSEDTAVYYCAR</td><td>155</td>

<td>VH1</td><td>RVTITADKSISTAYMELSSLRSEDTAVYYCAR</td><td>156</td>

<td>VH1</td><td>RVTITADTSTDTAYMELSSLRSEDIAVYYCAT</td><td>157</td>

<td>VH5</td><td>QVTISADKSISTAYLQWSSLKASDTAMYYCAR</td><td>158</td>

<td>VH5</td><td>HVTISADKSISTAYLQWSSLKASDTAMYYCAR</td><td>159</td>

<td>VH7</td><td>RFVFSLDTSVSTAYLQISSLKAEDTAVYYCAR</td><td>160</td>

<td></td><td>FR4</td><td></td>

<td>JH1, JH4, JH5a, JH5b</td><td>wGQGTLVTVSS</td><td>161</td>

<td>JH2</td><td>WGRGTLVTVSS</td><td>162</td>

<td>JH3a, JH3b</td><td>WGQGTMVTVSS</td><td>163</td>

<td>JH6</td><td>WGQGTTVTVSS</td><td>168</td>

<td></td><td>WGKGTTVTVSS</td><td>169</td>

Table 3B.

<td colspan="3">Skeletal regions of the human light chain of proteins specifically binding CD37.</td>

<td>Region V</td><td>Skeletal regions of VK of human origin</td><td>Seq. No.</td>

<td></td><td>FR1</td><td></td>

<td>VK3</td><td>EIVMTQSPATLSVSPGERATLSC</td><td>170</td>

<td>VK3</td><td>ENLTQSPATLSLSPGERATLSC</td><td>171</td>

<td>VK1</td><td>DIQMTQSPSSLSASVGDRVTITC</td><td>172</td>

<td>VK1</td><td>NIQMTQSPSAMSASVGDRVTITC</td><td>175</td>

<td>VK1</td><td>AIQLTQSPSSLSASVGDRVTITC</td><td>177</td>

EP-2132228B1PL

<td colspan="3">Skeletal regions of the human light chain of proteins specifically binding CD37.</td>

<td>Region V</td><td>Skeletal regions of VK of human origin</td><td>Seq. No.</td>

<td>VK1</td><td>DIQLTQSPSFLSASVGDRVTITC</td><td>178</td>

<td>VK1</td><td>AIRMTQSPFSLSASVGDRVTITC</td><td>179</td>

<td>VK1</td><td>AIQMTQSPSSLSASVGDRVITIC</td><td>180</td>

<td>VK1</td><td>DIQMTQSPSTLSASVGDRVTITC</td><td>181</td>

<td></td><td>FR2</td><td></td>

<td>VK3</td><td>WYQQKPGQAPRLLIY</td><td>182</td>

<td>VK1</td><td>WYQQKPGKAPKLLIY</td><td>184</td>

<td>VK1</td><td>WYQQKPGKVPKLLIY</td><td>185</td>

<td>VK1</td><td>WYQQKPGKAPKRLIY</td><td>186</td>

<td>VK1</td><td>WFQQKPGKVPKHLIY</td><td>187</td>

<td>VK1</td><td>WFQQKPGKAPKSLIY</td><td>188</td>

<td>VK1</td><td>WYQQKPAKAPKIFIY</td><td>191</td>

<td></td><td>FR3</td><td></td>

<td>VK3</td><td>GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC</td><td>194</td>

<td>VK3</td><td>GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC</td><td>195</td>

<td>VK1</td><td>GVPSRFSGSGSGTDPTLTISSLQPEDFATYYC</td><td>196</td>

<td>VK1</td><td>GVPSRFSGSGSGTDFTLTISSLQPEDVAIYYC</td><td>197</td>

<td>VK1</td><td>GVPSRFSGSGSGTEFTLTISSLQPEDFATYYC</td><td>198</td>

<td>VK1</td><td>GVPSRFSGSGSGIDYTLTISSLQPEDFATYYC</td><td>203</td>

<td>VK1</td><td>GVPSRFSGSGSGTEFTLTISSLQPDDFATYYC</td><td>205</td>

<td></td><td>FR4</td><td></td>

<td>JK1</td><td>FGQGTKVEIK</td><td>206</td>

<td></td><td>FGQCTKLEIK</td><td>207</td>

<td></td><td>FGPGTKVDIK</td><td>208</td>

<td></td><td>FGGGTKVEIK</td><td>209</td>

<td></td><td>FGQGTRLEIK</td><td>210</td>

[0084] Table 4 shows preferred exemplary components of CDR-37 specific SMIP molecules (including leader sequences used for expression and export that are removed from the mature fusion protein when it is secreted from the cell; linker sequences used to link domains light and heavy chain variables to obtain scFv binding domains, hinge regions used to link scFv binding domains to effector domains and effector domains), as well as specific SM37-specific SMIP molecules, including preferably CAS-024 fusion protein.

EP-2132228B1PL

Table 4.

<td colspan="3">Components and selected SMIP polypeptides specific for CD37</td>

<td>Construct Nr</td><td>SEQ. NO</td><td>Amino acid sequence</td>

<td>Leader sequence</td><td>223</td><td>MDFQVQIFSFLLISASVIIARGV</td>

<td>Leader sequence</td><td>224</td><td>MEAPAQLLFLLLLWLPDTTG</td>

<td>Variable domain linker</td><td>225</td><td>GGGGSGGGGSGGGGSS</td>

<td>Variable domain linker</td><td>226</td><td>GGGGSGGGGSGGGGAS</td>

<td>Variable domain linker</td><td>227</td><td>GGGGSGGSGSGGGGAS</td>

<td>Variable domain linker</td><td>228</td><td>GGGGSGGGGSGGGGTG</td>

<td>Variable domain linker</td><td>229</td><td>GGGGSGGGGSGGGGSGGGGSGGGGS</td>

<td>Hinge</td><td>230</td><td>CPPCP</td>

<td>Hinge (linking amino acids are marked in italics)</td><td>231</td><td>SEPKSSDKTHTSPPCP</td>

<td>Hinge (linking amino acids are marked in italics)</td><td>232</td><td>DLEPKSSDKTHTSPPCP</td>

<td>Hinge (linking amino acids are marked in italics)</td><td>233</td><td>DQEPKSSDKTHTSPPCP</td>

<td>Hinge (link amino acids are marked in italics)</td><td>234</td><td>GDQEPKSSDKTHTSPPCP</td>

<td>Hinge (linking amino acids are marked in italics)</td><td>235</td><td>GSSEPKSSDKTHTSPPCP</td>

<td>Mouse CD37 VL (CDR regions marked)</td><td>236</td><td>DIQMrQSPASLSASVGETVTlTCRTS £ 7VKESr £ / fWYQQKQ GKSPQLLVS £ A £ 7AEGVPSRFSGSGSGTQF SLKISSLQPE DSGSYFCgHHMWWTFGGTTELEIK</td>

<td>Humanized CD37 VL (CDR regions marked)^and</td><td>237</td><td>ETVLIQSPATLSL5PGERATLSCJiriSEAP75IŁ4WYQQKPG QAPRLUYi AK TL / IEGIP ARi SGSGSGTOFl LTISSLEPEDF AVYYCe /// 75i »A^rPIFrFGQGTKVt, lK</td>

<td>Humanized CD37 VL (CDR regions marked)^b</td><td>238</td><td>EWLTQSPATLSLSPGERATLSe / L4SEżVP'KSi'L4WYQQKPG QAPRLLIYE42rrLl £ GIPARF_:SGSGSGTDFTLTISSLEPEDF RVYYCQHHSDNPf ¥ ThGQG IKVEIK</td>

<td>Humanized CD37 VL (CDR regions marked)^c</td><td>239</td><td>ErVLTQSPATLSLSPGERA7LSC «rJ0AKFST £ 4WYQQKPG QAPRLLIY £ 4K2X4 £ GIPARFSGSGSGTDFTLTISSLEPEDF AYYYC ^ HjyjPAP ^ TF GQGTKVE1K</td>

EP-2132228B1PL

<td colspan="3">Components and selected SMIP polypeptides specific for CD37</td>

<td>Construct Nr</td><td>SEQ. NO</td><td>Amino acid sequence</td>

<td>Humanized CD37 VL (CDR regions</td><td>240</td><td>ElVLTQSPAT.LSLSPOERATLSC «7'5^.JF3^.f^/KS^.and^.I / iWYQQKPG QAPRLUYFXm4 £ GIPARFSGSGSGTDFILIlSSLEPEDF</td>

<td>indicated)^d</td><td></td><td>AVYYCfiJ7 // SD / VPW7FGQGTKVEIK</td>

<td>Mouse CD37 VL (CDR regions marked)</td><td>241</td><td>AVQL_;QQSGPESEKPGASVKISCKASGYSFTGKWJVWVKQ NNOKSLEWItSATO ^ nWniWRJtFJHTKATLTyDKSSSTA YMęLICSLISEDSAWYCAItyrGPA / DrWGpGlSYTYSS</td>

<td>Humanized CD37 VL (CDR regions marked)^and</td><td>242</td><td>E VQL .VQSGAJEVKKPGESLKISCKGSGY SF TGKVM? YWVRQ MPGKGLEWGM0PyyGG7JYAHJ &lt;FXGQVTlSADKSlSIA YLQWSSLKASOTAMYYCABAyGPMDPWGQGTLVIVSS</td>

<td>Humanized CD37 VL (CDR regions marked)^and</td><td>243</td><td>EVQLVQSGAEVKKPGESLK] SCKGSGYSFTMWW2VWVRQ MPGKGLEWGJYWPTGGrzyAKICFJrGpyTISADKSISTA YLQWSSLKASDT AMYYCARYKGPAijD EWGQGILVTVSS</td>

<td>Humanized CD37 VH (CDR regions marked)^b</td><td>244</td><td>EVQLVQSGAEVKKPGESUaSCKGSGYSFTGKVMAWVRQ MPGKGLEWMGMBPyFGGmWPAFiTGQVTISADKSISTA YLQWSSiKASDTAi \ rYYCAECyFGPFDyWGQGTLVTVSS</td>

<td>Humanized CD37 VH (CDR regions marked)^c</td><td>245</td><td>EVQŁVQSGAEVKKPGESLKISCKGSGYSFTGKYMWWVRQ MPGKGLEWMGA7BPyyGGm7VRKPAGQVTISADKSISTA YLQWSSLKASDTAMYYCARyKGPPZMWGQGTLVTVSS</td>

<td>IgG1 CH2CH3</td><td>246</td><td>APELLGGP SVF LFPPKPKDIL Ml SRIPEVTCVWDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLIVL HQDWLNGKEYKCKVSNKALPAPIEKIISKAKGQPREPQV Y TLPPSRDELTKNQVSL T CLVKGF YPSD1AVEWESNGQPE NNYK TTPPVL DSDGSFF L YSKLI VDKSRWQQGNVFSCSV MHEAL HNH YT QKSLSL SPGK</td>

<td></td><td></td><td></td>

EP-2132228B1PL

<td colspan="3">Components and selected SMIP polypeptides specific for CD37</td>

<td>Construct Nr</td><td>SEQ. NO</td><td>Amino acid sequence</td>

<td>CAS-006 (chimeric SMIP anti-CD37)</td><td>247</td><td>DJQMTQSPASLSASVGETVTITCffr5 £ AKKSTMWYQQKQ GKSPQLLYSK4KTiAEGVPSRFSGSGSGTQFSLKISSLQPE D SGSYFCgtfflSZW / WTFGGG TELEIK.GGGGSGGGGSGGG GSSAVQLQQSGPESEKPGASVKISCKASGYSF T GiWW7VWV KQNNGKSLEWIG7V £ OPiTGffJTy7V7tJŁFffGKATLTVDKSSS TAYMQLKSLTSEDSAVYYCARSFGPMDrWGQGTSVrVS SDL £ P7CS5Z) A: and? IrePPCPAPELLGGPSVFLFPPKPKDTLMlS RTPEVICWVDYSHEDPEVKFN WYVDGVEYHNAKTKPR EEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRJ3ELTKNQV5LrCLVKG EYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKJLI VDKSRWQQGNVFSCSVMKEALt £ NHY TQKSLSL SPGK</td>

<td>CAS-001</td><td>248</td><td>EIVLIQSPAT LSLSPGERATLSCRT.SfiAmYŁ / ł WYQQKPG QAPRLLIYEJJSY £ ^ EGlPARFSGSGSGIDFTLnSSLEPEDF AVYYCQJittSDNPffflGQGlKVEIK.GGGGSGGGGSGGGG 7GEVQLVQSGAEVKKPGESLK1SCKGSGYSFIGHW7VWV RQMPGKGLEWMGA / PPyYGG7iłWŁK7KGQVTlSADKSI STAYLQWSSLKASDTAMYYCARSFGP; WJ? FWGRGILVTV SSSfi £ PASSDA7W75P? GPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQ YN ST YRWS VLIVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK</td>

<td>CAS-002</td><td>249</td><td>EIVLTQSPATLSLSPGERAILSCR l ££ APYSyL / IOUT (3QKPG QAPRL UYK4JCTLtEGlPĄRFSGSGSGTDF TLTIS SLEPEDF AVYYCQHHSDNPfW7GQGTKVEIiiGGGGSGGGGSCGGG YGEVQLVQSGAEVKKPGESLKISCKGSGYSFTGKVM7VWV RQMPGKGLEWMGMPPFrGGrnW «£ FtfGQVTISADKSI S TAYLQWSSLKASDT AMYYCARSWRflD IWGQGILVT V SSSCEPASSD ^ mrSPPGPAPBLLGGPSYFLFPPKPKDlLMI SRIPEYTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSIYRVVSVLTVLBQDWLNGKEYKCKVSNKALP APIEKIISKAKGQPREPQVYTLPPSRDELTI &lt;NQVSLICLVK GFYPSDŁAVEWESNGQPENNYKTTPPYLDSDGSFFLYSK1 tvdksrwqqgnvfscsvmhealhnhytqkslslspgk</td>

<td></td><td></td><td></td>

EP-2132228B1PL

<td colspan="3">Components and selected SMIP polypeptides specific for CD37</td>

<td>Construct Nr</td><td>SEQ. NO</td><td>Amino acid sequence</td>

<td>CAS-003</td><td>250</td><td>EIVLTQSPATLSLSPGERATLSC2USEWrraYL4WYQQKPG QAPRLLIYr4Xn4 £ GIPARFSGSGSGTDFTLTISSLEPEDF AVYY CQHHSJ&gt; tWWTf GQG TKVE1KGGGGSGGGGSGGGG rGEVQŁVQSGAEVKKPGESLKISCKGSGYSFIGKVM3VWV RQMPGKGLEWMGWjDPFFGGTrFYRKFifGQVIISADKSI SIAYLQWSSLKASDTAMYYCAR £ YGP_JFASWGQGTLVTV SSD ^ £ PASSDXniraPPCPAPELLGGPSVFLFPPKPKDTLMI SRIPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKnPPVLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK</td>

<td>CAS-014 (mouse humanized hybrid molecule)</td><td>251</td><td>A VQLQQSGPESEKPGASVKISCKASGYSF T GTWNWVKQ NNOKSLEWIGAraPyyGG77WRAiffGKAILTVDKSSSTA YMQLKSLTSEDSAVYYCAR5FGPA? "IWGQGTSVTVSSG GGG5GGGG.S'GGGGÓ'GGGG5'JSEr / LTQSPATLSLSPGER.M LSCRTSRJVyEyyŁAWYQQKPGQAPRLLIYR4Jfr £ A £ GIPA RF SGSGSG IDFTLTISSLEPEDF AYYYCQHHSDNPWTPG (^ GIK.VEl} S.SSSEPKSSDKTHTSPPCPAPBLLGG? S&gt; VfLiPP'KP KDTLMISRTPEV7GVWDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSIYRWSVLIVLHQDWLNGKEYKCKVS NKAŁPAPIEKTISKAKGQPREPQVYILPPSRDELIKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKIIPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK</td>

<td>CAS-017 (mouse humanized hybrid molecule)</td><td>252</td><td>ELVLIQSPATLSLSPGERATLSCR73EAWPSri ^ WYQQKPG QAPRLIJYFAKTZA £ GIPARFSGSGSGrDFTLIISSLEPEDF &amp; VYYCQHHS &amp; NPHHPGQGTKVEJKGGGGSGGGGSGGGG X5AVQLQQSGPESEK.PGASVK1SCKASGYSFTG17VWVWV KQNNGKSLEWlGNi »PiTGG7TKVRArJSrGKATLrVDKSSS T AYMQIKSLTSED SAVYYCARJKGPM0FWGQGTSVrVS S ££ PK5SDK27f7SPPCPAPELIGGPSVFLFPPKPKDTLMlSR TPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKIKPRE EQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKT1SKAKGQPREPQVYTLPPSRDELTKNQVSLICLVKGF YPSDIAVEWESNGQPENNYKITPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK</td>

<td></td><td></td><td></td>

EP-2132228B1PL

<td colspan="3">Components and selected SMIP polypeptides specific for CD37</td>

<td>Construct Nr</td><td>SEQ. NO</td><td>Amino acid sequence</td>

<td>CAS-024</td><td>253</td><td>EVQLVQSGAEVK.KPGESLK1SCKGSGYŚFTGKVWVWVRQ MPQK.GLEVMGNIDPYYGGTTyNRiCFKGQ VTIS ADKSISIA YLQWSSLKASDTAMYYCAR5FGPiP5WGQGTLVTVSSG GGG5GGGG5GGGGSGGGG5GGGCGEIVLTQSPATLSLSPG ERATLSC / L &lt;(5 £ jVrYS'EC / iWYQQKPGQAPRLLlY / N / r / £ l £ GEPARFSGSGSGTDFTLTISSLEPEDFAWYCei / KyPATHT FGQGTKVElKGS2EPKSSnKraraPPCPAPELLGGPSVFLF PPKPKD1LMISRIPEY T CVWDVSHEDPEVKFNWYVD GV EYHNAKT KPREEQYNSTYRVVSVLT VLHQDWLNGKEYK CKVSNKALPAPIEK1ISKAKGQPREPQVY TLPPSKDELIKN QVSLICLVK.GFYPSDIAVEWESNGQPENNYKTTPPVLDSD GŚFFLYŚKL1VDKSRWQQGNVF SCS VMHEALHNH Y TQKS LSLSPGK</td>

EXAMPLE 2

EXPRESSION OF CAS-024 AND OTHER PROTEINLY BINDING PROTEINS [0085] CAS-024 and other SMIP specifically binding CD37 molecules have been cloned in an expression system based on mammalian Chinese hamster ovary (CHO) -springing cells. Transfected CHO cells producing SMIP molecules were grown in shake flasks, and in supernatants harvested from cell cultures titers were determined using the Octec Q Protein A sensor.

[0086] Table 5 shows that CAS-024 construct (VHVL form with 25 amino acid variable domain linker) unexpectedly had the highest level of expression, about 10 times higher than with other humanized SIMP anti-CD37 molecules (mainly having the form of VLVH with a 15 amino acid variable linker). Fully humanized VLVH constructs indeed exhibited poor expression (data not shown), as were mouse humanized hybrid molecules with both orientations (see Example 5).

Table 5.

<td colspan="3">SMIP expression</td>

<td>SMIP protein</td><td>Searched clones</td><td>Range of protein titer ^ g / ml)</td>

<td>CAS-001</td><td>492</td><td>65 - 80</td>

<td>CAS-002</td><td>425</td><td>200 - 280</td>

<td>CAS-003</td><td>611</td><td>300 - 360</td>

<td>CAS-024</td><td>203</td><td>500 - 650</td>

EP-2132228B1PL

EXAMPLE 3

PURIFICATION AND CHROMATOGRAPHY OF EXCLUDING CAS-024 AND OTHER PROTEIN BINDING PROTEINS [0087] To obtain a larger amount of protein, CAS-024 encoding nucleic acid and several other SMIP specifically binding CD37 molecules have been cloned into an expression system based on mammalian Chinese hamster ovary cells ( CHO). Transfected CHO cells that produced SMIP molecules were grown in shake flasks.

[0088] All SMIP specifically binding CD37 molecules were purified from supernatants from the CHO cell culture using protein A affinity chromatography. A column filled with 50 ml of protein A Sepharose® (GE Healthcare) was equilibrated with 15 column volumes (CV) dPBS. at a flow of 5.0 ml / min (150 cm / h). The culture supernatant was applied to a Sepharose FF column conjugated with recombinant protein A at 1.7 mL / min controlled by AKTA Explorer 100 Air (GE Healthcare), on which the recombinant SMIP molecules were captured. The column was washed with 5 column volumes (Column Volume, CV), followed by 10 M NaCl, 20 mM sodium phosphate, pH 6.0, followed by 25 mM NaCl, 25 mM NaOAc, pH 5, dPBS. Recombinant CD37 specific binding molecules were eluted from the column with 100 mM glycine, pH 35. The eluted product fractions were recovered (10 ml) and then adjusted to pH 5.0 with 0.5 M 2- (N-morpholino) ethanesulfonic acid (MES). ), pH 6.0 corresponding to 20% elution volume. The eluted product was concentrated to a protein concentration of about 25 mg / ml and filtered through a sterile filter.

[0089] The thickened and sterile protein was then purified by size exclusion chromatography (SEC) to separate the SMIP molecule (dimer) from the higher molecular weight aggregates. The XK 50/100 column (GE Healthcare), filled with 1L of Superdex 200Sepharose FF, was equilibrated with dPBS at a flow rate of 12.6 ml / min (38 cm / h) at 1 column volume (CV). A maximum sample volume of 54 ml (3% CV) was applied to the column. Column separation was continued at a flow rate of 12.6 ml / min, and the eluted protein was subjected to separation by collecting fractions of vol. 40 ml. Each fraction was analyzed for product quality using analytical HPLC. The eluted fractions were then combined to give more than about 95% of the protein of interest (in non-aggregated form).

[0090] Figures 2A-2D show elution profiles for SEC chromatography in which peaks corresponding to fractions containing a protein of interest (POIs), respectively, for CAS-001 (SEQ ID No. 6) are shown. , CAS002 (SEQ ID NO: 48), CAS-003 (SEQ ID NO: 52) and CAS -024 (SEQ ID NO: 253). The peak of CAS-024 is narrowest and more symmetrical than those observed for CAS-001, CAS002 and CAS-003 (wider and asymmetrical peaks). The (chimeric) molecule CAS-006 gives a sharp

A similar peak to that observed for CAS-024. For the CAS-001, CAS-002 and CAS-003 samples, all peaks had a small descending arm which, when integrated, accounted for approximately 35% of the POI area. The "arm" would be difficult to separate from the POI and it probably represents either defectively folded conformers or a heterogeneous population of molecules (e.g., molecules characterized by different levels of glycosylation). This means that CAS-024 is not only better expressed, but that the construct also allows a more homogeneous population of molecules.

EXAMPLE 4

CELL BINDING BY CAS-024 IS BETTER BETTER BINDING OBSERVED FOR OTHER PROTEINIC BINDING PROTEIN PROTEINS [0091] To compare the binding affinity of various small modular anti-CD37 (SMIP) molecules to CD37 present on Ramos cells (B-lymphoblastoid line derived from Burkitt's lymphoma) . The SIMP anti-CD37 chimeric molecule (CAS-006, SEQ ID NO: 247), purified with SEC, was labeled with FMAT Blue® fluorescent dye (Applied Biosystems) and used as a standard in competitive assays using purified, unlabelled chimeric SIMP molecule anti-CD37 (positive control) and purified and unlabeled tested humanized SIMP anti-CD37 molecules. Higher affinity is manifested by a weaker fluorescent signal, and the fluorescence value FL1 was used to obtain the curve obtained in the competition test. Briefly, the chimeric SIMP anti-CD37 molecule was labeled with FMAT Blue® reagent and diluted to a concentration of 2 μg / ml in FACS blocking buffer, whereas for purified protein samples (CAS-001 (SEQ ID NO: 6), CAS-002 ( SEQ ID NO: 48), CAS-003 (SEQ ID NO: 52) and CAS-024 (SEQ ID NO: 253)) serial dilutions in a 1: 2 ratio were prepared, covering a concentration range of 50 μg / ml to 0.02 μg / ml. Ramos cells were separated from the supernatant by centrifugation at 1000 rpm for 5 min. and suspended in 4 x 10 FACS blocking buffer the SIMP anti-CD37 simimeric molecule was labeled with FMAT Blue® reagent and diluted to a concentration of 2 μg / ml in FACS blocking buffer, whereas for purified protein samples (CAS-001 (SEQ ID NO: 6), CAS-002 (SEQ ID NO: ID. 48), CAS-003 (SEQ ID NO: 52) and CAS-024 (SEQ ID NO: 253)) serial dilutions in a 1: 2 ratio were prepared, covering a concentration range of 50 μg / ml to 0.02 μg / ml. Ramos cells were separated from the supernatant by centrifugation at 1000 rpm for 5 min. and suspended in 4 x 10 FACS blocking buffer the SIMP anti-CD37 simimeric molecule was labeled with FMAT Blue® reagent and diluted to a concentration of 2 μg / ml in FACS blocking buffer, whereas for purified protein samples (CAS-001 (SEQ ID NO: 6), CAS-002 (SEQ ID NO: ID. 48), CAS-003 (SEQ ID NO: 52) and CAS-024 (SEQ ID NO: 253)) serial dilutions in a 1: 2 ratio were prepared, covering a concentration range of 50 μg / ml to 0.02 μg / ml. Ramos cells were separated from the supernatant by centrifugation at 1000 rpm for 5 min. and suspended in 4 x 10 FACS blocking buffer Ramos cells were separated from the supernatant by centrifugation at 1000 rpm for 5 min. and suspended in 4 x 10 FACS blocking buffer Ramos cells were separated from the supernatant by centrifugation at 1000 rpm for 5 min. and suspended in 4 x 10 FACS blocking buffer⁶ cells / 10 ml of buffer. To each well on a black 96-well plate was added in sequence: 50 μΐ sample, 50 μΐ of FMP Blue® labeled SIMP anti-CD37 chimeric molecule and 50 μl Ramos cells (4x10⁴/hole). The plates were incubated at room temperature for 30 min, and the reading was performed using Cellular Detection System 8200 (Applied Biosystems) at gateway settings for medium cell size and low signal.

[0092] This FMAT competition assay showed that CAS-024 (a humanized anti-CD37 SMIP molecule scFv VHVL with a 25 amino acid variable linker) has the same affinity for CD37 as the original anti-CD37 chimeric SMIP molecule and, unlike the latter. , has an unexpectedly 4-fold higher affinity for CD37 than the humanized anti-CD37 SMIP reverse-VLVH molecule and the shorter linker of a 16-amino-acid variable domain (see Fig. 3). The best binding, though still much weaker than observed for CAS-006 or CAS-024, was demonstrated for the VLVH construct construct that did not have any mutations in the CDR region (CAS-001).

EP-2132228B1PL

However, CAS-001 was each time the worst expressed construct and in his case a heterogeneous population of purified molecules was obtained. Even with this construct, CAS-024 bound 15 to 2 times better than CAS-001.

[0093] Also this result was surprising because M99 and Y102 in the heavy chain CDR3 of the CAS-024 construct are mutated. Generally, position Y102 is conservative and one would expect the change only in this position would reduce or even abolish the binding (e.g., CAS-062 with the mutation at position Y102 has detectable but significantly reduced binding compared to CAS-001 or CAS-024, whereas each of the molecules from CAS-063 to CAS-067, in which mutations in the M99 or D101 position were additionally added, showed in this test binding activity from barely detectable to lack of binding capacity, data not shown). Thus, the structure of CAS-024 provided molecules that surprisingly bind as well as the chimeric molecule CAS-006.

EXAMPLE 5

EXPRESSION AND BINDING OF CELLS BY CAS-024 COMPARATED TO MOUSE HUMANIZED PROTEIN BINDING PROTEINS [0094] CAS-024 and other SM37 specific binding molecules CD37 were produced using recombinant DNA technology and transfected in HEK293 cells for 7 days. Supernatants from cell cultures were harvested on day 7 and titers were determined using the Octec Q Protein sensor.

[0095] Similar to the results obtained in Example 2, Table 6 herein shows that CAS-024 (in the form of VHVL with a 25 amino acid variable domain linker) undergoes about 5 to about 27 times better expression than other humanised or hybrid mouse humanized anti-CD37 molecules. The mouse humanized hybrid molecules were not well expressed, regardless of their VHVL or VLVH orientation.

Table 6.

<td colspan="2">SMIP expression</td>

<td>SMIP protein</td><td>Protein / fag titer)</td>

<td>CAS-002 (hVLhVH)</td><td>0.47</td>

<td>CAS-003 (hVLhVH)</td><td>2.39</td>

<td>CAS-014 (mVHhVL)</td><td>2.16</td>

<td>CAS-017 (hVLmVH)</td><td>0 70</td>

<td>CAS-006 (mVLmVH)</td><td>9.3</td>

<td>CAS-024 (hVHhVL)</td><td>12 7</td>

[0096] To compare the binding affinity to Ramos cells of different mouseized SIMP anti-CD37 hybrid molecules with CAS-024 affinity, the competitive assay described in Example 4 was used. The SIMP antiCD37 chimeric molecule (CAS-006, SEQ ID NO: 247) purified with SEC was labeled

EP-2132228B1PL FMAT Blue® fluorescent dye (Applied Biosystems) and used as standard in competition tests using purified unlabeled SIMP anti-CD37 molecule (CAS-006, positive control) and tested purified unlabeled humanized SIMP anti-CD37 molecules: CAS-002 (SEQ ID NO: 48), CAS-003 (SEQ ID NO: 52), CAS-014 (SEQ ID NO: 251), CAS-017 (SEQ ID NO: 252), and CAS-024 (SEQ ID NO: SEQ ID NO: 253).

[0097] These competitive tests using FMAT again demonstrated that CAS-024 (a humanized VHVL molecule with a 25 amino acid linker) has the same affinity for CD37 as the original SIMP anti-CD37 chimeric molecule (CAS-006), while when CAS-002 and CAS-003 (humanized VHVL molecules with a 16 amino acid linkage) do not bind well (2 to 3-fold decrease in their case) (see Figure 4A). Mouse humanized (hybrid) molecules, regardless of the orientation of the variable domain (miceVH-humanizedVL with a 22 amino acid linkage or humanizedVL-mysiaVH with a 16 amino acid linkage), are as good or even better (1.5 to 2 times better) than CAS-006 and CAS-024 (see Fig. 4B). These data show that a non-mutant murine humanized hybrid molecule, regardless of its orientation, it binds as well or better than CAS-006, and that a fully humanized VLVH construct devoid of mutations in the CDR region binds better than other humanized molecules, however, it still has a reduced binding compared to CAS-006 or CAS- 024. All of these data indicate that the absence of mutations in the CDR regions of this molecule provides better binding properties. In addition, a specific order (VLVH or VHVL) does not seem to solve the expression problem, even when a variable domain linker is used (see CAS-014). Thus, it was not possible to predict the selection of a CAS-024 molecule and properties similar to the CAS-006 starting molecule and that a fully humanized VLVH construct devoid of a mutation in the CDR region binds better than other humanized molecules, however, it still has a reduced binding compared to CAS-006 or CAS-024. All of these data indicate that the absence of mutations in the CDR regions of this molecule provides better binding properties. In addition, a specific order (VLVH or VHVL) does not seem to solve the expression problem, even when a variable domain linker is used (see CAS-014). Thus, it was not possible to predict the selection of a CAS-024 molecule and properties similar to the CAS-006 starting molecule and that a fully humanized VLVH construct devoid of a mutation in the CDR region binds better than other humanized molecules, however, it still has a reduced binding compared to CAS-006 or CAS-024. All of these data indicate that the absence of mutations in the CDR regions of this molecule provides better binding properties. In addition, a specific order (VLVH or VHVL) does not seem to solve the expression problem, even when a variable domain linker is used (see CAS-014). Thus, it was not possible to predict the selection of a CAS-024 molecule and properties similar to the CAS-006 starting molecule In addition, a specific order (VLVH or VHVL) does not seem to solve the expression problem, even when a variable domain linker is used (see CAS-014). Thus, it was not possible to predict the selection of a CAS-024 molecule and properties similar to the CAS-006 starting molecule In addition, a specific order (VLVH or VHVL) does not seem to solve the expression problem, even when a variable domain linker is used (see CAS-014). Thus, it was not possible to predict the selection of a CAS-024 molecule and properties similar to the CAS-006 starting molecule

EXAMPLE 6

CAS-006 AND OTHER SPECIFIC ANTIBODIES AGAINST CD37 ARE BINDING TO SUCH OR LINKING EPITOPES IN THEIR CD37 [0098] Experiments were carried out to identify epitopes in CD37 bound by CAS-006 and other CD37-specific antibodies described earlier. MB371 unconjugated (# 555457) and conjugated to FITC (# 555456) were obtained from BD Pharmingen (San Jose, California), BL14 conjugated to FITC (# 0457) from Immunotech / Beckman Coulter (Fullerton, CA), NMN46 conjugated with FITC (# RDI-CBL. 136FT) and unconjugated NMN46 (# RDI-CBL 136) from RDI (Flandria, NJ), IPO24 conjugated to FITC (# 186-040) and unconjugated IPO24 (# 186-020) from Ancell Corporation (Bayport, MN ), HHI conjugated to FITC (# 3081) and unconjugated HH1 (# 3080) from Diatec Com (Oslo, Norway), and WR17 conjugated to FITC (YSRTMCA483F) and WR17 unconjugated (YSRTMCA483S) from Accurate Chemical &amp; Scientific (Westbury, NY). The SMIP protein CAS-006 was prepared as described in Example 2.

[0099] CAS-006 was conjugated to FITC using the Molecular Probes Fluororeporter FITC Labeling Kit (F6434) as follows, according to the manufacturer's instructions: the peak of the CAS-006 protein of interest (POI) at 13.5 mg / ml was established using PBS to a concentration of 5 mg / ml. 1 mg (200 μΐ) and 1M NaHCO 3 (pH 8.5, which was adjusted with 6 N NaOH) were added to the tubes in the kit and containing the stirrer, which were added so that the final concentration was 0.1 M. DMSO in a volume of 50 μΐ was added to 370 μg FITC and added to the tubes at a FITC molar ratio: protein of 15, 20, 30 and 40 using the following formula to determine the amount of FITC microlitres, which should be added: [μΐ FITC solution to add = 5 mg / ml protein x 0.

[0100] Reaction mixtures were protected from light and mixed continuously for 75 min. in room temperature. The reaction mixtures were applied to the columns to be purified by centrifugation, which were prepared as described in the instructions for the kit, and centrifuged at 1100 g for 5 min. to replace the buffer with PBS containing azide and to remove unconjugated FITC molecules. The absorbance values ​​at 280 and 494 nm were determined for drops with vol. 2 μl using a Nanodrop camera. The extinction coefficient for CAS-016 was determined for this apparatus experimentally by reading the value for the initial unconjugated SMIP molecule. The concentration of each conjugate was 4.25 mg / ml and the following FITC ratios were determined: protein: 2.7 FITC / CAS-016 in a ratio of 15; 3.7 FITC / CAS-016 in a ratio of 20; 4.

[0101] To facilitate protein stabilization, BSA was added so that its concentration was 3 mg / ml. The binding of each fraction was evaluated for dilutions ranging from 100-24300, for Ramos cells and in the range 3200-25600, for human PBMCs. Binding was observed for all fractions, but the ratio for MR30 was chosen for further use because it gave high MFI values ​​that were maintained throughout the applied titration range, indicating the least amount of interference in binding avidity in this reaction. [0102] The titer of FITC labeled antibody conjugates was determined at concentrations of 10 ng / ml to 10 μg / ml during the initial binding studies to determine the optimal amount to be used in binding blocking studies. The level chosen was below the amount causing saturation and was kept constant in subsequent tests, while levels of the blocking antibody were increased 10-fold. Data are plotted as a plot of percent of maximum binding relative to the concentration of blocking antibody, such that higher levels indicate less effective blocking, and lower levels indicate more effective blocking activity. All of the antibodies tested exhibited blocking activity with maximum binding observed without unlabeled reagents (Figure 5). that higher levels indicate less effective blocking, and lower levels indicate more effective blocking activity. All of the antibodies tested exhibited blocking activity with maximum binding observed without unlabeled reagents (Figure 5). that higher levels indicate less effective blocking, and lower levels indicate more effective blocking activity. All of the antibodies tested exhibited blocking activity with maximum binding observed without unlabeled reagents (Figure 5).

[0103] BJAB cells, B-lymphoblastic line, were subsequently stained using a set of different anti-CD37 monoclonal antibody clones, including MB371, BL14, NMN46, IPO24, HH1, WR17 and using a chimeric SMIP CAS molecule. -006.

[0104] For performing a competitive binding assay, BJAB cells at 2.5 χ 10⁵cells were incubated in 96-well V-shaped well plates in labeling media (PBS with 2% mouse serum) containing the anti-CD37 monoclonal antibody conjugated to FITC at a concentration of 1.25 μg / ml in the presence of unconjugated monoclonal antibody anti-CD37 present at the indicated concentrations (25, 1.25, 0.6 or 0.3 μg / ml) or in the presence of labeling media for 45 minutes on ice in the dark. Blocking antibodies and FITC labeled antibody conjugates were added to the reaction mixtures before addition of the cells. The cells were then washed 2.5 times with PBS and fixed with 1% paraformaldehyde (USB, Cleveland, Ohio). Cells thus treated were analyzed by flow cytometry using a FACSCalibur instrument and CellQuest software (BD Biosciences, San Jose,

[0105] For cross-blocking tests performed using the FACS technique, 2.5 χ 10⁵ BJAB cells were incubated in 96-well V-shaped well plates in labeling media (PBS with 2% mouse serum) in the presence of unconjugated anti-CD37 monoclonal antibody at 5 μg / ml for 45 min labeling medium on ice, in the dark. Anti-CD37 conjugated FITC monoclonal antibodies were added so that their final concentration was 2 μg / ml, resulting in dilution of unlabelled reagents to a concentration of 33 μg / ml. The reaction mixtures were then incubated for 45 minutes at room temperature in the dark, then washed 2.5 times with PBS and finally fixed with 1% paraformaldehyde in PBS (USB, Cleveland, Ohio). Cells were analyzed by flow cytometry using a FACSCalibur instrument and Quest Cell software (BD Biosciences, San Jose, California). [0106] For the cell binding assay, cells were resuspended in PBS (Gibco / Invitrogen, Grand Island, NY) containing 2% FBS (Gibco / Invitrogen), (labeling medium) at about 4 χ 10⁶ cells / ml. The cells were then plated and added to the test samples diluted in labeling media in a 1: 1 ratio relative to the final determined concentration. Reactions were incubated for 45 minutes on ice. The samples were centrifuged and washed 2 times with PBS. The goat-anti-IgG antibody conjugated to FITC (CalTag, Burlingame CA) was added at a final dilution of 1:50 and incubated 45 minutes on ice. Samples were centrifuged, washed with PBS, and then fixed with 200 μl of 1% paraformaldehyde in PBS (USB, Cleveland, Ohio). Cells were analyzed by flow cytometry using a FACSCalibur instrument and Quest Cell software (BD Biosciences, San Jose, CA). [0107] Each antibody showed dose-dependent inhibition of binding, i.e. that all molecules tested bind to an identical or structurally similar epitope. Different binding inhibition potencies were observed for each antibody. IN

The SMIP CAS-006 showed the highest level of blocking activity, while HH1 showed an average level of blocking activity, and WR17, IPO24 blocked better than MB371, while they proved less effective in blocking than the other two unlabelled molecules (Figure 2). 5).

[0108] In addition to analyzing the blocking activity, a similar series of experiments was performed in which different antibodies directed against CD37 were tested for their ability to compete with each other for binding to the CD37 receptor. The results of these experiments, as well as the results obtained in the blocking studies performed for all of the molecules tested, showed that different antibodies directed against CD37 and CAS-006 have the same or closely overlapping epitopes.

EXAMPLE 7

RELATIVE TO THE DOSES RESPONSE TO CAS-024 ON THE PODSKÓRNA MODEL

HUMAN GUEST (DOHH2) HETER SUPERVISION IN SCID MICE [0109] The aim of this experiment was to study the dose-dependent response to treatment of CAS15 024 on a subcutaneous human tumor xenograft model in SCID mice. DOHH2 is a human CD20 + / CD37 + B lymphoblastoid line derived from a patient with follicular lymphoma (Kluin-Nelemans et al. Leukemia 5: 221, 1991). Thus, DOHH2 is derived from a patient with Hodgkin's lymphoma (NHL) that is not Burkitt's lymphoma.

[0110] Five million DOHH2 cells were injected subcutaneously in the flank of CB-17SCID female mice (Harlan, Somerville, New Jersey) at 6.5 weeks of age and with an average weight of 18.0 ± 0.1 g (ranging from 14.6 to 22.6 g). On day 8 after tumor implantation, palpable tumors appeared in most mice. Tumor-bearing mice were divided into four groups with the same average tumor volume (n = 14 in the group, 2 cages of 5 mice and 1 cage of 4 mice for each group). The day the mouse was divided into groups was defined as day 0.

The diameters of the tumors were determined using a pair of calipers, and the tumor volume was calculated according to the formula: V = ¹/ 2 [length x (width)²]. The initial mean tumor volume was 228 mm³, the median for the initial tumor size was 224 mm³and the range ranged from 179 to 284 mm³.

Table 7.

<td colspan="4">Reagents for in vivo use</td>

<td>Reagent</td><td>% POI</td><td>Concentration and endotoxin</td><td>Preparation for injections</td>

<td>PBS</td><td>ON</td><td>1x Endotoxin &lt;0.03 EU / mg</td><td>ON</td>

<td>Human IgG (hulgG)</td><td>No tested</td><td>10 mg / ml Endotoxin = 10 EU / mg</td><td>Diluted to 1.0 mg / ml PBS</td>

<td>CAS-024</td><td>100</td><td>9.6 mg / ml Endotoxin = 0 01 EU / mg</td><td>Diluted to 10 mg / ml with PBS at a dose of 200 μg, then diluted 1: 2 to prepare a 100 μg dose and then serially diluted 1: 3 to prepare other dose solutions.</td>

[0111] Groups of tumor-bearing SCID mice were administered on days 0, 4 and 8 as an ip injection, 0..2 ml of PBS containing 200 μg hulgG (negative control) or 200, 100, 30, 10 or 3 μg. CAS-024. The two lowest dose solutions of CAS-024 were prepared on the day of the injection to avoid the need to add the carrier protein to the most diluted solutions. Drug solutions were determined using a color-based code as described below (see Table 8, below).

Table 8.

<td colspan="6">Experiment Plan</td>

<td>Mark group</td><td>The number of mice, the road injections and treatment days</td><td>Dose for injection (μ-g)</td><td>mg / kg for injection^and</td><td>Dose cumulative (PG)</td><td>Dose cumulative (~ Mg / kg)^and</td>

<td>huIgG</td><td></td><td>200</td><td>11.1</td><td>600</td><td>33</td>

<td>CAS-024</td><td></td><td></td><td></td><td></td><td></td>

<td>200</td><td>14 in the group</td><td>200</td><td>11.1</td><td>600</td><td>33</td>

<td>CAS-024</td><td></td><td></td><td></td><td></td><td></td>

<td>100</td><td>Injection ip</td><td>100</td><td>5.6</td><td>300</td><td>16.7</td>

<td>CAS-024</td><td></td><td></td><td></td><td></td><td></td>

<td>thirty</td><td></td><td>thirty</td><td>17</td><td>90</td><td>5.0</td>

<td>CAS-024</td><td>Days 0, 4, 8</td><td></td><td></td><td></td><td></td>

<td>10</td><td></td><td>10</td><td>0.6</td><td>thirty</td><td>1.7</td>

<td>CAS-024</td><td></td><td></td><td></td><td></td><td></td>

<td>3</td><td></td><td>3</td><td>0.2</td><td>9</td><td>0.5</td>

<td colspan="6">^andIt should be remembered that hulgG and CAS-024 were administered in the amount specified in units of μg / mouse, not mg / kg. The approximate unit mg / kg was determined for convenience and based on the average weight of mice (18.0 ± 01 g) on ​​day 0. The weight range in this experiment was from 14.6 to 22.6 g.</td>

[0112] Dose solutions were prepared in similar volumes, and the contents of the tubes were labeled with removable labels. An investigator who did not take care of mice and did not participate in their study, placed a colored code on each tube and wrote down the code and the designation of the contents of the tubes in the laboratory notebook. Mice were monitored daily by visual inspection. An observer who did not take care of mice and did not participate in their study determined weekly their weight, and at least 3 times a week the diameters of tumors (M = Monday, W = Wednesday, F = Friday). Tumor volumes were calculated as described above. Mice were euthanized when the tumor volume reached more than 1500 mm³ (or 1200 mm³on Fridays). Death was not the end point in the protocol on tumors, unless otherwise stated. The term "survival" in the case of mice was dependent on the time in which it was euthanized due to tumor volume that reached certain limits. (Protocol

The euthanasia of mice was implemented when (1) their tumor size exceeded the parameters described above, (2) tumor ulceration, (3) tumor inhibited mouse mobility, and (4) when weight loss exceeded 20% body weight).

[0113] One mouse in the group administered with 100 μg of CAS-024 was euthanized on day 35 due to a weight loss of more than 20%. At this time, the tumor volume in this mouse was 266 mm³ and this mouse was treated in the survival analysis as censored observation (not subjected to euthanasia on day 35 due to tumor growth). When calculating the incidence rate of tumor-free mice at the end of the experiment, this mouse was classified as a euthanized mouse during the study due to the growth of its tumor (its tumor grew again at the time of death). None of the mice died and was not euthanized due to weight loss, tumor ulceration or motor impairment. No visible signs of toxicity or weight loss were observed in the study groups (data not shown). [0114] All statistical analyzes were performed using GraphPad Prism software. Significant differences for mean tumor volumes and mean relative tumor volumes were determined using a one-way ANOVA test for non-parametric data (Kruskal-Wallis test) using a post-hoc test of Dunn's multiple comparison. All groups were compared to determine the differences between each group treated with CAS-024 and the huIgG treated group. The huIgG group was excluded only for comparisons between CAS-024 treated groups. In addition, the high and medium dose groups (200, 100 and 30 μg) were analyzed as one set of data, and the medium and low dose groups (30, 10 and 3 μg) were analyzed as a second set of data. Significant differences in mouse survival over time were determined using Kaplan-Meier survival analysis with the logrank test for comparing survival curves. Significant differences in the incidence of cases of tumor-free mice were determined using Fisher's exact test. P values ​​&lt;0.05 were considered significant.

[0115] CAS-024 exhibited a dose-dependent inhibitory effect on the growth of DOHH2 tumors. With the exception of the low dose group (3 mg), as early as day 5, the mean tumor volume for each of the CAS-024 treated groups was significantly lower than for the human IgG treated group and remained lower until day 12. HuIgG-treated mice were euthanized , starting from day 12, the comparison of tumor volumes in the CAS-024 treated groups with the huIgG group was not carried out for later time points. In terms of dose response, there was no significant difference in mean tumor volumes between the two highest dose groups at any time point of the study. In contrast to the results above, the mean tumor volumes for these two groups were significantly different from those observed for each of the three lower dose groups from day 12 to day 16 (day 16 was the last estimated time point for the low dose group). Similarly, mean tumor volumes in mice of the 30 μg and 10 μg dose groups differed between each other and the low dose group over the same period of time.

[0116] Tumors in huIgG-treated mice grew rapidly, and all mice in this group were euthanized on day 19. As shown in Tables 9 and 10 below, survival of mice treated with any of the CAS-024 dose regimens increased over huIgG-treated groups (p &lt;0.0001 in all cases). In terms of dose response, there was no significant difference between survival curves for mice receiving the highest dose regimen (200 and 100 μg) (p = 0 7091). Except for the comparison for this group, there was no significant difference between the survival curve of the group receiving any of the doses and the survival curve of any of the treatment groups with the lower dose regimen (p values ​​ranged from 0..0132 to &lt;0.0001).

Table 9.

<td colspan="6">Median survival time and incidence of tumor free mice</td>

<td>Group treated^and</td><td>Dose cumulative</td><td>Median survival time (Days)^b</td><td>Death (no being result large volume tumor)</td><td>The incidence of the case of tumor-free mice^c</td><td>The value of p for Fisher's exact test (comparison of the incidence of a tumor-free case)^d</td>

<td>huIgG 200</td><td>600 μο</td><td>14</td><td>0/14</td><td>0/14 (0%).</td><td>ON</td>

<td>CAS024</td><td>600 μο</td><td>undefined^ef</td><td>0/14</td><td>11/14 (79%)⁸</td><td>&lt;0.0001</td>

<td>CAS024 100</td><td>300 μο</td><td>undefined^ef</td><td>1/14^b</td><td>11/14 (79%)</td><td>&lt;0 0001</td>

<td>CAS024 30</td><td>90 μο</td><td>35</td><td>0/14</td><td>5/14 (36%)</td><td>0 0407</td>

<td>CAS024 10</td><td>30 μο</td><td>28</td><td>0/14</td><td>0/14 (0%)</td><td>ON</td>

<td>CAS024 3</td><td>9 μο</td><td>19</td><td>0/14</td><td>0/14 (0%)</td><td>ON</td>

<td colspan="6">^andMice were treated by injecting ip labeled protein on days 0, 4 and 8. The numbers indicate the amount of protein (pg) injected for the day.^bThe "survival" of mice was determined on the day when it was euthanized due to tumor growth. One mouse in the group receiving CAS-024 at 100 μο was euthanized on day 35 due to a weight loss greater than 20%. At that time, a tumor with a volume of 266 mm developed in this mouse³. This mouse was treated as an observation truncated in the survival analysis (on day 35, the tumor volume did not reach the defined limit value). None of the other mice were euthanized for reasons other than tumor volume reaching a certain limit. The "tumor-free" mouse did not have any tangible SC tumors. The lack of cancer cells in histological examination was not confirmed. The tests were completed on day 61.^dEach group was compared to the HuIgG-treated control group.^eThe median survival time is not determined when more than 50% of mice are alive at the end of the observation period. ^fThe values ​​written in bold mean that the survival curves for the indicated group differ significantly from those for the HuIgG-treated controls (in each case p &lt;0.0001, log-rank test). ^gThe values ​​written in bold are significantly different from the values ​​for the control group treated with HuIgG ^bOne mouse was euthanized on day 35 due to weight loss greater than 20%. At this time, the tumor developed a 266 mm tumor in this mouse³. This mouse was treated as an observation cut off in the Kaplan-Meier analysis.</td>

EP-2132228B1PL

Table 10.

<td colspan="3">P values ​​for comparison of survival curves and tumor-free cases for groups</td>

<td></td><td colspan="2">treated with CAS-024.</td>

<td rowspan="2">Comparison groups</td><td colspan="2">P values ​​for the indicated comparison</td>

<td>Log-rank test (comparison of survival curves)</td><td>Fisher's exact test (comparison of the incidence of a tumor-free case)</td>

<td>200 vs 100</td><td>.7091</td><td>1.0000</td>

<td>200 vs 30</td><td>.0132^h</td><td>.0542</td>

<td>200 vs 10</td><td>&lt;0.0001</td><td>&lt;0.0001</td>

<td>200 vs 3</td><td>&lt;0.0001</td><td>&lt;0.0001</td>

<td>100 vs 30</td><td>.0035</td><td>.0542</td>

<td>100 vs 10</td><td>&lt;0.0001</td><td>&lt;0.0001</td>

<td>100 vs 3</td><td>&lt;0.0001</td><td>&lt;0.0001</td>

<td>30 vs 10</td><td>0.0002</td><td>.0407</td>

<td>30 vs 3</td><td>&lt;0.0001</td><td>.0407</td>

<td>10 vs 3</td><td>&lt;0.0001</td><td>ON</td>

<td colspan="3">^andSee the legend in Table 7 for information on groups. ^bValues ​​of p &lt;0.05 are written in bold to distinguish them.</td>

[0117] All mice in the HulgG group and in the groups treated with the two lowest doses (10 and 3 μg) of CAS-024 were euthanized due to the increase in their tumors. In contrast to these results, for the majority of tumors in the group of mice treated with a dose of 200 μg or 100 μg of CAS-024, the regression level was observed to a degree which was characterized by the fact that the tumor was not perceptible. At the end of the 11/14 study (79%) mice in each of the two highest dose groups and 5/14 (36%) of mice in the 30 μg group remained in a "tumor free" state (compared to the HulgG group, p values ​​were p &lt;0.0001 and 0.0407, respectively).

[0118] Thus, CAS-024 exhibited a dose-dependent inhibitory effect on the growth of an implanted subcutaneous human tumor xenograft (DOHH2) in SCID mice. Dosage schedules involving the two highest doses (100 or 200 μg ip injection, a cumulative dose of 300 or 600 μg, corresponding to about 16.7 or 33 mg / kg, respectively) showed similar inhibitory effects and were most effective in therapy tested for inhibition of tumor growth, prolonging the survival time and causing complete tumor regression.

EXAMPLE 8

CAS-024 AND RITUXAN® EFFICACY AS SINGLE FACTORS IN

RECEIVED HUMAN HEALTHCARE (DOHH2) HAPPY HARD-POST-MODE IN SCID MICE

[0119] The aim of this experiment was to investigate the efficacy of CAS-024 and Rituxan® as single factors on the received subcutaneous human tumor xenograft (DOHH2) model in SCID mice. DOHH2 is a human CD20 + / CD37 + B lymphoblastoid line derived from a patient with follicular lymphoma.

[120] Five million DOHH2 cells were given subcutaneously to the flank of GB-17SCID female mice (Harlan, Somerville, NJ) at 6.5 weeks of age. On day 8 after tumor inoculation, palpable tumors were present in the majority of mice. Tumor-bearing mice were divided into four groups with the same average tumor volume (n = 15 in the group, 3 cages with 5 mice for each group). The grouping day was defined as the day 0 of the study. The tumor diameters were marked with a pair of calipers calipers and the tumor volume was calculated according to the formula:¹/ 2 [length x (width)²] 3. The initial mean tumor volume was 228 mm³, the median for the initial tumor size was 227 mm³and the range was from 181 to 272 mm³. Mice (15 for each treatment group) were treated on days 0, 4 and 8 by ip injection. 0.2 ml of PBS containing 200 μg of IgG, CAS-024 or Rituxan® (total dose after three treatments) was 600 μg). For groups treated with ip HulgG, CAS-024 and Rituxan®, solutions were prepared in similar volumes, and the contents of the tubes were labeled on removable labels. An investigator who did not take care of mice and did not participate in their study placed a colored code on each test tube and recorded the code and the designation of the contents of test tubes in a laboratory notebook.

[0121] Mice were monitored daily by visual inspection. An observer who did not take care of mice and did not participate in their study, every week determined the weight and at least 3 times a week the tumor diameters (M = Monday, W = Wednesday, F = Friday). Tumor volumes were calculated as described above. Tumor volumes on the last day in which all mice in each group lived were also expressed as tumor volumes against day 0, using the formula:

(volume on the day of testing - volume on day 0)

Relative tumor volume on study day = ------------------------------------------- -------------------------- volume on day 0 [0122] Mice were euthanized if the tumor volume reached a value of more than 1500 mm³(or 1200 mm³ on Fridays). Death was not the end point in our tumor development protocols, and unless otherwise stated, the "survival" of mice determined the time at which it was euthanized due to the tumor volume that reached the set limits (according to our protocol, the condition to subject the mice to euthanasia was exceeding tumor parameters described above, tumor ulceration, tumor-induced mice mobilization and weight loss exceeding 20%.

[0123] All statistical analyzes were performed using GraphPad Prism software. Significant differences for mean tumor volumes and mean relative tumor volumes were

EP-2132228B1PL determined using a one-way ANOVA test for nonparametric data (Kruskal-Wallis test) using the post-hoc test of Dunn's multiple comparison. Significant differences in the incidence of tumor-free mice were determined using Fisher's exact test (p values ​​&lt;0.05 were considered significant).

[0124] Mice were euthanized when the tumor volume reached the limits described above. One mouse in the CAS-024 group was euthanized on day 45 due to a weight loss greater than 20%. At this time, this mouse did not have a visible SC tumor and was treated as an observation truncated in the survival analysis (not euthanized on day 45 due to tumor growth) and was not included at the end of the experiment in the absence of tumor-free cases. None of the mice died and was not euthanized due to weight loss, tumor ulceration or motor impairment. No obvious signs of toxicity or weight loss were observed in any of the treatment groups (data not shown).

[0125] Mice treated with CAS-024 and Rituxan® showed a rapid response to treatment. Early, because on Day 4, the average tumor volumes in the CAS-024- and Rituxan® groups were significantly lower than in the human IgG group (after a single injection of the drug) and remained lower until day 11. In the period up to 11. on the day there were no significant differences in mean tumor volumes or mean relative tumor volumes between the CAS-024 and Rituxan® groups. Mice receiving HulgG were euthanized from day 11, no comparison of tumor volumes at further time points.

[0126] Tumors in hulgG-treated mice increased rapidly and all mice in this group were euthanized on day 15. In contrast, for most tumors from the CAS-024 and Rituxan® treated groups, regression was observed to a degree that was characterized by in that the tumor was not sensed. It is worth noting that a sustained response to treatment was observed only in the group treated with CAS-024. At the end of the study, all mice that were treated with Rituxan® were euthanized due to an increase in their tumors, whereas M0114 (71%) of the mice in the CAS-024 group remained tumor free. See table 9. Therefore, at the end of the study, survival curves and the incidence of tumor-free mice in the CAS-024 treated group were significantly different from the survival curves for the hulgG treated group and the Rituxan® receiving group. Figure 6 shows that CAS-024 was statistically superior to Rituxan® during the in vivo treatment of follicular lymphoma on this animal model.

EP-2132228B1PL

Table 11.

<td colspan="7">Median survival time and incidence of tumor free mice</td>

<td>Group subjected treatment</td><td>Days of treatment and cumulative dose</td><td>Median survival time (Days)^and</td><td>The p value determined in the log-rank test^b</td><td>Death (for reasons other than euthanasia due to the size of the tumor)</td><td>Mice free from tumor in Day 81.^c</td><td>Fisher's exact test (comparison of the incidence of a tumor-free case)^b</td>

<td>HuIgG</td><td>Days 0, 4, 8 600 μg</td><td>13</td><td>-</td><td>0/15</td><td>0/15 (0%)</td><td>ON</td>

<td>CAS-024 ip</td><td>Days 0, 4, 8 600 μg</td><td>undefined^{d, e}</td><td>&lt;0 0001</td><td>1/15^f</td><td>10/14 (71%)^r</td><td>&lt;0.0001</td>

<td>Rituxan ip</td><td>Days 0, 4, 8 600 μg</td><td>43</td><td>&lt;0.0001</td><td>0/15</td><td>0/15 (0%)</td><td>ON</td>

<td colspan="7">^and"Survival" was determined on the day the mouse was euthanized due to tumor growth. In contrast to the one mouse in the CAS-024 group (see (f)), none of the mice were euthanized for reasons other than tumor volume reaching a certain limit.^bEach group was compared to a control group receiving HuIgG^cThe "tumor-free mouse" had no detectable SC tumors; no tumor cells were confirmed in histological examination.^d The median survival time is undefined when more than 50% of mice live at the end of the observation period. ^eThe values ​​highlighted in bold typeface show significant differences in comparison to the control group receiving the HuIgG.^fOne mouse was euthanized on day 45 due to a weight loss greater than 20%. At this time, no SC tumor was observed in this mouse and was excluded from the group when compared to tumor free mice on day 81.</td>

[0127] In conclusion, CAS-024 and Rituxan® were effective as single agents on a human tumor xenograft (DOHH2) model in SCID mice. While both drugs caused initial tumor regression in the majority of mice, long-term tumor regression was observed only in the group of mice treated with CAS-024, because tumor disease recurrence was observed after the optimal anti-CD20 treatment. Accordingly, CAS-024, a humanized anti-CD37 SMIP molecule, exhibits significant efficacy in preclinical tumor xenograft models, including models that have shown that treatment with Rituxan® has failed over time. Therefore, these results suggest that the treatment of patients with B-cell lymphoma and leukemia with CAS-024 is beneficial and is a viable alternative for patients,

EXAMPLE 9

CAS-024 ASSESSMENT IN CHIROTHERAPEUTIC COMBINATIONS IN IN VITRO CONDITIONS [0128] CAS-006 has previously been shown to have a synergistic effect in combination with fludarabine chemotherapeutic in killing cells of chronic lymphocytic leukemia (CL.L.) in vitro (see e.g. .: U.S. patent application, publication No. 2007/0059306). Because

CLL cells are not actively distributed in in vitro cell culture, these data indicate that cell proliferation is not required for the apoptotic effect of CAS-006 or CAS-024 and for its synergistic action with chemotherapeutics. The aim of this study was therefore to determine whether CAS-024 and various chemotherapeutics demonstrate effective effects on the cell line lymphoma of the coat cell zone (MCL) - Rec-1, which is actively growing and dividing in cell culture in vitro, and whether the CAS-0 combination 024 with a chemotherapeutic (drug) removes the sensitivity or increases the response of lymphoma cells from the cells of the coat zone to various chemotherapeutics. The chemotherapeutic agents tested were doxorubicin, vincristine and fludarabine.

[0129] Rec-1 cells, a human CD37 + B cell line derived from a patient with mantle area cell lymphoma, were tested for growth inhibition in response to cross-linked CAS-024 in the presence or absence of doxorubicin, vincristine or fludarabine (see Fig. 7 ). CAS-024 was pre-incubated with anti-IgG F (ab) '2 to crosslink the protein. The cells were grown on the medium alone or on a medium containing various concentrations of cross-linked CAS-024 protein, in the presence or absence of doxorubicin, vincristine or fludarabine, used at various concentrations. Cell cultures were incubated for 96 hours and inhibition of growth was assessed using an ATP-based cell viability detection system (e.g., the amount of viable cells was calculated based on the amount of ATP released.

[0130] The Chou and Talalaya method - Median effect / Combination Index (Cl) was used for data analysis (Adv Enzyme Regulation 22: 27, 1984). The numerical value assigned to each drug combination at fixed dose levels allowed a quantitative comparison of the drug / drug interaction between different drug combinations. The results are expressed as the ratio of the combination index (Cl) relative to the level of the effect, where the effect level is the percentage of inhibition of cell growth. The average value of Cl ± SEM for each effect level was the mean value determined for three experiments. Cl &lt;10 was considered a synergy effect, Cl = 1.0 as additive effect and Cl&gt; 1.0 - as a result of antagonism. The values ​​shown represent the mean ± SEM for each effect level and represent the average of the values ​​obtained in three independent tests.

[0131] The combination of CAS-024 with vincristine or fludarabine showed a synergistic effect (Cl &lt;1.0), and the combination of CAS-024 and doxorubicin - additive effect (Cl does not significantly differ from 1.0). For all effect levels, none of the CAS-024 combination with the chemotherapeutic agent was antagonistic (Cl&gt; 1.0). Therefore, the combination of CAS-024 with each of the three chemotherapeutic agents tested does not abolish the sensitivity of target cells to drug-induced growth inhibition and instead demonstrates synergistic or additive effects that inhibit the growth of target cells. A preferred embodiment would be a combination of CAS-024 (SEQ ID NO: 253) with vincristine or fludarabine. These data indicate that the efficacy of established chemotherapeutic agents increased in combination with CAS-024.

EP-2132228B1PL

EXAMPLE 10

RESULTS OF THE PRINCIPLE FOR CLINICAL TRIALS 1/2 [0132] As shown herein, preclinical trials have shown that anti-CD37 SMIP molecules, when compared to other therapeutic antibodies used in the treatment of CLL, mediate significantly greater direct and NK cell-dependent ( natural killer) killing cells of chronic lymphocytic leukemia (CLL). Therefore, the ½ phase of open clinical trials involving dose escalation during the study, which included patients with recurrent chronic lymphocytic leukemia (CLL), was initiated.

[0133] Patients with relapsed / refractory CLL lymphoma or small-cell lymphoma (SLL) who were in an appropriate state of organ function, platelet count greater than 30,000 / mm were eligible.³. Six doses and two different patterns (cohorts 1-10) have been studied or are planned to be studied. Planned doses, given iv once a week in the form of 4 doses (cohorts 1-6 and

9), are in the range of 0-3 mg / kg to 10 mg / kg. In the second diagram (cohorts 7, 8 and 10), doses of 3.0, 6.0 or 10.0 mg / kg will be tested on days 1, 3 and 5 in the first week, followed by three doses per week. Increasing and decreasing the dose is based on the toxicity scale according to the Universal Toxicity (CTC AE) criteria. Patients may receive 2 additional cycles, provided that a positive biological effect occurs after the first cycle.

[0134] Results: To date, 22 patients have been qualified (cohorts 1-7 and 9) and they have completed treatment (all have previously been treated with fludarabine and rituximab). Six patients received a second cycle and two patients entered the third cycle. Treated patients underwent a number of previous treatment regimens (eg: cohort 4 patients were subjected to 6 to 10 treatment regimens (median is 6), and 5 cohorts from 5 to 13 treatment regimens (median 9.5). Eight out of ten patients were characterized by genetic traits determining the high risk of disease [del (17p13.1), n ​​= 5 and del (11q22.3), n = 3] There was no development of toxicity that would result in dose limitation or serious adverse effects. stage 1-2), depending on the intravenous infusion, was observed in three patients. Starting at a dose of 0.3 mg / kg, for all eight patients, including those with del (17p13.1), biological activity has been demonstrated. Two patients showed partial removal of skin leukemia and an average decrease in peripheral lymphocytes in mm³ was 64% (see Figure 5). One patient showed a 99% decrease in peripheral lymphocytes in mm³, which did not involve any serious adverse side effects and an ongoing response to treatment after three months of treatment (see Figure 6). In one patient, an increase in hemoglobin concentration by 40% and a decrease in lymph node size by 36% were observed, as determined in the CT study. After 3 months of treatment, the patient continued to respond to the treatment (see Figure 7). Two patients observed a significant increase in the number of platelets in mm³.

[0135] Conclusion: Up to now, this anti-CD37 SMIP molecule is a well-tolerated drug exhibiting minimal intravenous toxic effect due to intravenous infusion and no toxic effect that limits the dose. It also does not seem to have complemented its function, since patients with a significant decrease in lymphocytes in mm³ they did not show symptoms of the οuza decay syndrome. Already at low doses anti-CD37 SMIPs, which are not saturating doses, there was a promising reduction in the number of neoplastic lymphocytes in mm³ blood reduction, lymph node / spleen size reduction, cleansing of leukemia cells and / or partial bone marrow depletion and / or improvement of normal hematopoietic function in patients with high, dependent on οenom, risk of CLL.

EXAMPLE 11

CAS-024 EFFICACY IN BENDAMUSTINE COMBINATION IN IN VITRO CONDITIONS The aim of the study was to determine the effects of CAS-024, bendamustine and the combination of CAS-024 and bendamustine on Rec-1 cells (mantle cell lymphoma cell line) and cells SU-DHL-6 (lymphoma cell line spilled from large cells). [0137] The following human cell lines expressing CD37 were used: Rec-1 and SU-DHL6 (both from DSMZ, Braunschwei, Germany). Bendamustine (TREANDA®) was purchased at the University of Washington, The University of Washington and dissolved in PBS and stored at -20 ° C until "use".

[0138] Rec-1 and SU-DHL-6 cells were plated at 1 x 10⁴ cells / well in 100 μl medium on 96-well plates with black sides and bottom. Cells were treated with various concentrations of CAS-024, pre-incubated with anti-GF (ab)₂and then the plates were incubated for 96 hours at 37 ° C, 5% CO2 in the presence of serial dilutions of bendamustine. The final volume in each well was 150 μl. After incubation, the plates were cooled to room temperature and labeled with ATPlite labeling reagent (Perkin Elmer, Boston, MA) at 100 μl / well. The test uses cellular measurement of ATP as a marker of viable cells. Samples were analyzed using a luminescence measurement carried out with a Topcount NXT plate reader (Perkin Elmer, Waltham, MA). The data was reduced using a 4-parameter fit curve using the Prism software (version 4.0, Graphpad Software, San Diego, California), and the IC50 is defined as the concentration causing 50% inhibition compared to non-treated cell cultures.

[0139] To determine the synerographic effect, a Median Effect / Combination Index (Cl) method was used for data analysis (Chou and Talalay). The numerical value assigned to each combination of drugs at specific doses enables a quantitative comparison of drug / drug interactions between different combinations of drugs. Based on Cl values, interactions were assigned to three categories: synaptic, additivity and antagonism (Cl &lt;1.0, = 1 or&gt; 1.0, respectively). After labeling and data reduction, the values ​​of the Cl values ​​were determined using the Calcusyn software package (Biosoft, Cambridide, UK). Results

The results obtained in two separate experiments show that the combination of CAS-024 and bendamustine produced a synergistic inhibitory effect on the growth of target cells (see Fig. 11). Similar results were obtained by showing that the combination of CAS-024 and bendamustine also showed a synergistic inhibitory effect on the growth of SU DHL-6 cells.

[0140] The effects of the combination of GAS-024 with other alkylating drugs, chlorambucil, are also determined by the method described above, and concentrations are shown in Figure 12. Unlike bendamustine, the synergistic effect of inhibiting the growth of SU-DHL-6 cells was not shown by chlorambucil in combination from CAS-024 (see Fig. 13).

EXAMPLE 12

CAS-024 EFFICACY WITH COMBINATION WITH BENDAMUSTIN ON A MODEL

HETEROF THE HUMAN GUZA.

[0141] The aim of this study was to compare the effectiveness of CAS-024 in combination with bendamustine for each factor administered during treatment on a subcutaneous human tumor xenograft model in SCID mice.

[0142] Obtaining tumor xenografts and dividing into groups for treatment. As described above, DOHH2 is a human B-lymphoblastoid CD20 + / CD3T + cell line derived from a patient with follicular lymphoma. Five million DOHH2 cells were injected subcutaneously in the flank of female SCID CB-17 mice. On day 8 after tumor inoculation, palpable tumors were present in the majority of mice. Tumor-bearing mice with the same average tumor volume were divided into five groups (n = 15 in the group, 3 cages with 5 mice for each group). The day of dividing the mice into groups was defined as day 0. The diameters of the tumors were marked with a pair of calipers, and the tumor volume was calculated according to the formula: V = / [length x (width)²]. The initial mean tumor volume was 231 mm³, the median tumor size before treatment was 229 mm³and the range was from 201 to 261 mm³.

[0143] In vivo treatment. Groups of mice were treated with 0.2 μ PBS injections containing 10 μg of HulgG (days 0, 4, 8, iv), 10 mg / kg CAS-024 (days 0, 4, 8, iv), 10 mg / kg bendamustine (0, 2, 4, 7, 9 and p) or 10 μg of CAS-024 (days 0, 4, 8, iv) and 10 mg / kg of bendamustine (0, 2, 4, 7, 9, ip).

[0144] Monitoring and endpoints. Mice were monitored daily by visual inspection. An investigator who did not deal with treated groups and did not participate in their study performed a weekly weight measurement, and measured tumor diameters at least 3 times a week (M, W, F) (see above). Tumor volumes were calculated as described above.

[0145] Mice were euthanized if their tumor volume reached more than 1500 mm³ (or 1200 mm³ on Fridays). Death was not the end point in this study, and unless otherwise stated, the "survival" of the mice determined the time in which it was euthanized due to the volume of the tumor that reached the set limits. Mice were euthanized, if their tumor volume exceeded the parameters described above, tumor ulcer occurred if the tumor inhibited mouse mobility and the body weight loss exceeded 20%.

[0146] Statistical analyzes. All statistical analyzes were performed using GraphPad Prism software. Significant differences for mean tumor volumes and mean relative tumor volumes were determined using a one-way ANOVA test for non-parametric data (Kruskal-Wallis test) using a post-hoc test of Dunn's multiple comparison. Significant differences in mouse survival over time were determined by Kaplan-Meier survival analysis using the log-rank test to compare survival curves. Significant differences in the incidence of tumor-free mice were determined using Fisher's exact test. The values ​​of p &lt;0 05 were considered significant.

[0147] In the case of bendamustine-treated groups, dirty fur and diarrhea were observed from around day 6. On the 10th day, one mouse from the group treated with CAS-024 combination with bendamustine was euthanized because of a weight loss greater than or equal to 20%. This mouse was treated as an observation cut during the analysis of survival curves. There were no clinical signs associated with toxicity in the CAS-024-treated group alone.

[0148] For all treatment regimens, the inhibitory effect on DOHH2 increase compared to hulgG was demonstrated. On day 13 (which was the last day on which all mice were alive), the values ​​of the average tumor volume and relative tumor volume for all treated groups showed statistical differences compared to the mice in the HulgG control group (Figures 14A and 4B). A significant difference in mean tumor volumes and mean relative tumor volumes was also observed between the bendamustine treated group and the bendamustine and CAS-024 combination treatment group. There were no significant differences in mean tumor volumes or mean relative tumor volumes between the two other treatment groups. The average tumor volumes over time for four groups are shown in Figure 15.

[0149] Tumors in hulgG-treated mice grew rapidly and all mice in this group were euthanized on day 17. As shown in Figure 16 and shown in Tables 12 and 13, survival of mice receiving doses of either combination was prolonged compared to the treatment group HulgG (p &lt;0.0001 for all groups). There was also a significant difference between the survival curves for all three treatment groups and between each of them and the CAS-024 / bendamustine combination, which is superior to a single agent.

[0150] None of the mice treated with HulgG were alive (i.e. none of them were tumor free) at the end of the study (day 34) (Fig. 17 and Table 12). The incidence of the case of tumor free mice in the remaining groups was 0/15 (0%), for the CAS-024 and bendamustine treated groups, and 2/14 (14%) for the group treated with the CAS-024 combination with bendamustine. There was no significant difference in the incidence of tumor-free mice for any of the treatment groups.

EP-2132228B1PL

Table 12. Median survival time and incidence of the case of tumor-free mice at the end of the observation period

<td>The group is treated^and</td><td>Days of treatment</td><td>Median time survival (Days)^and</td><td>The incidence of tumor-free cases at the end of the study</td>

<td>HuIgG</td><td>Days 0, 4, 8</td><td>15</td><td>0/15 (0%)</td>

<td>CAS-024 10 μg</td><td>Days 0, 4, 8</td><td>17^b</td><td>0/15 (0%)</td>

<td>bendamustine 10 mg / kg</td><td>Ways 0.2. 4, 7, 9</td><td>17</td><td>0/15 (0%)</td>

<td>CAS-024 + Bendamustyna</td><td>Days 0,4,8 0,2,4,7,9</td><td>24</td><td>2/14 (14%)^d</td>

<td colspan="4">^andThe "survival" of mice determined the day when it was euthanized due to tumor growth. One mouse in the group receiving the combination CAS-024 with bendamustine was euthanized on day 10 due to a weight loss greater than or equal to 20%. This mouse was treated as an observation cut off while calculating the survival curves. No other mice were euthanized for reasons other than tumor volume reaching a certain limit.^bValues ​​marked in bold indicate that the survival curves of the indicated group are significantly different from those for the hulgG receiving group (p &lt;0.0001 for all groups, log-rank test).^cThe "tumor-free" mice did not have a perceptible SC tumor. Lack of tumor cells was not confirmed by histological examination. The tests were completed on day 34.^dOne mouse in the group receiving the combination CAS-024 with bendamustine was euthanized on day 10 due to a weight loss greater than or equal to 20%. No other mice were euthanized due to toxicity.</td>

Table 13. P values ​​for comparison of survival curves between treatment groups

<td colspan="5">P values ​​for comparison of survival curves (log-rank test)</td>

<td></td><td>HuIgG</td><td>TRU-016</td><td>bendamustine</td><td>TRU-016 + bendamustyna</td>

<td>HuIgG</td><td>ON</td><td>&lt;0.0001</td><td>&lt;0.0001</td><td>&lt;00001</td>

<td>TRU-016</td><td>&lt;0.0001^and</td><td>ON</td><td>0.0050</td><td>0.01</td>

<td>bendamustine</td><td>&lt;0.0001</td><td>0.0050</td><td>ON</td><td>&lt;0.0001</td>

<td>TRU-016 + bendamustyna</td><td>&lt;0.0001</td><td>0.01</td><td>&lt;0.0001</td><td>ON</td>

[0151] This study shows that the combination of CAS-024 and bendamustine has tumor growth inhibitory effects on DOHH2 in SCID mice, greater than those observed for both of these factors alone.

[0152] These and other changes may be embodiments in the light of the above detailed description. In general, in the following claims, the terms used should not be construed as limiting the claims to specific embodiments disclosed in the specification and claims, but should be construed as all possible embodiments together with the full range of equivalents to which these claims apply. Consequently, the claims are not limited by this disclosure.

EP-2132228B1PL

SEQUENCE LIST [0153] &lt;110&gt; Trubion Pharmaceuticals, Inc.

Tan, Phillip

Simon, Sandy A.

Cerveny, Charles G.

Nilsson, Christy Anne Brady, William Ledbetter, Jeffrey A.

Hayden-Ledbetter, Martha S.

Thompson, Peter A.

Morales, Cecile &lt;120&gt; IMMUNOTHERAPEUTIC CONTROLLED AGAINST CD37 AND HIS

COMBINATION WITH DUAL FUNCTIONAL CHEMOTHERAPEUTICS &lt;130&gt; 910180.420PC &lt;140&gt; PCT &lt;141&gt; 2009-04-10 &lt;150&gt; US 61 / 190,067 &lt;151&gt; 2008-04-11 &lt;160&gt; 269 &lt;170&gt; Patentln version 3.3 &lt;210&gt; 1 &lt;211&gt; 1510 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

EP-2132228B1EN &lt;400&gt;1 aagcttgccg ccatggattt tcaagtgcag attttcagct tcctgctaat cagtgcttca 60 gtcataattg ccagaggagt cgacatccag atgactcagt ctccagcctc cctatctgca 120 tctgtgggag agactgtcac catcacatgt cgaacaagtg aaaatgttta cagttatttg 180 gcttggtatc agcagaaaca gggaaaatct cclcagctcc tggtctcttt tgcaaaaacc 240 ttagcagaag gtgtgccalc aaggttcagt ggcagtggat caggcacaca gttttctctg 300 aagatcagca gcctgcagoc tgaagattct ggaagttatt tctgtcaaca tcattccgat 360 aatccgtgga cgttcggtgg aggcaccgaa ctggagatca aaggtggcgg tggctcgggc 420 ggtggtgggt cgggtggcgg cggatcgtca gcggtccagc tgcagcagtc tggacctgag 480 tcggaaaagc ctggcgcttc agtgaagatt tcctgcaagg cttctggtta ctcattcact 540 ggctacaata tgaactgggt gaagcagaat aatggaaaga gccttgagtg gattggaaat 600 attgatcctt attatggtgg tactacctac aaccggaagt tcaagggcaa ggccacattg 660 actgtagaca aatcctccag cacagcctac atgcagctca agagtctgac atctgaggac 720 tctgcagtctattactgtgc aagatcggtc ggccdatgg actactgggg tcaaggaacc 780 tcagtcaccg tctcttcaga tctggagccc aaatcttctg acaaaactca cacatctcca 840 ccgtgcccag cacctgaact cttgggtgga ccgtcagtct tcctcttccc cccaaaaccc 900 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 960 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1020 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1080 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1140 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1200 gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accagglcag cctgacctgc 1260 ctggtcaaag gcttctatcc aagcgacatc gccgtggagt gggagagcaa tgggcaaccg 1320 gagaacaact acaagaccac gcctcccgtg ctggactccg acggclcctt cttcctctac 1380 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1440 atgcatgagg ctctgcacaaccadacacg cagaagagoc tctccctgtc tccgggtaaa 1500 tgagtctaga 1510 &lt;210&gt; 2 &lt;211&gt; 496 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 2

Met Asp Phe Gin Val Gin Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser 15 10 15

Val Ile Ile Ala Arg Gly Val Asp Ile Ile Gin Met Thr Gin Ser Pro Ala 20 25 30

Cheese Leu Cheese Ala Cheese Val Gly Glu Thr Val Thr Ile Thr CysArg Thr 35 40 45

EP-2132228B1PL

Ser Glu Asn Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Gin Gly 50 55 60

Lys Ser Pro Gin Leu Leu Val Ser Phe Ala Lys Thr Leu Ala Glu Gly 65 70 75 80

Val Pro Ser Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Gin Phe Ser Leu 85 90 95

Lys Ile Ser Ser Leu Gin Pro Glu Asp Ser Gly Cheese Tyr Phe Cys Gin 100 105 110

His His Ser Asp Asn Pro Trp Thr Phe Gly Gly Gly Thr Glu Leu Glu 115 120 125

Ile Lys Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130 135 140

Cheese Cheese Ala Val Gin Leu Gin Gin Cheese Gly Pro Glu Cheese Glu Lys Pro 145 150 155 160

Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr 165 170 175

Gly Tyr Asn Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser Leu Glu 180 185 190

Trp Ile Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg 195 200 205

Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Cheese Ser Thr 210 215 220

Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 225 230 235 240

Tyr Cys Ala Arg Ser Vai Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr 245 250 255

Cheese Val Thr Val Ser Cheese Asp Leu Glu Pro Lys Cheese Ser Asp Lys Thr 260 255 270

EP-2132228B1PL

His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 275 280 285

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Me) Ile Ser Arg 290 295 300

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 305 310 315 320

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 325 330 335

Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val 340 345 350

Val Leu Thr Val Leu cheese His Gin Asp Trp Leu Asn Gly Lys Glu Tyr 355 360 365

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 370 375 380

Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gir Val Tyr Thr Leu 385 390 395 400

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys 405 410 415

Leu Val Lys Gly Phe Tyr Pro Ser Asp. Ile Ala Val Glu Trp Glu Ser 420 425 430

Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 435 440 445

Cheese Asp Gly Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Cheese 450 455 460

Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465 470 475 480

Leu His Asn His Tyr Thr Gin Lys Ser Leu Leu Ser Ser Pro Gly Lys 485 490 495 &lt;210&gt; 3 &lt;400&gt; 3,000 &lt;210&gt; 4 &lt;400&gt; 4,000 &lt;210&gt; 5 &lt;211&gt; 1482 &lt;212&gt; DNA &lt; 213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

EP-2132228B1EN &lt;400&gt;5 atggaagccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccafcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc Iggaggaggt 420 gggaccggtg aggtgcagct ggtgcagtct ggagcagagg tgaaaaagcc cggagagtct 480 ctgaagattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540 cgccagatgc ccgggaaagg cctcgagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta Hactgtgca 720 cgctcagtcggccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctctgat 780 caggagccca aatcttclga caaaactcac acatctccac cgtgcccagc acctgaactc 840 ctgggtggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 900 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 960 ttcaaetggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1020 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1080 aatggcaagg aglacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1140 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc tgaccaagaa ccaggtcagc 1200 cgggatgagc ctgacctgcc tggtcaaagg cttctatcca 1260 agcgacatcg cogłggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg tggactccga cggctccttc 1320 cctcocgtgc ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1380 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct 1440ctccctgtct ccgggtaaat ga 1482 &lt;210&gt; 6 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

EP-2132228B1EN &lt;400&gt; 6

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Len Leu Leu Trp Leu Pro 15 10 15

AspThrThr Gly Glu Ile Val Leu ThrGIn Ser Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

EP-2132228B1PL

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Gfu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Mel His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 7 &lt;211&gt; 1482 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 7 alggaagccc cagctcagct tctcttcctc clgclactct ggclcccaga taccaccgga 60 gaaattgtgl tgacacagtc tccagccacc etgtctttgt ctccaggoga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct calclatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagłggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300

EP-2132228B1PL gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 gggagctctg aggtgcagct ggtgcagtct ggagcagagg tgaaaaagcc cggagagtct 480 ctgaagattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540 cgccagatgc ccgggaaagg cctcgagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca cogccatgta ttactgtgca 720 cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctctgat 780 caggagccca aatcttctga caaaactcac acatctccac cgtgcccagc acctgaactc 840 cgtcagtctt cctcttcccc ccaaaaccca ctgggtggac aggacaccct catgatctcc cggacccctg 900 aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt 960 acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1020cagtacaaca gcacgtaccg tgtggtcagc glcctcaccg tcctgcacca ggactggctg 1080 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1140 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1200 cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc łggtcaaagg cttctatcca 1260 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1320 cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1 380 agcaggtggc agcaggggaa cglcltctca tgctocgtga tgcatgaggc tctgcacaac 1440 cactacacgc agaagagcct ctccctgtct ccgggtaaat ga 1482 &lt;210&gt; 8 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 8

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese

EP-2132228B1PL

25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gore Ghoul Ser 135

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp ValArg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile SerThrAla Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr

EP-2132228B1PL

245, 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 9 &lt;211&gt; 1482 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 9

EP-2132228B1PL atggaagccc cagctcagct tctcttcctc clgctactct ggctcccaga taccaccgga SO gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaaoct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata alccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 aggtgcagct gggaccggtg ggtgcagtct ggagcagagt cgaaaaagcc oggagagtct 480 ctgaagattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540 cgccagatgc ccgggaaagg cctcgagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctctgat 780 caggagccca aatcttctga caaaactcac acatctccac cgtgcccagc acctgaactc 840 ctgggtggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct caigatctcc 900 cggacccctg aggtcacatg cgtggtggtg gacgtgagoc acgaagaccc tgaggtcaag 960 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1020 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1080 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1140 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc tgaccaagaa ccaggtcagc 1200 cgggatgagc ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1260 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1320 ttcctctaca gcaagclcac 1 380 agcaggtggc agcaggggaa cglggacaag cgtcttatca Igetccgtga tgcatgaggc tctgcacaac cactacacgc 1440agaagagoct ctccctgtct ccgggtaaat ga 1482 &lt;210&gt; 10 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 10

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gh Ser Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu how much Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

EP-2132228B1PL

Val Gin Leu Val Gin Cheese Gly Ala Glu Cheese Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

GlnTrp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Gtu Glu Gin Tyr Asn SerThrTyrArg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

EP-2132228B1PL

Va1 Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys SerVal Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 11 &lt;211&gt; 1482 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Protein-specific binding CD37 &lt;400&gt; 11 atggaagccc cagctcagct tctcttcctc ctgctactct ggctcccaga laccaccgga 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtca aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggl ggctcgggcg gtggtggatc tggaggaggt 420

EP-2132228B1PL gggaccggtg aggtgcagct ggtgcagtct ggagcagagg tgaaaaagcc cggagagtct 480 ctgaagattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540 cgccagatgc ccgggaaagg cctcgagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720 cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctctgat 780 caggagccca aatcttctga caaaactcac acatctccac cgtgcccagc acctgaactc 840 cgtcagtctt cctcttcccc ccaaaaccca ctgggtggac aggacaccct catgatctcc cggacccctg 900 aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt 960 acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc 1020 gtcctcaocg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1080 aacaaagccc tcccagcccc catcgagaaa 1140accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1200 cgggatgagc tgaocaagaa ccaggtcagc ctgacctgcc tgglcaaagg cttctatcca 1260 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1320 cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1 380 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1440 cactacacgc agaagagcct ctccctgtct ccgggtaaat ga 1482 &lt;210&gt; 12 &lt;211&gt; 493 &lt; 212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 12

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Cheese Cys Arg Thr Cheese Gin Asn

EP-2132228B1PL

40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser

EP-2132228B1PL

260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Vai Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Cheese Leu Cheese Pro Gly Lys

485 490 &lt;210&gt; 13 &lt;211&gt; 1482 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 13

EP-2132228B1PL alggaagccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60 gaaattg tgt tgacacagtc tccag ccacc etgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aagtgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt gggaccggtg 420 aggtgcagct ggtgcagtct ggagcagagg tgaaaaagcc cggagagtct 480 ctgaagattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540 cgccagatgc ccgggaaagg cctcgagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtl caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca cogccatgta ttactgtgca 720cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctctgat 780 caggagccca aatcttctga caaaactcac acatctccac cgtgcccagc acctgaactc 840 ctgggtggac cgtcagtcłt cctcttcccc ccaaaaccca aggacaccct catgatctcc 900 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 960 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1020 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1080 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1140 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc tgaccaagaa ccaggtcagc 1200 cgggatgagc ctgacctgcc tggtcaaagg cttctatcca agcgacatcg ccgtggagtg ggagagcaat 1260 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1320 ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1380 tgctccgtga tgcatgaggc tctgcacaac cactacacgc 1440agaagagcct ctccctgtct ccgggtaaat ga 1482 &lt;210&gt; 14 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 14

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Cheese Glu Ser 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

EP-2132228B1PL

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Vai Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val ValSer Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

EP-2132228B1PL

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 15 &lt;211&gt; 1482 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Protein-specific binding CD37 &lt;400&gt; 15 atggaagccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggoga aagagccacc 120 ctctcctgcc gagcaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct calctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 aggtgcagct gggaccggtg ggtgcagtct ggagcagagg tgaaaaagcc cggagagtct 480 ctgaagattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540

EP-2132228B1PL cgccagatgc ccgggaaagg cctcgagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720 cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctctgat 780 caggagccca aatcttctga caaaactcac acatctccac cgtgcccagc acctgaactc 840 ctgggtggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 900 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt 960 acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg 1020 tgtgglcagc gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 1080 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1140 gaaccacagg tgtacaccct gcccccalcc tgaccaagaa ccaggtcagc 1200 cgggatgagc ctgacctgcc tggtcaaagg cttctatccaAgcgacatcg ccgtggagtg ggagagcaat 1260 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1320 ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1380 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1440 ccgggtaaat ga 1482 &lt;210&gt; 16 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 16

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Al Pro

EP-2132228B1PL

55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Al Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

EP-2132228B1PL

275, 280,285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 17 &lt;211&gt; 1479 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 17

EP-2132228B1PL atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gacatccaga tgactcagtc tccagcctcc ctatctgcat ctgtgggaga gactgtcacc 120 atcacatgtc gaacaagtga aaatgtttac agttatttgg cttggtatca gcagaaacag 180 ggaaaatctc ctcagctcct ggtctctttt gcaaaaacct tagcagaagg tgtgccatca 240 aggttcagtg gcagtggatc aggcacacag ttttctctga agatcagcag cctgcagcct 300 gaagattctg gaagttattt ctgtcaacat cattccgata atccgtggac gttcggtgga 360 ggcaccgaac tggagatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 420 aggtgcagct ggagctagcg ggtgcagtct ggagcagagg tgaaaaagcc cggagagtct 480 ctgaggattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tctccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcagaagagcctctc cctgtctccg ggtaaatga 1479 &lt;210&gt; 18 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 18

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Asp. Ile Gin Met Thr. Gin. Ser Pro. Ala. Ser Leu Cheese 20 25 30

Ala Ser Val Gly Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Gin Gly Lys Pro Pro 50 55 60

Gin Leu Leu Val Ser Phe Ala Lys Thr Leu Ala Glu Gly Val Pro Ser 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Gin Phe Cheese Leu Lys Ile Ser 85 90 95

Leu Gin Pro Cheese Glu Asp Ser Gly Cheese Tyr Phe Cys Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Arg Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

EP-2132228B1PL

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gty Thr Leu Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro SerVal Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Vat 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val As Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn SerThrTyr Arg Val Val SerVal Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Asn Lys Ala Leu Pro Al Pro Pro how much Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

EP-2132228B1PL

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Cheese Ser Leu Cheese Pro Gly Lys 485 490 &lt;210&gt; 19 &lt;211&gt; 1479 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Protein-specific binding CD37 &lt;400&gt; 19 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc etgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtagtggatc tggaggaggt 420 ggagctagcg cggtccagct gcagcagtct ggacctgagt cggaaaagcc tggcgcttca 480 gtgaagattt cctgcaaggc ttctggttac tcattcactg gctacaatat gaactgggtg 540 aagcagaata atggaaagag ccttgagtgg attggaaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggcaag gccacattga ctgtagacaa atcctccagc 660

EP-2132228B1PL acagcctaca tgcagctcaa gagtctgaca tctgaggact ctgcagtcta ttactgtgca 720 agatcggtcg gccctatgga ctactggggt caaggaacct cagtcaccgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tctccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatclcccgg 900 acccctgagg tcacatgcgt ggtggtggac glgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 lacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctalccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctcl gcacaaccac 1440 tacacgcaga agagcclctc cctgtctccg ggtaaatga 1479 &lt;210&gt; 20 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 20

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala

EP-2132228B1PL

70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gala Ala Ser 130 130 140

Val Gin Leu Gin Gin Cheese Gly Pro Glu Cheese Glu Lys Pro Gly Ala Ser 145 150 155 160

Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser Leu Glu Trp Ile Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met 210 215 220

Gin Leu Lys Ser Leu Thr Cheese Glu Asp Ser Al Val Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

EP-2132228B1PL

290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Vai Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Ser Leu Ser Leu Pro Gly Lys 485 490 &lt;210&gt; 21 &lt;211&gt; 1479 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 21

EP-2132228B1PL atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 aggtgcagct ggagctagcc ggtggagtct ggtggaggcg tggtccagcc tgggaggtcc 480 ctgagactct cctgtgcagc ctctggattc accttcagtg gctacaatat gaactgggtc 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tctccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcagaagagcctctc cctgtctccg ggtaaatga 1479 &lt;210&gt; 22 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 22

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130

Val Gin Leu Val Glu Cheese Gly Gly Gly Val Val Gin Pio Gly Arg Cheese 145 150 155 160

Leu Arg Leu Cheese Cys Ala Ala Cheese Gly Phe Thr Phe Cheese Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

EP-2132228B1PL

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

GlnTrp Cheese Ser Leu LysAlaSerAspThrAla Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val As Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn SerThrTyrArg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

EP-2132228B1PL

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Cheese Ser Leu Cheese Pro Gly Lys 485 490 &lt;210&gt; 23 &lt;211&gt; 1503 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt;23 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gcgglccagc tgcagcagtc tggacctgag tcggaaaagc ctggcgcttc agtgaagatt 120 tcctgcaagg cttctggtta ctcattcact ggctacaata tgaactgggt gaagcagaat 180 aalggaaaga gccltgagtg gattggaaat attgatcctt attatggtgg tactacctac 240 aaccggaagt tcaagggcaa ggccacattg actgtagaca aatcctccag cacagcctac 300 atgcagctca agagtctgac atctgaggac tctgcagtct attactgtgc aagatcggtc 360 ggccctatgg actactgggg tcaaggaacc tcagtcaccg tctcttctgg tggcggtggc 420 tcgggcggtg gtgggtcggg tggcggcgga tcaggaggag gcgggagtgc tagcgaaatt 480 gtgttgacac agtctccagc caccctgtct ttgtctccag gcgaaagagc caccctctcc 540 tgccgaacaa gtgaaaatgt ttacagctac ttagcctggt accaacagaa acctggccag 600 gctcctaggc tcctcatcta ttttgcaaaa accttagcag aaggaattcc agccaggttc 660 agtggcagtg gatccgggac agacttcact ctcaccatca gcagcctaga gcctgaagat 720 tttgcagtttattactgtca acatcattcc gataatccgt ggacattcgg ccaagggacc 780

EP-2132228B1PL aaggtggaaa tcaaaggctc gagcgagccc aaatcttctg acaaaactca cacatctcca 840 ccgtgcccag cacctgaact cctgggtgga ccgtcagtct tcctcttccc cccaaaaccc 900 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 960 cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 1020 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1080 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1140 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1200 gtglacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 1260 ctggtcaaag gcttctatcc aagcgacatc gccgtggagt gggagagcaa tgggcagccg 1320 gagaacaact acaagaccac gcctcccglg ctggactccg acggctcctt citcctctac 1380 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1440 atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctglc tccgggtaaa1500 tga 1503 &lt;210&gt; 24 &lt;211&gt; 500 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 24

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Ala Val Gin Leu Gin Gin Gly Pro Pro Glu Ser Glu 20 25 30

Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser 35 40 45

Phe Thr Gly Tyr Asn Met Asn Trp Val Lys G! N Asn Asn Gly Lys Ser 50 55 60

Leu Glu Trp How many Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr 65 70 75 80

EP-2132228B1PL

Asn Arg Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser 85 90 95

Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Cheese Glu Asp Ser Al 100 105 110

Val Tyr Tyr Cys Ala Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin 115 120 125

Gly Thr Cheese Val Thr Val Ser Cheese Gly Gly Gly Gly Cheese Gly Gly Gly 130 135 140

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali G Serl Cheese G Glr Glu Ile 145 150 155 160

Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly Glu Arg 165 170 175

Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn Val Tyr Ser Tyr Leu Ala 180 185 190

Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile Tyr Phe 195 200 205

Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly Cheese Gly 210 215 220

Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro Glu Asp 225 230 235 240

Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp Thr Phe 245 250 255

Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Cheese Ser Glu Pro Lys Ser 260 265 270

Asp Lys Thr His Thr Pro Pro Pro Cys Pro Ala Pro Glu Leu Leu 275 280 285

Gly Gly Pro Cheese Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 290 295 300

EP-2132228B1PL

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 305 310 315 320

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 325 330 335

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr 340 345 350

Tyr Arg Val Val Val Val Leu Thr Val Leu His Gin Asp Trp Leu Asn 355 350 365

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 370 375 380

How Many Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin 385 390 395 400

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val 405 410 415

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cheese Asp. Ile Ala Val 420 425 430

Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro 435 440 445

Pro Val Leu Asp cheese Asp Gly Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr 450 455 460

Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val 465 470 475 480

Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu 485 490 495

Pro Gly Lys 500 cheese &lt;210&gt; 25 &lt;211&gt; 1488 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 25

EP-2132228B1PL atggattttc aagtgcagat tttcagcttc ctgctaatca gtgcttcagt cataattgcc 60 agaggagtcg aaattglgtt gacacagtct ccagccaccc Igtctttgtc tccaggcgaa 120 agagccaccc tctcctgccg aacaagtgaa aatgtttaca gctacttagc ctggtaccaa 180 cagaaacctg gccaggctcc taggctcctc atclattttg caaaaacctt agcagaagga 240 attccagcca ggttcagtgg cagtggatcc gggacagact tcactctcac catcagcagc 300 ctagagcctg aagattttgc agtttattac tgtcaacatc attccgataa tccgtggaca 360 ttcggccaag ggaccaaggt ggaaatcaaa ggtggcggtg gctcgggcgg tggtggatct 420 ggaggaggtg gagctagcgc ggtccagctg cagcagtctg gacctgagtc ggaaaagcct 480 ggcgcttcag tgaagattlc ctgcaaggct tctggttact cattcactgg ctacaałatg 540 aacigggtga agcagaataa tggaaagagc cttgagtgga ttggaaatat tgatccttat 600 tatggtggta ctacctacaa ccggaagttc aagggcaagg ccacattgac tgtagacaaa 660 tcctccagca cagcctacat gcagctcaag agtctgacat ctgaggactc tgcaglctat 720lactgtgcaa gatcggtcgg ccctatggac tactggggtc aaggaacctc agtcaccgtc 780 tcctcgagcg agcccaaatc ttctgacaaa actcacacat ctccaccgtg cccagcacct 840 gaacłcctgg gtggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 900 atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 960 gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1020 gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1080 tggctgaatg gcaaggagta caagtgcaag gtclccaaca aagccctccc agcccccatc 1140 gagaaaacca Ictccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1200 ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1260 tatccaagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1320 accacgcclc ccgtgctgga ctccgacggc tccttcltcc tctacagcaa gctcaccgtg 1380 gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1440 cacaaccactacacgcagaa gagcctctcc ctgtctccgg gtaaatga 1488 &lt;210&gt; 26 &lt;211&gt; 495 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 26

EP-2132228B1PL

Met Asp Phe Gin Val Gin Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser 15 10 15

Val Ile Ile Ala Arg Gly Vat Glu Ile Val Leu Thr Gin Ser Pro Ala 20 25 30

Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr 35 40 45

Ser Glu Asn Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly 50 55 60

Gin Ala Pro Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly 65 70. 75 80

Ile Pro Ala Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu 85 90 95

Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin 100 105 110

His His Ser Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu 115 120 125

Ile Lys Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130 135 140

Ala Ser Al Val Gin Leu Gin Gin Gly Pro Cheese Glu Ser Glu Lys Pro 145 150 155 160

Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr 165 170 175

Gly Tyr Asn Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser Leu Glu

EP-2132228B1PL

180 185 190

Trp Ile Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg 195 200 205

Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Cheese Ser Thr 210 215 220

Ala Tyr Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr 225 230 235 240

Tyr Cys Ala Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr 245 250 255

Cheese Val Thr Val Cheese Cheese Cheese Glu Pro Lys Cheese Cheese Asp Lys Thr His 260 265 270

Thr Pro Pro Pro Cys Pro Al Pro Glu Leu Leu Gly Pro Ser Val 275 280 285

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 290 295 300

Pro Glu Val Thr Cys Val Val Val Asp Val His Ser Glu Asp Pro Glu 305 310 315 320

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 325 330 335

Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser 340 345 350

Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 355 360 365

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile 370 375 380

Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 385 390 395 400

Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu

EP-2132228B1PL

405 410 415

Val Lys Gly Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn 420 425 430

Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 435 440 445

Asp Gly Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg 450 455 460

Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 465 470 475 480

His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 495 &lt;210&gt; 27 &lt;211&gt; 1503 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt;27 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gcggtccagc tgcagcagtc tggacctgag tcggaaaagc ctggcgcttc agtgaagatt 120 tcctgcaagg cttctggtta ctcattcact ggctacaata tgaactgggt gaagcagaat 180 aatggaaaga gccttgagtg gattggaaat attgatcctt attatggtgg tactacctac 240 aaccggaagt tcaagggcaa ggccacattg actgtagaca aatcctccag cacagcctac 300 atgcagctca agagtctgac atctgaggac tctgcagtct attactgtgc aagatcggtc 360 ggccctatgg actactgggg tcaaggaacc tcagtcaccg tctcttctgg tggcggtggc 420 tcgggcggtg gtgggtoggg tggcggcgga tcaggaggag gcgggagtgc tagcgaaatt 480 gtgttgacac agtctccagc caccctglct ttgtctccag gcgaaagagc caccctctcc 540 tgccgaacaa gtgaaaatgt ttacagctac ttagcctggt accaacagaa acctggccag 600 gctcctaggc tcctcatcta ttttgcaaaa accttagcag aaggaattcc agccaggttc 660 agtggcagtg gatccgggac agacttcact ctcaccatca gcagcctaga gcctgaagat 720gcagcctaga gcctgaagat 720gcagcctaga gcctgaagat 720

EP-2132228B1PL tttgcagttt attactgtca acatcattcc gataatccgt ggacattcgg ccaagggacc 780 aaggtggaaa tcaaaggctc gagcgagccc aaatcttctg acaaaactca cacatgccca 840 ccgtgcccag cacctgaact cctgggtgga ccgtcagtct tcctcttccc cccaaaaccc 900 aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 960 cacgaagacc ctgagglcaa gttcaactgg tacglggacg gcgtggaggt gcataatgcc 1020 aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1080 gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtclc caacaaagcc 1140 ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1200 gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 1260 etggtcaaag gcttctatcc aagcgacatc gccgtggagt gggagagcaa tgggcagccg 1320 gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1380 agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg1440 atgcalgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1500 (ga 1503 &lt;210&gt; 28 &lt;211&gt; 500 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 28

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Ala Val Gin Leu Gin Gin Gly Pro Pro Glu Ser Glu 20 25 30

Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser 35 40 45

Phe Thr Gly Tyr Asn Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser 50 55 60

Leu Glu Trp. Ile Gly Asn Ile Asp. Tyr Tyr Gly Gly Thr Thr Tyr

EP-2132228B1PL

70 75 80

Asn Arg Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser 85 90 95

Ser Thr Ala Tyr Met Gin Leu Lys Ser Leu Thr Cheese Glu Asp Ser Al 100 105 110

Val Tyr Tyr Cys Ala Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin 115 120 125

Gly Thr Cheese Val Thr Val Ser Cheese Gly Gly Gly Gly Cheese Gly Gly Gly 130 135 140

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali G Serl Cheese G Glr Glu Ile 145 150 155 160

Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly Glu Arg 165 170 175

Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn Val Tyr Ser Tyr Leu Ala 180 185 190

Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile Tyr Phe 195 200 205

Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly Cheese Gly 210 215 220

Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro Glu Asp 225 230 235 240

Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp Thr Phe 245 250 255

Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Cheese Ser Glu Pro Lys Ser 260 265 270

Asp Lys Thr His Thr Cys Pro Pro Cys Pro Al Pro Glu Leu Leu 275 280 285

Gly Gly Pro Cheese Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

EP-2132228B1PL

290 295 300

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 305 310 315 320

His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 325 330 335

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr 340 345 350

Tyr Arg Val Val Val Val Leu Thr Val Leu His Gin Asp Trp Leu Asn 355 360 365

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 370 375 360

How Many Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin 385 390 395 400

Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val 405 410 415

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cheese Asp. Ile Ala Val 420 425 430

Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro 435 440 445

Pro Val Leu Asp cheese Asp Gly Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr 450 455 460

Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val 465 470 475 480

Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu 485 490 495

Pro Gly Lys 500 cheese &lt;210&gt; 29 &lt;211&gt; 1479 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

EP-2132228B1EN &lt;400&gt;29 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct calctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 ggagctagcg cggtccagct gcagcagtct ggacctgagt cggaaaagcc tggcgcttca 480 gtgaagattt cctgcaaggc ttctggttac tcattcactg gctacaatat gaactgggtg 540 aagcagaata atggaaagag ccttgagtgg attggaaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggcaag gccacattga ctgtagacaa atcctccagc 660 acagcctaca tgcagctcaa gagtctgaca tctgaggact ctgcagtcta ttactgtgca 720 agatcggtcggccctatgga ctactggggt caaggaacct cagtcaccgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tctccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcaga agagcctctccctgtctccg ggtaaatga 1479 &lt;210&gt; 30 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

EP-21322281EN &lt;400&gt; 30

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly G! U Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gala

Val Gin Leu Gin Gin Cheese Gly Pro Glu Cheese Glu Lys Pro Gly Ala Ser 145 150 155 160

Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn 165 170 175

EP-2132228B1PL

Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser Leu Glu Trp Ile Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met 210 215 220

Gin Leu Lys Ser Leu Thr Cheese Glu Asp Ser Al Val Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Va1 His Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

EP-2132228B1PL

Asp Glu Leu Thr Lys Asn Gin Vat Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Ser Leu Ser Leu Pro Gly Lys 485 490 &lt;210&gt; 31 &lt;211&gt; 1479 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Protein-specific binding CD37 &lt;400&gt; 31 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 ggagctagcg cggtccagct gcagcagtct ggacctgagl cggaaaagcc tggcgcttca 480 gtgaagattt cctgcaaggc ttctggttac tcattcactg gctacaatat gaactgggtg 540 aagcagaata atggaaagag ccttgagtgg attggaaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggcaag gccacattga ctgtagacaa atcctccagc 660

100

EP-2132228B1PL acagcctaca tgcagctcaa gagtctgaca tctgaggact ctgcagtcta ttactgtgca 720 agatcggtcg gccctatgga ctactggggt caaggaacct cagtcaccgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcaga agagcctctc cctgtctccg ggtaaatga 1479 &lt;210&gt; 32 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 32

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala

101

EP-2132228B1PL

70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gala

Val Gin Leu Gin Gin Cheese Gly Pro Glu Cheese Glu Lys Pro Gly Ala Ser 145 150 155 160

Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser Leu Glu Trp Ile Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met 210 215 220

Gin Leu Lys Ser Leu Thr Cheese Glu Asp Ser Al Val Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Mel Ile Ser Arg Thr Pro Glu Val

102

EP-2132228B1PL

290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val As Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile G! U Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Ser Leu Ser Pro Pro Gly Lys 485 490 &lt;210&gt; 33 &lt;211&gt; 1479 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 33

103

EP-2132228B1PL atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 aggtgcagct ggagctagcc ggtggagtct ggtggaggcg tggtccagcc tgggaggtcc 480 ctgagactct octgtgcagc ctctggattc accttcagtg gctacaatat gaactgggtc 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gcoccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcagaagagcctctc cctgtctccg ggtaaatga 1479 &lt;210&gt; 34 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 34

104

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu ThrGIn Ser Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130

Val Gin Leu Val Glu Cheese Gly Gly Gly Val Val Gin Pro Gly Arg Ser 145 150 155 160

Leu Arg Leu Cheese Cys Ala Ala Cheese Gly Phe Thr Phe Cheese Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

105

EP-2132228B1PL

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro 250 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val H is Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

106

EP-2132228B1PL

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Cheese Ser Leu Cheese Pro Gly Lys 485 490 &lt;210&gt; 35 &lt;211&gt; 1479 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt;35 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 ggagctagcc aggtgcagct ggtggagtct ggtggaggcg tggtccagcc tgggaggtcc 480 ctgagactct cctgtgcagc ctctggattc accttcagtg gctacaatat gaactgggtc 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720 cgctcagtcggccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780

107

EP-2132228B1PL gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 lacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcaga agagcclctc cctgtctccg ggtaaatga 1479 &lt;210&gt; 36 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 36

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese

108

EP-2132228B1PL

90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130

Val Gin Leu Val Glu Cheese Gly Gly Gly Val Val Gin Pro Gly Arg Ser 145 150 155 160

Leu Arg Leu Cheese Cys Ala Ala Cheese Gly Phe Thr Phe Cheese Gly Tyr Asn 165 170 175

Met Asn Trp ValArg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe

109

EP-2132228B1PL

305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val As Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Ser Leu Ser Pro Pro Gly Lys 485 490 &lt;210&gt; 37 &lt;211&gt; 1476 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 37

110

EP-2132228B1PL atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctg tctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaaoct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata alccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 aggtgcagct ggggctagcg ggtggagtct ggtggaggct tggtccagcc tggagggtcc 480 ctgagactct cctgtgcagc ctctggattc accttcagtg gctacaatat gaactgggtc 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tctccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcagaagagcctctc cctgtctccg ggtaaa 1476 &lt;210&gt; 38 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 38

111

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Glu Cheese Gly Gly Gly Leu Val Gin Pro Gly Gly Cheese 145 150 155 160

Leu Arg Leu Cheese Cys Ala Ala Cheese Gly Phe Thr Phe Cheese Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

112

EP-2132228B1PL

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Vat Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met background Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Gtu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val As Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gtn Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 39 &lt;211&gt; 1476

113

EP-2132228B1EN &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt;39 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc etgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 ggggctagcg aggtgcagct ggtggagtct ggtggaggct tggtccagcc tggagggtcc 480 ctgagactct cctgtgcagc ctctggattc accttcagtg gctacaatat gaactgggtc 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720 cgctcagtcggccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaae aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcaga agagcclctccctgtctccg ggtaaa 1476 &lt;210&gt; 40 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 40

114

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser

100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Glu Cheese Gly Gly Gly Leu Val Gin Pro Gly Gly Cheese 145 150 155 160

Leu Arg Leu Cheese Cys Ala Ala Cheese Gly Phe Thr Phe Cheese Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Aa Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

115

EP-2132228B1PL

325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Cheese Ser Leu Cheese Pro Gly Lys 485 490 &lt;210&gt; 41 &lt;211&gt; 1476 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 41 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120

116

EP-2132228B1PL ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaaoct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 ggggctagcg aggtgcagct ggtggagtct ggtggaggct ctgtccagcc tggagggtcc 480 ctgagactct cctgtgcagc ctctggattc accttcagtg gctacaatat gaactgggtc 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720 cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tctccaccgt gcccagcacc tgaactcctg 840ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcaga agagcctctc cctgtctccg ggtaaa 1476 &lt;210&gt; 42 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 42

117

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Glu Cheese Gly Gly Gly Cheese Val Gin Pro Gly Gly Cheese 145 150 155 160

Leu Arg Leu Cheese Cys Ala Ala Cheese Gly Phe Thr Phe Cheese Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

118

EP-2132228B1PL

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val As Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 340 345 350

VaS Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Va! Met His Glu Ala Leu His As His His 465 470 475 480

Tyr Thr Gin Lys Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 43 &lt;211&gt; 1476 &lt;212&gt; DNA &lt;213&gt; Artificial sequence

119

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt;43 atggaagcac cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccggt 60 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gaacaagtga aaatgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240 aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 ggggctagcg aggtgcagct ggtggagtct ggtggaggct ctgtccagcc tggagggtcc 480 ctgagactct cctgtgcagc ctctggattc accttcagtg gctacaatat gaactgggtc 540 cgccagatgc ccgggaaagg cctggagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720 cgctcagtcggccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctcgagc 780 gagcccaaat cttctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 840 ggtggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 900 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 960 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1020 tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1080 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1140 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1200 gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc 1260 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1320 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1380 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1440 tacacgcaga agagcctctccctgtctccg ggtaaa 1476 &lt;210&gt; 44 &lt;211&gt; 492 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 44

120

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin Hts His Ser 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly

121

EP-2132228B1PL

115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Glu Cheese Gly Gly Gly Cheese Val Gin Pro Gly Gly Cheese 145 150 155 160

Leu Arq Leu Cheese Cys Ala Ala Cheese Gly Phe Thr Phe Cheese Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro 260 265 270

Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 275 280 285

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 290 295 300

Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 305 310 315 320

Asn Trp Tyr Val Asp Gly Val Glu Val As Asn Ala Lys Thr Lys Pro 325 330 335

Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

122

EP-2132228B1PL

340 345 350

Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 355 360 365

Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala 370 375 380

Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 385 390 395 400

Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly 405 410 415

Phe Tyr Pro Cheese Asp. Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro 420 425 430

Glu Asn Asn Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese 435 440 445

Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin 450 455 460

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 465 470 475 480

Tyr Thr Gin Lys Leu Cheese Ser Leu Cheese Pro Gly Lys 485 490 &lt;210&gt; 45 &lt;211&gt; 1482 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 45 atggaagccc cagctcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60 gaaattgtgt tgacacagtc tccagccacc etgtctttgt ctccaggcga aagagccacc 120 ctctcctgcc gagcaagtca aagtgtttac agctacttag cctggtacca acagaaacct 180 ggccaggctc ctaggctcct catctatttt gcaaaaacct tagcagaagg aattccagcc 240

123

EP-2132228B1PL aggttcagtg gcagtggatc cgggacagac ttcactctca ccatcagcag cctagagcct 300 gaagattttg cagtttatta ctgtcaacat cattccgata atccgtggac attcggccaa 360 gggaccaagg tggaaatcaa aggtggcggt ggctcgggcg gtggtggatc tggaggaggt 420 gggaccggtg aggtgcagct ggtgcagtct ggagcagagg tgaaaaagcc cggagagtct 480 ctgaagattt cctgtaaggg atccggttac tcattcactg gctacaatat gaactgggtg 540 cgccagatgc ccgggaaagg cctcgagtgg atgggcaata ttgatcctta ttatggtggt 600 actacctaca accggaagtt caagggccag gtcactatct ccgccgacaa gtccatcagc 660 accgcctacc tgcaatggag cagcctgaag gcctcggaca ccgccatgta ttactgtgca 720 cgctcagtcg gccctatgga ctactggggc cgcggcaccc tggtcactgt ctcctctgat 780 caggagccca aatcttctga caaaactcac acatctccac cgtgcccagc acctgaactc 840 cgtcagtctt cctcttcccc ccaaaaccca ctgggtggac aggacaccct catgatctcc cggacccctg 900 aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 960ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1020 cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1080 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1140 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1200 cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatcca 1260 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1320 cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1 380 agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1440 cactacacgc agaagagcct ctccctgtct ccgggtaaat ga 1482 &lt;210&gt; 46 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 46

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

124

EP-2132228B1PL

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Cheese Cys Arg Ala Cheese Gin Cheese 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin T rp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

125

EP-2132228B1PL

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn SerThrTyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu ThrVal Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 47 &lt;211&gt; 1500 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

126

EP-2132228B1EN &lt;400&gt;47 aagcttgccg ccalggaagc cccagcgcag cttctcttcc tcctgctact ctggctccca 60 gataccaccg gagaaattgt gttgacacag tctccagcca ccctgtcttt gtctccaggc 120 gaaagagcca ccctctcctg ccgagcaagt gaaaatgttt acagctactt agcctggtac 180 caacagaaac ctggccaggc tcctaggctc ctcatctatt ttgcaaaaac cttagcagaa 240 ggaattccag ccaggttcag tggcagtgga tccgggacag acttcactct caccatcagc 300 agcctagagc ctgaagattt tgcagtttat tactgtcaac atcattccga taatccgtgg 360 acattcggcc aagggaccaa ggtggaaatc aaaggtggcg gcggctcggg cggtggtgga 420 tctggaggag gtgggaccgg tgaggtgcag ctggtgcagt ctggagcaga ggtgaaaaag 480 cccggagagt ctctgaagat ttcctgtaag ggatccggtt actcattcac tggctacaat 540 atgaactggg tgcgccagat gcccgggaaa ggcctcgagt ggatgggcaa tattgatcct 600 tattatggtg gtactaccta caaccggaag ttcaagggcc aggtcactat ctccgccgac 660 aagtccatca gcaccgccta cctgcaatgg agcagcctga aggcctcgga caccgccatg 720 tattactgtgcacgctcagt cggccctttc gactactggg gccagggcac cctggtcact 780 gtctcctctg atcaggagcc caaatcttct gacaaaactc acacatctcc accgtgccca 840 gcacctgaac tcctgggtgg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 900 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 960 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1140 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1200 aaccaggtca gcctgacctg cctgglcaaa 1260 ggcttctatc caagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1320 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1380 aacgtcttct catgctccgt gatgcatgag 1440 gctctgcaca accactacacgcagaagagc ctctccctgt ctccgggtaa atgatctaga 1500 &lt;210&gt; 48 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 48

127

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Thr Gly Glu

128

EP-2132228B1PL

130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

129

EP-2132228B1PL

355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Leu Cheese Ser Pro Gly Lys 485 490 &lt;210&gt; 49 &lt;400&gt; 49,000 &lt;210&gt; 50 &lt;400&gt; 50,000 &lt;210&gt; 51 &lt;211&gt; 1381 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 51 aagcttgccg ccatggaagc cccagcgcag cttctcttcc tcctgctact ctggctccca 60 gataccaccg gagaaattgt gttgacacag tctccagcca ccctgtcttt gtctccaggc 120

130

EP-2132228B1PL gaaagagcca ccctctcctg ccgagcaagt gaaaatgttt acagctactt agcctggtac 180 caacagaaac ctggccaggc tcctaggctc ctcatctatt ttgcaaaaac cttagcagaa 240 ggaattccag ccaggttcag tggcagtgga tccgggacag acttcactct caccatcagc 300 agcctagagc ctgaagaltt tgcagtttat tactgtcaac atcattccga taatccgtgg 360 acattcggcc aagggaccaa ggtggaaatc aaaggtggcg gtggctcggg cggtggtgga 420 tctggaggag gtgggaccgg tgaggtgcag ctggtgcagt clggagcaga ggtgaaaaag 480 cccggagagt ctctgaagat ttcctgtaag ggatccggtt actcattcac tggctacaat 540 atgaactggg tgcgccagat gcccgggaaa ggcctcgagt ggatgggcaa tattgatcct 600 tattatggtg gtactaccta caaccggaag ttcaagggcc aggtcactat ctccgccgac 660 aagtccatca gcaccgccta cctgcaatgg agcagcctga aggcctcgga caccgccatg 720 tattactgtg cacgctcagt cggccctttc gactcctggg gccagggcac cctggtcact 780 gtctcctctg atcaggagcc caaatcttct acacatctcc accgtgccca 840 gacaaaactcgcacctgaac tcctgggtgg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 900 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 960 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1140 cocatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1200 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 1260 ggcttctatc caagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1320 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc 1380 a 1381 &lt;210&gt; 52 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 52

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

131

EP-2132228B1PL

10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala

132

EP-2132228B1PL

225 230 235 240

Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gin Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Giy 435 440 445

Ser Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin

450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 53 &lt;400&gt; 53

000 &lt;210&gt; 54 &lt;400&gt; 54,000

133

EP-2132228B1EN &lt;210&gt; 55 &lt;400&gt; 55

000 &lt;210&gt; 56 &lt;400&gt; 56

000 &lt;210&gt; 57 &lt;400&gt; 57

000 &lt;210&gt; 58 &lt;400&gt; 58

000 &lt;210&gt; 59 &lt;400&gt; 59

000 &lt;210&gt; 60 &lt;400&gt; 60

000 &lt;210&gt; 61 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 61

Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala 1 5 10 &lt;210&gt; 62 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 62

Arg Thr Ser Glu Asn Val Tyr Ser Tyr Leu Ala 1 5 10 &lt;210&gt; 63 &lt;211&gt; 5 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 63

Gly Tyr Mel Asn Met 1 5 &lt;210&gt; 64 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 64

Phe Ala Lys Thr Leu Ala Glu 1 5 &amp; lt; 210 &amp; gt; 65 &amp; lt; 211 &amp; gt; 17

134

EP-2132228B1EN &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 65

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 15 10 15

Gly &lt;210&gt; 66 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 66

Gin His His Cheese Asp Asn Pro Trp Thr 1 5 &lt;210&gt; 67 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 67

Ser Val Gly Pro Phe Asp Tyr 1 5 &lt;210&gt; 68 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 68

Ser Val Gly Pro Phe Asp Ser 1 5 &lt;210&gt; 69 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 69

Ser Val Gly Pro Met Asp Tyr 1 5 &lt;210&gt; 70 &lt;400&gt; 70

000 &lt;210&gt; 71 &lt;400&gt; 71

000 &lt;210&gt; 72 &lt;400&gt; 72

000

135

EP-2132228B1EN &lt;210&gt; 73 &lt;400&gt; 73

000 &lt;210&gt; 74 &lt;400&gt; 74

000 &lt;210&gt; 75 &lt;400&gt; 75

000 &lt;210&gt; 76 &lt;400&gt; 76

000 &lt;210&gt; 77 &lt;400&gt; 77

000 &lt;210&gt; 78 &lt;400&gt; 78

000 &lt;210&gt; 79 &lt;211&gt; 1500 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 79

136

EP-2132228B1PL aagcttgccg ccatggaagc cccagcgcag cttctcttcc tcctgctact ctggctccca 60 gataccaccg Gagaa attgt gttgacacag tctccagcca ccctgtcttt gtctccaggc 120 gaaagagcca ccctctcctg ccgagcaagt gaaaatgttt acagctactt agcctggtac 180 caacagaaac ctggccaggc tcctaggctc ctcatctatt ttgcaaaaac cttagcagaa 240 ggaattccag ccaggttcag tggcagtgga tccgggacag acttcactct caccatcagc 300 agcctagagc ctgaagattt tgcagtttat tactgtcaac atcattccga taatccgtgg 360 acattcggcc aagggaccaa ggtggaaatc aaaggtggcg gtggctcggg cggtggtgga 420 tctggaggag gtgggaccgg tgaggtgcag ctggtgcagt ctggagcaga ggtgaaaaag 480 cccggagagt ctctgaagat ttcctgtaag ggatccggtt actcattcac tggctacaat 540 atgaactggg tgcgccagat gcccgggaaa ggcctcgagt ggatgggcaa tattgatcct 600 tattatggtg gtactaecta caaccggaag ttcaagggcc aggtcactat ctccgccgac 660 aagtccatca gcaccgccta cctgcaatgg agcagcctga aggcctcgga caccgccatg 720lattactgtg cacgctcagt cggccctttc gacctctggg gcagaggcac cclggtcact 780 gtctcctctg atcaggagcc caaatcttct gacaaaactc acacatctcc accgtgccca 840 gcacctgaac tcctgggtgg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 900 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 960 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1140 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1200 aaccaggtca gcctgacctg cctggtcaaa 1260 ggcttctatc caagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1320 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1380 aacgtcttct catgctccgt gatgcatgag 1440 gctctgcacaaccactacac gcagaagagc ctctccctgt ctccgggtaa atgatctaga 1500 &lt;210&gt; 80 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 80

137

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu ThrGIn Ser Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

138

EP-2132228B1PL

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

139

EP-2132228B1PL

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Leu Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 81 &lt;211&gt; 1494 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt;81 aagcttgccg ccatggaagc cccagctcag cttotcttcc tcctgctact ctggctccca 60 gataccaccg gagaaattgt gttgacacag tctccagcca ccctgtcttt gtctccaggc 120 gaaagagcca ccctctcctg ccgagcaagt gaaaatgttt acagctactt agcctggtac 180 caacagaaac ctggccaggc tcctaggctc ctcatctatt ttgcaaaaac cttagcagaa 240 ggaattccag ccaggttcag tggcagtgga tccgggacag acttcactct caccalcagc 300 agcctagagc ctgaagattt tgcagtttat tactgtcaac alcattccga taatccgtgg 360 acattcggcc aagggaccaa ggtggaaatc aaaggtggcg gtggctcggg cggtggtgga 420 tctggaggag gtggggctag cgaggtgcag ctggtgcagt ctggagcaga ggtgaaaaag 480 cccggagagt ctctgaagat ttcctgtaag ggatccggtt actcattcac tagctacaat 540 atgaactggg tgcgccagat gcccgggaaa ggcctggagt ggatgggcaa tattgatcct 600 tattatggtg gtactaacta cgcccagaag ttccagggcc aggtcactat ctccgccgac 660 aagtccatca gcaccgccta cctgcaatgg agcagcctga aggcctcgga caccgccatg 720 tattactgtgcacgctcagt cggccctatg gactactggg gccgcggcac cctggtcact 780 gtctcctctg atcaggagcc caaatcttct gacaaaactc acacatctcc accgtgccca 840

140

EP-2132228B1PL gcacctgaac tcctgggtgg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 900 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacglgag ccacgaagac 960 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1140 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1200 ctgcccccat cccgggatga gctgaccaag aaccaggtca gcctgacctg cctggtcaaa 1260 ggcttctatc caagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1320 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1380 aacgtcttct catgctccgt gatgcatgag 1440 gctctgcaca accactacac gca gaagagc ctctccctgt ctccgggtaa atga 1494 &lt;210&gt; 82 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 82

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

141

EP-2132228B1PL

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 150

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Cheese Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Asn Tyr Ala Gin Lys Phe Gin 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Va! Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

142

EP-2132228B1PL

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 360

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Ser Phe Phe Leu Tyr Cheese Lys Leu Thr Va! Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 83 &lt;211&gt; 1476 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 83 aagcttgccg ccatggaagc cccagcgcag ctlctcttcc tcctgctact ctggctccca 60

143

EP-2132228B1PL gataccaccg gagaaattgt gttgacacag tctccagcca ccctgtcttt gtctccaggc 120 gaaagagcca ccctctcctg ccgagcaagt gagaatgttt acagctactt agcctggtac 180 caacagaaac ctggccaggc tccłaggctc ctcatctatt ttgcaaaaac cttagcagaa 240 gggattccag ccagattcag tggcagtggt tccgggacag acttcactct caccatcagc 300 agcctagagc ctgaagattt tgcagtttat tactgtcaac atcattccga taatccgtgg 360 acattcggcc aagggaccaa ggtggaaatc aaaggtggcg gtggctcggg cggtggtgga 420 tctggaggag gtgggagcgg aggaggagct agcgaggtgc agctggtgca gtctggagca 480 gaggtgaaaa agcccggaga gtctctgaag atttcctgta agggatccgg ttactcattc 540 actggctaca atatgaactg ggtgcgccag atgcccggga aaggcctcga atggatgggc 600 aatattgatc cttattatgg tggtactacc tacaaccgga agttcaaggg ccaggtcact 660 atctccgccg acaagtccat cagcaccgcc tacctgcaag gagcagcctg aaggcctcgg 720 acaccgccat gtattactgt gcacgctcag tcggcccttt cgactcctgg ggccagggca 780ccctggtcac tgtdcgagt tgtccaccgt gcccagcacc tgaactcctg ggtggaccgt 840 cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg acccctgagg 900 tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc aactggtacg 960 tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag tacaacagca 1020 cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt 1080 acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc atctccaaag 1140 ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg gatgagctga 1200 ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatccaagc gacatcgccg 1260 tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct cccgtgctgg 1320 actccgacgg clccttcttc ctctacagca agctcaccgt ggacaagagc aggtggcagc 1380 aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac tacacgcaga 1440 agagcclctc cctgtctccg ggtaaatgac TCTAGA 1476 &lt;210&gt; 84 &lt;211&gt; 485 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 84

144

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 130 135 140

Gly Ala Ser Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys 145 150 155 160

Pro Gly Glu Leu Cheese Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe 165 170 175

Thr Gly Tyr Aso Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu 180 185 190

Glu Trp Met Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn 195 200 205

145

EP-2132228B1PL

Arg Lys Phe Lys Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser 210 215 220

Thr Ala Tyr Leu Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Ala Met 225 230 235 240

Tyr Tyr Cys Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gin Gly 245 250 255

Thr Leu Val Thr Val Ser Ser Cys Pro Pro Cys Pro Ala Pro Glu Leu 260 265 270

Leu Gly Gly Pro Cheese Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 275 280 285

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Val Val 290 295 300

Ser His Glu Asp Pro Glu Vai Lys Phe Asn Trp Tyr Val Asp Gly Val 305 310 315 320

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Cheese 325 330 335

Thr Tyr Arg Val Val Val Val Thu Val Leu His Gin Asp Trp Leu 340 345 350

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 355 360 365

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro 370 375 380

Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin 385 390 395 400

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cheese Asp Ile Ala 405 410 415

Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr 420 425 430

Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu Tyr Cheese Lys Leu 435 440 445

Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser 450 455 460

Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Cheese 465 470 475 480

Leu Ser Pro Gly Lys 485 &lt;210&gt; 85 &lt;211&gt; 1494

146

EP-2132228B1EN &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt;85 aagcttgccg ccatggaagc cccagctcag cttctcttcc tcctgctact ctggctccca 60 gataccaccg gagaaattgt gttgacacag tctccagcca ccctgtcttt gtctccaggc 120 gaaagagcca ccctctcctg ccgaacaagt gaaaatgttt acagctactt agcctggtac 180 caacagaaac ctggccaggc tcctaggctc ctcatctatt ttgcaaaaac cttagcagaa 240 ggaattccag ccaggttcag tggcagtgga tccgggacag acttcactct caccatcagc 300 agcctagagc ctgaagattt tgcagtttat tactgtcaac atcattccga taatccgtgg 360 acattcggcc aagggaccaa ggtggaaatc aaaggtggcg gtggctcggg cggtggtgga 420 tctggaggag gtgggaccgg tgaggtgcag ctggtgcagt ctggagcaga ggtgaaaaag 480 cccggagagt ctctgaagat ttcctgtaag ggatccggtt actcattcac tggctacaat 540 atgaactggg tgcgccagat gcccgggaaa ggcctggagt ggatgggcaa tattgatcct 600 tattatggtg gtactaccta caaccggaag ttcaagggcc aggtcactat ctccgccgac 660 aagtccatca gcaccgccta cctgcaatgg agcagcctga aggcctcgga caccgccatg 720 tattactgtgcacgctcagt cggccctatg gactactggg gccgcggcac cctggtcact 780 gtctcctctg atcaggagcc caaatcttct gacaaaactc acacatctcc accgtgccca 840 gcacctgaac tcctgggtgg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 900 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 960 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1140 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1200 aaccaggtca gcctgacctg cctggtcaaa 1260 ggcttctatc caagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1320 tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1380 aacgtcttct catgctccgt gatgcatgag 1440 gctctgcaca accactacacgcagaagagc ctctccctgt ctccgggtaa atga 1494 &lt;210&gt; 86 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 86

147

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Vai Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

148

EP-2132228B1PL

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Va! Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 87 &lt;211&gt; 1494 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 87 aagcttgccg ccatggaagc cccagctcag cttctcltcc tcctgctact ctggctccca 60 gataccaccg gtgaaattgt gttgacacag tctccagcca ccctgtcttt gtctccaggc 120 gaaagagcca ccctctcctg ccgaacaagt gaaaatgttt acagctactt agcctggtac 180

149

EP-2132228B1PL caacagaaac ctggccaggc tcctaggctc ctcatctatt ttgcaaaaac cttagcagaa 240 ggaattccag ccaggttcag tggcagtgga tccgggacag acttcactct caccatcagc 300 agcctagagc ctgaagattt tgcagtttat tactgtcaac atcattccga taatccgtgg 360 acattcggcc aagggaccaa ggtggaaatc aaaggtggcg gtggctcggg cggtggtgga 420 tctggaggag gtggggctag cgaggtgcag ctggtgcagt ctggagcaga ggtgaaaaag 480 cccggagagt ctctg aggat ttcctgtaag ggatccggtt actcattcac tggctacaat 540 atgaactggg tgcgccagat gcccgggaaa ggcctggagt ggatgggcaa tattgatcct 600 tattatggtg gtactaccta caaccggaag ttcaagggcc aggtcactat ctccgccgac 660 aagtccatca gcaccgccta cctgcaatgg agcagcctga aggcctcgga caccgccatg 720 tattactgtg cacgctcagt cggccctatg gactactggg gccgcggcac cctggtcact 780 gtctcctctg atcaggagcc caaatcttct gacaaaactc acacatctcc accgtgccca 840 gcacctgaac tcctgggtgg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 900ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 960 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 1140 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 1200 ctgcccccat cccgggatga gclgaccaag aaccaggtca gcctgacctg cctggtcaaa 1260 ggcttctatc caagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 1320 tacaagacca cgcctcccgt gctggactcc gacggctcct tctlcctcta cagcaagctc 1380 accglggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcałgag 1440 gctctgcaca accactacac gcagaagagc ctctccctgt ctccgggtaa atga 1494 &lt;210&gt; 88 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 88

150

EP-2132228B1PL

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 50 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala 65 70 75 80

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Ser 145 150 155 160

Leu Arg Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr Asn 165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

151

EP-2132228B1PL

Gin Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala 225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr 245 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser 260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 325 330 335

Pro Arg Glu Glu Gin Tyr Asn SerThrTyrArg Val Val Ser Val Leu 340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys 370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin 450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 465 470 475 480

His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 &lt;210&gt; 89 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 89 gagcccaaat cttgtgacaa aactcacaca tgtccaccgt gccca 45

152

EP-2132228B1EN &lt;210&gt; 90 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 90

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 15 10 15 &lt;210&gt; 91 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 91 gagcccaaat cttctgacaa aactcacaca tgtccaccgt gccca &lt;210&gt; 92 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 92

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 15 10 15 &lt;210&gt; 93 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 93 gagcccaaat cttctgacaa aactcacaca tgtccaccgt gctca &lt;210&gt; 94 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 94

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Ser 15 10 15 &lt;210&gt; 95 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 95 gagcccaaat cttgtgacaa aactcacaca tgtccaccga gctca &lt;210&gt; 96 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial s ekvention

153

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 96

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Ser Ser 15 10 15 &lt;210&gt; 97 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 97 45 gagcccaaat cttctgacaa aactcacaca tctccaccga gccca &lt;210&gt; 98 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 98

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro 15 10 15 &lt;210&gt; 99 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 99 gagcccaaat cttctgacaa aactcacaca tctccaccga gctca &lt;210&gt; 100 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 100

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Ser 15 10 15 &lt;210&gt; 101 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 101 gagcccaaat cttgtgacaa aactcacaca tctccaccgt gccca &lt;210&gt; 102 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 102

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Pro Ser Pro Cys Pro 15 10 15

154

EP-2132228B1EN &lt;210&gt; 103 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 103 gagcccaaat cttgtgacaa aactcacaca tctccaccgt gctca &lt;210&gt; 104 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 104

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Cys Ser 15 10 15 &lt;210&gt; 105 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 105 gagcccaaat cttctgacaa aactcacaca tctccaccgt gccca &lt;210&gt; 106 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 106

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Cys Pro 15 10 15 &lt;210&gt; 107 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 107 gagcccaaat cttctgacaa aactcacaca tctccaccgt gctca &lt;210&gt; 108 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 108

Glu Pro Lys Ser Series Asp Lys Thr His Thr Ser Pro Pro Cys Ser 15 10 15 &lt;210&gt; 109 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence

155

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 109 gagcccaaat cttgtgacaa aactcacaca tctccaccga gccca 45 &lt;210&gt; 110 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 110

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Pro Ser Pro Ser Pro 15 10 15 &lt;210&gt; 111 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 111 gagcccaaat cttgtgacaa aactcacaca tctccaccga gctca 45 &lt;210&gt; 112 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 112

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Ser Pro Pro Ser Ser 15 15 &lt;210&gt; 113 &lt;400&gt; 113

000 &lt;210&gt; 114 &lt;400&gt; 114

000 &lt;210&gt; 115 &lt;211&gt; 19 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 115

Val Pro Cheese Thr Pro Pro Thr Pro Cheese Pro Thr Pro Pro Pro Thr Pro 15 10 15

Ser Pro Ser &lt;210&gt; 116 &lt;211&gt; 6 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region

156

EP-2132228B1EN &lt;400&gt; 116

Val Pro Pro Pro Pro Pro 1 5 &lt;210&gt; 117 &lt;211&gt; 186 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 117 gagctcaaaa ctcctctcgg ggatacgacc catacgtgtc cccgctgtcc tgaaccgaag 60 tcctgcgata cgcctccgcc atgtccacgg tgcccagagc ccaaatcatg cgatacgccc 120 ccaccgtgtc cccgctgtcc tgaaccaaag tcatgcgata ccccaccacc atgtccaaga 180 tgccca 186 &lt;210&gt; 118 &lt;211&gt; 62 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt; 220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 118

Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro Arg Cys 15 10 15

Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 20 25 30

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro Glu 35 40 45

Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 50 55 60 &lt;210&gt; 119 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 119 gagcccaaat cttctgacac acctccccca tgcccacggt gcccc 45 &lt;210&gt; 120 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 120

Glu Pro Lys Ser Ser Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 15 10 15 &lt;210&gt; 121 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence

157

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 121 gagcccaaat cttgtgacac acctccccca tccccacggt cccca &lt;210&gt; 122 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 122

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Ser Pro Arg Ser Pro 15 10 15 &lt;210&gt; 123 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 123 gagcccaaat cttctgacac acctccccca tccccacggt cccca &lt;210&gt; 124 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 124

Glu Pro Lys Ser Ser Asp Aspreme Pro Pro Pro Pro Arg Ser Pro 15 10 15 &lt;210&gt; 125 &lt;211&gt; 45 &lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 125 gagcccaaat cttgtgacac acctccccca tccccacggt gccca &lt;210&gt; 126 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 126

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Ser Pro Arg Cys Pro 15 10 15 &lt;210&gt; 127 &lt;211&gt; 58 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 127

158

EP-2132228B1PL

Glu Ser Pro Lys Ala Gin Ala Ser Ser Val Pro Thr Ala Gin Pro Gin 15 10 15

Ala Glu Gly Leu Ser Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg 20 25 30

Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys Glu 35 40 45

Glu Gin Glu Glu Arg Glu Thr Lys Thr Pro 50 55 &lt;210&gt; 128 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 128

Arg Thr Ser Gin Asn Val Tyr Cheese Tyr Leu Ala 1 5 10 &lt;210&gt; 129 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 129

Arg Thr Ser Glu Ser Val Tyr Ser Tyr Leu Ala 1 5 10 &lt;210&gt; 130 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 130

Arg Ala Ser Gin Cheese Val Tyr Cheese Tyr Leu Ala 1 5 10 &lt;210&gt; 131 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 131

Arg Ala Ser Gin Cheese Val Ser Ser Tyr Leu Ala 1 5 10 &lt;210&gt; 132 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 132

159

EP-2132228B1PL

Arg Ala Ser Gin Ser Val Ser Tyr Tyr Leu Ala 1 5 10 &lt;210&gt; 133 &lt;211&gt; 5 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 133

Cheese Tyr Met Asn Met 1 5 &lt;210&gt; 134 &lt;211&gt; 5 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 134

Cheese Tyr Trp Ile Gly 1 5 &lt;210&gt; 135 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 135

Ala Ala Ser Ser Leu Gin Ser 1 5 &lt;210&gt; 136 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 136

Gly Ala Ser Thr Arg Ala Thr 1 5 &lt;210&gt; 137 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 137

Asp Ala Ser Asn Arg Ala Thr 1 5 &lt;210&gt; 138 &lt;211&gt; 17 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR

160

EP-2132228B1EN &lt;400&gt; 138

How Much Does Tire Pro Gly Asp Ser Asp Thr Arg Tire Ser Pro Cheese Phe Gin 15 10 15

Gly &lt;210&gt; 139 &lt;211&gt; 17 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 139

Arg Asp Ast Cheese Asp Ser Tyr Thr Asn Tyr Cheese Pro Cheese Phe Gin 15 10 15

Gly &lt;210&gt; 140 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 140

Gin Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 &lt;210&gt; 141 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 141

Gin Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Cheese 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser 20 25 30 &lt;210&gt; 142 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 142

Gin Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Cheese 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser 20 25 30

161

EP-2132228B1EN &lt;210&gt; 143 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 143

G! U Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Pro Gly Ala 15 10 15

Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr 20 25 30 &lt;210&gt; 144 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 144

Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Pro Gly Glu 15 10 15

Leu Cheese Lys Ile Ser Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr 20 25 30 &lt;210&gt; 145 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 145

Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Pro Gly Glu 15 10 15

Cheese Leu Arg Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr 20 25 30 &lt;210&gt; 146 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 146

Gin Val Gin Leu Val Gin Cheese Gly Cheese Glu Leu Lys Lys Pro Gly Ala 15 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 &lt;210&gt; 147 &lt;211&gt; 14 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region

162

EP-2132228B1EN &lt;400&gt; 147

Trp Val Arg Gin Ala Pro Gly Gin Gly Leu Glu Trp Met Gly 1 5 10 &lt;210&gt; 148 &lt;400&gt; 148

000 &lt;210&gt; 149 &lt;400&gt; 149

000 &lt;210&gt; 150 &lt;211&gt; 14 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 150

Trp Val Gin Gin Ala Pro Gly Lys Gly Leu Glu Trp Met Gly 1 5 10 &lt;210&gt; 151 &lt;211&gt; 14 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 151

Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 1 5 10 &lt;210&gt; 152 &lt;400&gt; 152

000 &lt;210&gt; 153 &lt;400&gt; 153

000 &lt;210&gt; 154 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 154

Ara Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr M et Glu 15 10 15

Leu Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 &lt;210&gt; 155 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Frame region

163

EP-2132228B1EN &lt;400&gt; 155

Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu

10 15

Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 &lt;210&gt; 156 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 156

Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Mei Glu 15 10 15

Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 &lt;210&gt; 157 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 157

Arg Val Thr Ile Thr Ala AspThr SerThrAspThrAla Tyr Met Glu 15 10 15

Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr 20 25 30 &lt;210&gt; 158 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 158

Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gin 15 10 15

Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg 20 25 30 &lt;210&gt; 159 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 159

His Val Thr Ile Ser Al Asp Lys Ser Ile Ser Thr Al Tyr Leu Gin 15 10 15

Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg 20 25 30

164

EP-2132228B1EN &lt;210&gt; 160 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 160

Arg PheVal Phe Ser Leu Asp Thr SerVal Ser Thr Ala Tyr Leu Gin 15 10 15

Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 &lt;210&gt; 161 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 161

Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 1 5 10 &lt;210&gt; 162 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 162

Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 1 5 10 &lt;210&gt; 163 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 163

Trp Gly Gin Gly Thr Met Val Thr Val Ser Ser 1 5 10 &lt;210&gt; 164 &lt;400&gt; 164

000 &lt;210&gt; 165 &lt;400&gt; 165

000 &lt;210&gt; 166 &lt;400&gt; 166

000 &lt;210&gt; 167 &lt;400&gt; 167

000 &lt;210&gt; 168 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence

165

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 168

Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser 1 5 10 &lt;210&gt; 169 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 169

Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser 1 5 10 &lt;210&gt; 170 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 170

Glu Ile Va1 Met Thr Gin Ser Pro Ala Thr Leu SerVal Ser Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys 20 &lt;210&gt; 171 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 171

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly 15 10 15

Glu Arg Ala Thr Leu Ser Cys 20 &lt;210&gt; 172 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 172

Asp Ile Gin Met Thr Gin Cheese Pro Ser Ser Leu Cheese Ala Cheese Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys 20 &amp; lt; 210 &amp; gt; 173 &amp; lt; 400 &amp; gt; 173,000

166

EP-2132228B1EN &lt;210&gt; 174 &lt;400&gt; 174

000 &lt;210&gt; 175 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 175

Asn Ile Gin Met Thr. Gin. Cheese. Pro. Ser. Al Ser. Cheese. Cheese Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys 20 &amp; lt; 210 &amp; gt; 176 &amp; lt; 400 &amp; gt; 176

000 &lt;210&gt; 177 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 177

Ala Ile Gin Leu Thr Gin Cheese Pro Cheese Cheese Leu Cheese Ala Cheese Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys 20 &lt;210&gt; 178 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 178

Asp Ile Gin Leu Thr Gin Cheese Pro Cheese Phe Leu Cheese Ala Cheese Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys &lt;210&gt; 179 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region

167

EP-2132228B1EN &lt;400&gt; 179

Ala Ile Arg Met Thr Gin Cheese Pro Phe Cheese Leu Cheese Ala Cheese Val Gly

10 15

Asp Arg Val Thr Ile Thr Cys 20 &lt;210&gt; 180 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 180

Ala Ile Gin Met Thr Gin Cheese Pro Cheese Cheese Leu Cheese Ala Cheese Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys 20 &lt;210&gt; 181 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 181

Asp Ile Gin Met Thr. Gin. Ser Pro. Ser. Thr Leu. Ser. Ala Cheese. Val Gly 15 10 15

Asp Arg Val Thr Ile Thr Cys 20 &lt;210&gt; 182 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 182

Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile Tyr 15 10 15 &lt;210&gt; 183 &lt;400&gt; 183

000 &lt;210&gt; 184 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 184

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 15 10 15 &lt;210&gt; 185 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence

168

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 185

Trp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr 15 10 15 &lt;210&gt; 186 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 186

Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr 15 10 15 &lt;210&gt; 187 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 187

Trp Phe Gin Gin Lys Pro Gly Lys Val Pro Lys His Leu Ile Tyr 15 10 15 &lt;210&gt; 188 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 188

Trp Phe Gin Gin Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile Tyr 15 10 15 &lt;210&gt; 189 &lt;400&gt; 189

000 &lt;210&gt; 190 &lt;400&gt; 190

000 &lt;210&gt; 191 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 191

Trp Tyr Gin Gin Lys Pro Ala Lys Ala Pro Lys Leu Phe Ile Tyr 15 10 15 &lt;210&gt; 192 &lt;400&gt; 192

000 &lt;210&gt; 193 &lt;400&gt; 193

000

169

EP-2132228B1EN &lt;210&gt; 194 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 194

Gly Ile Pro Ala Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Glu Phe Thr 15 10 15

Leu Thr Ile Ser Ser Leu Gin Ser Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 &lt;210&gt; 195 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 195

Gly Ile Pro Ala Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr 15 10 15

Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 20 25 30 &lt;210&gt; 196 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 196

Gly Val Pro Ser Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr 15 10 15

Leu Thr Ile Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 &lt;210&gt; 197 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 197

Gly Val Pro Ser Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr 15 10 15

Leu Thr Ile Ser Ser Leu Gin Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 30 &lt;210&gt; 198 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region

170

EP-2132228B1EN &lt;400&gt; 198

Gly Val Pro Ser Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Glu Phe Thr 15 10 15

Leu Thr Ile Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 &lt;210&gt; 199 &lt;400&gt; 199

000 &lt;210&gt; 200 &lt;400&gt; 200

000 &lt;210&gt; 201 &lt;400&gt; 201

000 &lt;210&gt; 202 &lt;400&gt; 202

000 &lt;210&gt; 203 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 203

Gly Val Pro Ser Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Tyr Thr 15 10 15

Leu Thr Ile Ser Ser Leu Gin Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 &lt;210&gt; 204 &lt;400&gt; 204

000 &lt;210&gt; 205 &lt;211&gt; 32 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 205

Gly Val Pro Ser Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Glu Phe Thr 15 10 15

Leu Thr Ile Ser Ser Leu Gin Pro Asp Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 &lt;210&gt; 206 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 206

Phe Gly Gin Gly Thr Lys Val Glu Ile Lys

5 10

171

EP-2132228B1EN &lt;210&gt; 207 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 207

Phe Gly Gin Gly Thr Lys Leu Glu Ile Lys 1 5 10 &lt;210&gt; 208 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 208

Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 1 5 10 &lt;210&gt; 209 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 209

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 1 5 10 &lt;210&gt; 210 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Frame region &lt;400&gt; 210

Phe Gly Gin Gly Thr Arg Leu Glu Ile Lys

5 10 &lt;210&gt; 211 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 211

Ser Val Gly Pro Met Asp Tyr 1 5 &lt;210&gt; 212 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR

172

EP-2132228B1EN &lt;400&gt; 212

Ser Val Gly Pro Phe Asp Tyr 1 5 &lt;210&gt; 213 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 213 Val Gly Pro Met Met Val Val 1 5 &lt;210&gt; 214 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 214

<img file="PL2132228T3_D0001.tif" />

5 &lt;210&gt; 215 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 215

Ser Val Gly Pro Phe Asp Pro 1 5 &lt;210&gt; 216 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 216

Cheese Va! Gly Pro Phe Gin His 1 5 &lt;210&gt; 217 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 217

Ser Val Gly Pro Phe Asp Val 1 5 &lt;210&gt; 218 &lt;211&gt; 7

173

EP-2132228B1EN &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 218

Cheese Val Gly Pro Phe Asp Ile

5 &lt;210&gt; 219 &lt;211&gt; 7 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 219

Ser Val Gly Pro Phe Asp Leu 1 5 &lt;210&gt; 220 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CDR &lt;400&gt; 220

Gin His His Ser Asp Aspect Pro Trp Thr 1 5 &lt;210&gt; 221 &lt;211&gt; 1530 &lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Protein-specific binding CD37 &lt;400&gt; 221 aagcttgccg ccatggaagc cccagctcag cttctcttcc tcctgctact ctggctccca 60 gataccaccg gagaggtgca gctggtgcag tctggagcag aggtgaaaaa gcccggagag 120 tctctgaaga tttcctgtaa gggctccggt tactcattca ctggctacaa tatgaactgg 180 gtgcgccaga tgcccgggaa aggcctcgag tggatgggca atattgatcc ttattatggt 240 ggtactacct acaaccggaa gttcaagggc caggtcacta Ictccgccga caagtccatc 300 agcaccgcct acctgcaatg gagcagcctg aaggcctcgg acaccgccat gtattactgt 360 gcacgctcag tcggcccttt cgactcctgg ggccagggca ccctggtcac tgtctcctct 420 gggggtggag gctctggtgg cggtggctct ggcggaggtg gatccggtgg cggcggatct 480

174

EP-2132228B1PL ggcgggggtg gctctgaaat tgtgttgaca cagtctccag ccaccctgtc tttgtctcca 540 ggcgaaagag ccaccclctc ctgccgagca agtgaaaatg tttacagcta cttagcctgg 600 taccaacaga aacctggcca ggctcctagg ctcctcatct altttgcaaa aaccttagca 660 gaaggaattc cagccaggtt cagtggcagt ggctccggga cagacttcac tctcaccatc 720 agcagcctag agcctgaaga ttttgcagtt tattactgtc aacatcattc cgataatccg 7S0 tggacattcg gccaagggac caaggtggaa atcaaaggtg atcaggagcc caaatcttct 840 gacaaaactc acacatctcc accgtgccca gcacctgaac tcctgggtgg accgtcagtc 900 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 960 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 1020 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080 caggactggc tgaatggcaa ggagtacaag 1140 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1200gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 1260 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc caagcgacat cgccgtggag 1320 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1380 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1440 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1500 ctctccctgt ctccgggtaa atgatctaga 1530 &lt;210&gt; 222 &lt;211&gt; 503 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 222

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro

Asp Thr Thr Gly Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys

Lys Pro Gly Glu Cheese Leu Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese

175

EP-2132228B1PL

40 45

Phe Thr Gly Tyr Asn Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly 50 55 60

Leu Glu Trp Met Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr 65 70 75 80

Asn Arg Lys Phe Lys Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile 85 90 95

Cheese Thr Ala Tyr Leu Gin Trp Cheese Ser Leu Lys Aa Cheese Asp Thr Aa 100 105 110

Met Tyr Tyr Cys Aa Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gin 115 120 125

Gly Thr Leu Val Thr Val Ser Cheese Gly Gly Gly Gly Cheese Gly Gly Gly 130 135 140

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 145 150 155 160

Cheese Glu Ile Val Leu Thr Gin Cheese Pro Aa Thr Leu Cheese Leu Cheese Pro 165 170 175

Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser 180 185 190

Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu 195 200 205

How much Tyr Phe Aa Lys Thr Leu Ala Glu Gly Ile Pro Aa Arg Phe Cheese 210 215 220

Gly Cheese Gly Cheese Gly Th r Asp Phe Thr Leu Thr Ile Cheese Ser Leu Glu 225 230 235 240

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Cheese Asp Asn Pro 245 250 255

Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Asp Gin Glu

176

EP-2132228B1PL

260 265 270

Pro Lys Ser Ser Asp Lys Thr His Thr Pro Pro Pro Cys Pro Al Pro 275 280 285

Glu Leu Leu Gly Gly Pro Cheese Val Phe Leu Phe Pro Pro Lys Pro Lys 290 295 300

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 305 310 315 320

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 325 330 335

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr 340 345 350

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin Asp 355 360 365

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 370 375 380

Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg 385 390 395 400

Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 405 410 415

Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 420 425 430

Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn Tyr Lys 435 440 445

Thr Thr Pro Pro Va! Leu Asp Ser Asp Gly Cheese Phe Phe Leu Tyr Cheese 450 455 460

Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Cheese 465 470 475 480

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser

485 490 495

Leu Ser Leu Cheese Pro Gly Lys 500 &lt;210&gt; 223 &lt;211&gt; 23 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Linker sequence &lt;400&gt; 223

Met Asp Phe Gin Val Gir Ile Phe Cheese Phe Leu Leu Ile Ser Ala Ser 15 10 15

Val Ile Ile Ala Arg Gly Val &lt;210&gt; 224 &lt;211&gt; 20

177

EP-2132228B1EN &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Linker sequence &lt;400&gt; 224

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 15 10 15

Asp Thr Thr Gly &lt;210&gt; 225 &lt;211&gt; 16 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Linker sequence &lt;400&gt; 225

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gyal Ser 15 10 15 &lt;210&gt; 226 &lt;211&gt; 16 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Linker sequence &lt;400&gt; 226

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Ser 15 15 15 &lt;210&gt; 227 &lt;211&gt; 16 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Linker sequence &lt;400&gt; 227

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Ala Ser 1 5 10 15 &lt;210&gt; 228 &lt;211&gt; 16 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Linker sequence &lt;400&gt; 228

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Thr Gly 15 10 15 &lt;210&gt; 229 &lt;211&gt; 25 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Linker sequence &lt;400&gt; 229

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 15

Gly Gly Gly Cheese Gly Gly Gly Gly Cheese

25

178

EP-2132228B1EN &lt;210&gt; 230 &lt;211&gt; 5 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Sequence hinge &lt;400&gt; 230

Cys Pro Pro Cys Pro 1 5 &lt;210&gt; 231 &lt;211&gt; 16 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Sequence hinge &lt;400&gt; 231

Ser Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys Pro 15 10 15 &lt;210&gt; 232 &lt;211&gt; 17 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Sequence hinge &lt;400&gt; 232

Asp Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys 15 10 15

Pro &lt;210&gt; 233 &lt;211&gt; 17 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Sequence hinge &lt;400&gt; 233

Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys 15 10 15

Pro &lt;210&gt; 234 &lt;211&gt; 18 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Sequence hinge &lt;400&gt; 234

Gly Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro 15 10 15

Cys Pro &lt;210&gt; 235 &lt;211&gt; 18 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Sequence hinge

179

EP-2132228B1EN &lt;400&gt; 235

Gly Cheese Cheese Glu Pro Lys Cheese Cheese Asp Lys Thr His Thr Cheese Pro Pro

10 15

Cys Pro &lt;210&gt; 236 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable light chain region &lt;400&gt; 236

Asp Ile Gin Met Thr Gin Cheese Pro Ala Ser Leu Cheese Ala Cheese Val Gly 15 10 15

Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Gin Gly Lys Ser Pro Gin Leu Leu Val 35 40 45

Ser Phe Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Gin Phe Cheese Leu Lys Ile Cheese Cheese Leu Gin Pro

70 75 80

Glu Asp Ser Gly Cheese Tyr Phe Cys Gin His His Cheese Asp Asn Pro Trp

90 95

Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys

100 105 &lt;210&gt; 237 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable light chain region &lt;400&gt; 237

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly

10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Thr Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys

100 105 &lt;210&gt; 238 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable light chain region &lt;400&gt; 238

180

EP-2132228B1PL

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Lau Cheese Pro Gly 15 10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Ala Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Aa Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Aa Lys Thr Leu Ala Glu Gly Ile Pro Aa Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys

100 105 &lt;210&gt; 239 &lt;211 107 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable light chain region &lt;400&gt; 239

Glu Ile Val Leu Thr Gin Cheese Pro Ala Th r Leu Cheese Leu Cheese Pro Gly 15 10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Thr Cheese Gin Asn Val Tyr Cheese Tyr 20 25 30

Leu Aa Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Aa Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys

100 105 &lt;210&gt; 240 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable light chain region &lt;400&gt; 240

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly 15 10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Thr Cheese Glu Cheese Val Tyr Cheese Tyr 20 25 30

Leu Aa Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Aa Lys Thr Leu Ala Glu Gly Ile Pro Aa Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys

100 105 &lt;210&gt; 241 &lt;211&gt; 116 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable region of the heavy chain &lt;400&gt; 241

181

EP-2132228B1PL

Ala Val Gin Leu Gin Gin Cheese Gly Pro Glu Cheese Glu Lys Pro Gly Ala

5 10 15

Cheese Val Lys Ile Cheese Cys Lys Ala Cheese Gly Tyr Cheese Phe Thr Gly Tyr

25 30

Asn Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser Leu Glu Trp Ile 35 40 45

Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe 50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Serrahr Tyr

70 75 80

Met Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

90 95

Ala Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr Ser Val

100 105 110

Thr Val Ser Ser

115 &lt;210&gt; 242 &lt;211&gt; 116 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable region of the heavy chain &lt;400&gt; 242

Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu

10 15

Leu Cheese Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr 20 25 30

Asn Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe 50 55 60

Lys Gly Gin Vai Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

70 75 80

Leu Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Al Met Tyr Tyr Cys

90 95

Ala Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Val Ser Ser 115 &lt;210&gt; 243 &lt;211&gt; 116 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable region of the heavy chain &lt;400&gt; 243

Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu

10 15

Leu Cheese Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr 20 25 30

Asn Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe 50 55 60

Lys Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

70 75 80

Leu Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Al Met Tyr Tyr Cys

90 95

Ala Arg Ser Val Gly Pro Met Asp Val Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Val Ser Ser

115 &lt;210&gt; 244 &lt;211&gt; 116 &lt;212&gt; PRT &lt;213&gt; Artificial sequence

182

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; variable region of the heavy chain &lt;400&gt; 244

Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu

5 10 15

Leu Cheese Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr 20 25 30

Asn Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe 50 55 60

Lys Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

70 75 80

Leu Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Al Met Tyr Tyr Cys

90 95

Ala Arg Ser Val Gly Pro Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Val Ser Ser 115 &lt;210&gt; 245 &lt;211&gt; 116 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; variable region of the heavy chain &lt;400&gt; 245

Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu

10 15

Leu Cheese Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr 20 25 30

Asn Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe 50 55 60

Lys Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

70 75 80

Leu Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Al Met Tyr Tyr Cys

90 95

Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Val Ser Ser 115 &lt;210&gt; 246 &lt;211&gt; 217 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CH2 and CH3 regions of human IgG1 &lt;400&gt; 246

183

EP-2132228B1PL

Ala Pro Glu Leu Leu Gly Gly Pro Cheese Val Phe Leu Phe Pro Pro Lys

10 15

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

25 30

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60

Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His

70 75 80

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys

90 95

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin 100 105 110

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 115 120 125

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 130 135 140

Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn

145 150 155 160

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu

165 170 175

Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val

180 185 190

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin 195 200 205

Lys Ser Leu Ser Leu Cheese Pro Gly Lys 210 215 &lt;210&gt; 247 &lt;211&gt; 473 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 247

Asp Ile Gin Met Thr Gin Cheese Pro Ala Ser Leu Cheese Ala Cheese Val Gly 15 10 15

Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Val Tyr Ser Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Gin Gly Lys Ser Pro Gin Leu Leu Val 35 40 45

Phe Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Cheese Gly

184

EP-2132228B1PL

55 60

Cheese Gly Cheese Gly Thr Gin Phe Cheese Leu Lys Ile Cheese Cheese Leu Gin Pro

70 75 80

Glu Asp Ser Gly Cheese Tyr Phe Cys Gin His His Cheese Asp Asn Pro Trp

90 95

Thr Phe Gly Gly Gly Thr Glu Leu Glu Ile Lys Gly Gly Gly Gly Cheese 100 105 110

Gly Gly Gly Gly Cheese Gly Gly Gly Gly Cheese Ser Gal Val Gin Leu Gin 115 120 125

Gin Cheese Gly Pro Glu Cheese Glu Lys Pro Gly Ala Cheese Val Lys Ele Cheese 130 135 140

Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val

145 150 155 160

Lys Gin Asn Asn Gly Lys Leu Ser Glu Trp How many Gly Asn Ile Asp Pro

165 170 175

Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys Gly Lys Ala Thr

180 185 190

Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser

195,200 205

Leu Thr Ser Glu Asp Ser Al Val Tyr Tyr Cys Ala Arg Ser Val Gly

210 215 220

Pro Met Asp Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Asp 225 230 235 240

Leu Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys Pro 245 250 255

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 260 265 270

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 275 280 285

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

290 295 300

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 305 310 315 320

Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 325 330 335

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 340 345 350

Ala Leu Pro Ala Pro Ile Glu Lys Thr He Ser Lys Ala Lys Gly Gin 355 360 365

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu

370 375 380

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 385 390 395 400

Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn 405 410 415

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu 420 425 430

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val 435 440 445

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin

450 455 460

Lys Ser Leu Cheese Leu Cheese Pro Gly Lys 465 470 &lt;210&gt; 248 &lt;211&gt; 473 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

185

EP-2132228B1EN &lt;400&gt; 248

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly

10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Thr Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly

55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Cheese 100 105 110

Gly Gly Gly Gly Gly Gly Gly Gly Thr Gly Glu Val Gin Leu Val 115 120 125

Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu Cheese Leu Lys Ile Cheese

130 135 140

Cys Lys Gly Cheese Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val

145 150 155 160

Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Asn Ile Asp Pro

165 170 175

Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys Gly Gin Val Thr

180 185 190

Ile Ser Ala Asp Lys Ser Ile Ser Thr Al Tire Leu Gin Trp Cheese Ser

195,200 205

Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Ser Val Gly

210 215 220

Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Asp 225 230 235 240

Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys Pro 245 250 255

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 260 265 270

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 275 280 285

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

290 295 300

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 305 310 315 320

Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 325 330 335

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 340 345 350

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin 355 360 365

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu

370 375 380

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

385 390 395 400

Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn 405 410 415

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu 420 425 430

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val 435 440 445

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin 450 455 460

Lys Ser Leu Cheese Leu Cheese Pro Gly Lys

465 470 &lt;210&gt; 249 5 &lt;211&gt; 473 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; A CD37 specific binding protein

186

EP-2132228B1EN &lt;400&gt; 249

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly 15 10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Ala Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Aa Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Aa Lys Thr Leu Ala Glu Gly Ile Pro Aa Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Cheese 100 105 110

Gly Gly Gly Gly Gly Gly Gly Gly Thr Gly Glu Val Gin Leu Val

115 120 125

Gin Cheese Gly Aa Glu Val Lys Lys Pro Gly Glu Cheese Leu Lys Ile Cheese

130 135 140

Cys Lys Gly Cheese Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val

145 150 155 160

Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Asn Ile Asp Pro

165 170 175

Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys Gly Gin Val Thr

180 185 190

Ile Ser Aa Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gin Trp Cheese Ser

195,200 205

Leu Lys Aa Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Ser Val Gly

210 215 220

Pro Phe Asp Tyr Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Asp

225 230 235 240

Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys Pro

245, 250 255

Ala Pro Glu Leu Leu Gly Gly Pro Cheese Val Phe Leu Phe Pro Pro Lys

260 265 270

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val

275, 280,285

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

290 295 300

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 305 310 315 320

Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Va1 Leu His 325 330 335

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 340 345 350

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin 355 360 365

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu

370 375 380

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

385 390 395 400

Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn

405 410 415

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu 420 425 430

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val 435 440 445

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin

450 455 460

Lys Ser Leu Cheese Leu Cheese Pro Gly Lys 465 470 &lt;210&gt; 250 5 &lt;211&gt; 473 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 250

187

EP-2132228B1PL

Glu as Va1 Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly

10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Ala Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu He 35 40 45

Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Cheese 100 105 110

Gly Gly Gly Gly Gly Gly Gly Gly Thr Gly Glu Val Gin Leu Val 115 120 125

Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Leu Ser Lys Ile Ser 130 135 140

Cys Lys Gly Cheese Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val

145 150 155 160

Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly Asn Ile Asp Pro

165 170 175

Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys Gly Gin Val Thr

180 185 190

Ile Ser Ala Asp Lys Ser Ile Ser Thr Al Tire Leu Gin Trp Cheese Ser

195,200 205

Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Ser Val Gly

210 215 220

Pro Phe Asp Ser Trp Gly Gin Gly Thr Leu Val Thr Val Ser Cheese Asp 230 230 235 240

Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys Pro 245 250 255

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 260 265 270

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 275 280 285

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

290 295 300

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 305 310 315 320

Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 325 330 335

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 340 345 350

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin 355 360 365

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu

370 375 380

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 385 390 395 400

Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn 405 410 415

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu 420 425 430

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val 435 440 445

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin

450 455 460

Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 &lt;210&gt; 251 &lt;211&gt; 480 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 251

Ala Val Gin Leu Gin Gin Cheese Gly Pro Glu Cheese Glu Lys Pro Gly Ala

10 15

Cheese Val Lys Ile Cheese Cys Lys Ala Cheese Gly Tyr Cheese Phe Thr Gly Tyr

188

EP-2132228B1PL

25 30

Asn Met Asn Trp Val Lys Gin Asn Asn Gly Lys Ser Leu Glu Trp Ile

40 45

Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe

55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Al Tyr

70 75 80

Mel Gin Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

90 95

Ala Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Gin Gly Thr Ser Val 100 105 110

Thr Val Ser Cheese Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 115 120 125

Gly Gly Cheese Gly Gly Gly Gly Cheese Ala Ser Glu Ile Val Leu Thr Gin 130 135 140

Pro Pro Ala Thr Leu Cheese Leu Cheese Pro Gly Glu Arg Ala Thr Leu Cheese

145 150 155 160

Cys Arg Thr Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp Tyr Gin Gin

165 170 175

Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu

180 185 190

Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp

195,200 205

Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr 210 215 220

Tyr Cys Gin His His Ser Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr

225 230 235 240

Lys Val Glu Ile Lys Gly Cheese Cheese Glu Pro Lys Cheese Cheese Asp Lys Thr

245, 250 255

His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 260 265 270

Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 275 280 285

Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 290 295 300

Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala

305 310 315 320

Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val

325 330 335

Val Leu Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr

340 345 350

Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr

355 360 365

Ile Ser Lys Al Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu

370 375 380

Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys

385 390 395 400

Leu Val Lys Gly Phe Tyr Pro Cheese Asp Ile Al Val Glu Trp Glu Cheese

405 410 415

Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430

Cheese Asp Gly Cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Cheese 435 440 445

Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460

Leu His Asn His Tyr Thr Gin Lys Leu Ser Leu Cheese Pro Gly Lys

465 470 475 480 &lt;210&gt; 252 &lt;211&gt; 472 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 252

189

EP-2132228B1PL

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly

10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Thr Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Cheese 100 105 110

Gly Gly Gly Gly Cheese Gly Gly Gly Gly Ala Ser Gal Val Gin Leu Gin 115 120 125

Gin Cheese Gly Pro Glu Cheese Glu Lys Pro Gly Ala Cheese Val Lys Ile Ser 130 135 140

Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val

145 150 155 160

Lys Gin Asn Asn Gly Lys Leu Ser Glu Trp How many Gly Asn Ile Asp Pro

165 170 175

Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys Gly Lys Ala Thr

180 185 190

Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gin Leu Lys Ser 195 200 205

Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Val Gly 210 215 220

Pro Met Tyr Trp Gly Gin Gly Thr Ser Val Thr Val Ser Ser Ser

225 230 235 240

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys Pro Ala

245, 250 255

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 260 265 270

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 275 280 285

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 290 295 300

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin

305 310 315 320

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gin

325 330 335

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 340 345 350

Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro 355 360 365

Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 370 375 380

Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

385 390 395 400

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr

405 410 415

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu Tyr 420 425 430

Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe 435 440 445

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin Lys 450 455 460

Leu Ser Leu Cheese Pro Gly Lys 465 470 &lt;210&gt; 253 &lt;211&gt; 483 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 253

190

EP-2132228B1PL

Glu Val Gin Leu Val Gin Cheese Gly Ala Glu Val Lys Lys Pro Gly Glu

10 15

Leu Cheese Lys Ile Cheese Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Gly Tyr

25 30

Asn Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45

Gly Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe 50 55 60

Lys Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile SerThrAla Tyr

70 75 80

Leu Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Al Met Tyr Tyr Cys

90 95

Ala Arg Ser Val Gly Pro Phe Asp Ser Trp Gly Gin Gly Thr Leu Val 100 105 110

Thr Val Ser Cheese Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Glyn Ser Glu Ile Val 130 135 140

Leu Thr Gin Cheese Pro Ala Thr Leu Leu Ser Pro Cheese Gly Glu Arg Ala

145 150 155 160

Thr Leu Ser Cys Arg Ala Ser Glu Asn Val Tyr Ser Tyr Leu Ala Trp

165 170 175

Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile Tyr Phe Ala

180 185 190

Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly Cheese Gly Cheese

195,200 205

Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe 210 215 220

Ala Val Tyr Tyr Cys Gin His Asp Ser Asn Pro Trp Thr Phe Gly

225 230 235 240

Gin Gly Thr Lys Val Glu Ile Lys Gly Asp Gin Glu Pro Lys Ser Ser

245, 250 255

Asp Lys Thr His Thr Ser Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 260 265 270

Gly Pro Cheese Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 275 280 2B5

Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 290 295 300

Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val

305 310 315 320

His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr

325 330 335

Val Val Val Thu Val Leu, his Gin Asp Trp Leu Asn Gly

340 345 350

Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile

355 360 365

Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val

370 375 380

Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin Val Ser

385 390 395 400

Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu

405 410 415

Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 420 425 430

Val Leu Asp cheese Asp Gly cheese Phe Phe Leu Tyr Cheese Lys Leu Thr Val 435 440 445

Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 450 455 460

His Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Cheese 465 470 475 480

Pro Gly Lys &lt;210&gt; 254 &lt;211&gt; 473 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 254

191

EP-2132228B1PL

Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly

10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Ala Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala Arg Phe Cheese Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Cheese 100 105 110

Gly Gly Gly Gly Gly Gly Gly Gly Thr Gly Glu Val Gin Leu Val 115 120 125

Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Leu Ser Lys Ile Ser 130 135 140

Cys Lys Gly Cheese Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val

145 150 155 160

Arg Gin Mel Pro Gly Lys Gly Leu Glu Trp Met Gly Asn Ile Asp Pro

165 170 175

Tyr Tyr Gly Gly Thr Thr Tyr Asn Arg Lys Phe Lys Gly Gin Val Thr

180 185 190

Ile Ser Ala Asp Lys Ser Ile Ser Thr Al Tire Leu Gin Trp Cheese Ser

195,200 205

Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Ser Val Gly

210 215 220

Pro Met Asp Val Trp Gly Gin Gly Thr Thr Val Thr Val Ser Ser Asp 230 230 235 240

Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Pro Ser Pro Cys Pro 245 250 255

Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 260 265 270

Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 275 280 285

Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr

290 295 300

Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 305 310 315 320

Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 325 330 335

Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 340 345 350

Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin 355 360 365

Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu

370 375 380

Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro

385 390 395 400

Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin Pro Glu Asn Asn

405 410 415

Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Cheese Phe Phe Leu 420 425 430

Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gin Gin Gly Asn Val 435 440 445

Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gin

450 455 460

Lys Ser Leu Cheese Leu Cheese Pro Gly Lys 465 470 &lt;210&gt; 255 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 255

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Ser Pro 15 10 15 &lt;210&gt; 256 &lt;211&gt; 15

192

EP-2132228B1EN &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 256

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Ser Ser 15 10 15 &lt;210&gt; 257 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 257

Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Ser Pro 15 10 15 &lt;210&gt; 258 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 258

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro 15 10 15 &lt;210&gt; 259 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 259

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Ser Pro

10 &lt;210&gt; 260 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 260

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Ser Pro Arg Cys Pro 15 10 15 &lt;210&gt; 261 &lt;211&gt; 15 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Hinge region &lt;400&gt; 261

Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Ser Pro 15 10 15 &lt;210&gt; 262 &lt;211&gt; 493 &lt;212&gt; PRT &lt;213&gt; Artificial sequence

193

EP-2132228B1EN &lt;220&gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 262

Met Glu Ala Pro Ala Gin Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro 1 5 10 15

Asp Thr Thr Gly Glu Ile Val Leu Thr Gin Cheese Pro Ala Thr Leu Ser 20 25 30

Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Asn 35 40 45

Val Tyr Cheese Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro 5 0 55 60

Arg Leu Leu Ile Tyr Phe Ala Lys Thr Leu Ala Glu Gly Ile Pro Ala

70 75 BO

Arg Phe Cheese Gly Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese

90 95

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Cheese Gin His His Cheese 100 105 110

Asp Asn Pro Trp Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly 115 120 125

Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gali Glae Glu 130 135 140

Val Gin Leu Val Gin Gly Cheese Ala Glu Val Lys Lys Pro Gly Glu Cheese

145 150 155 160

Leu Lys Ile Ser Cys Lys Gly Cheese Gly Tyr Cheese Phe Thr Cheese Tyr Asn

165 170 175

Met Asn Trp Val Arg Gin Met Pro Gly Lys Gly Leu Glu Trp Met Gly 180 185 190

Asn Ile Asp Pro Tyr Tyr Gly Gly Thr Gly Tyr Ala Gin Lys Phe Gin 195 200 205

Gly Gin Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu 210 215 220

Gin Trp Cheese Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala

225 230 235 240

Arg Ser Val Gly Pro Met Asp Tyr Trp Gly Arg Gly Thr Leu Val Thr

245, 250 255

Val Ser Ser Asp Gin Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser

260 265 270

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 275 280 285

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 290 295 300

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

305 310 315 320

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

325 330 335

Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

340 345 350

Thr Val Leu His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

355 360 365

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Ile Glu Lys Thr Ile Ser Lys

370 375 380

Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 385 390 400

Arg Asp Glu Leu Thr Lys Asn Gin Val Ser Leu Thr Cys Leu Val Lys 405 410 415

Gly Phe Tyr Pro Cheese Asp Ile Ala Val Glu Trp Glu Cheese Asn Gly Gin 420 425 430

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 435 440 445

Ser Phe Phe Leu Tyr Cheese Lys Leu Thr Val Asp Lys Ser Arg Trp Gin

450 455 460

Gin Gly Asn Val Phe Ser Cys Ser Val Mel His Glu Ala Leu His Asn

465 470 475 480

His Tyr Thr Gin Lys Ser Leu Cheese Leu Cheese Pro Gly Lys

485 490 &lt;210&gt; 263 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 263

Glu Pro Lys Ser Cys Asp Lys Thr His Thr 1 5 10

194

EP-2132228B1EN &lt;210&gt; 264 &lt;211&gt; 4 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 264

Cys Pro Pro Cys 1 &lt;210&gt; 265 &lt;211&gt; 4 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 265 Gly Thr Cys Tyr 1 &lt;210&gt; 266 &lt;211&gt; 473 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220 &gt;

&lt;223&gt; CD37 specific binding protein &lt;400&gt; 266

Glu how much Val Leu Thr Gin Cheese Pro Ala Thr Leu Cheese Leu Cheese Pro Gly 15 10 15

Glu Arg Ala Thr Leu Cheese Cys Arg Ala Cheese Glu Asn Val Tyr Cheese Tyr

25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu Ile 35 40 45

Tyr Phe Ala Lys Thr Leu Ala Glu Gly how much Pro Ala Arg Phe Ser Gly 50 55 60

Cheese Gly Cheese Gly Thr Asp Phe Thr Leu Thr Ile Cheese Cheese Leu Glu Pro

70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gin His His Ser Asp Asn Pro Trp

90 95

Thr Phe Gly Gin Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Cheese 100 105 110

Gly Gly Gly Gly Gly Gly Gly Gly Thr Gly Glu Val Gin Leu Val 115 120 125

Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Leu Ser Lys Ile Ser 130 135 140

Cys Lys Gly Cheese Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn Trp Val

145 150 155 160