Fusion protein

The invention relates to a fusion protein, composed of mutants or variants of human interleukin-3 (hlL-3), fused to a second colony-stimulating factor (CSF), including cytokine, lymphoxine, interleukin, hematopoietic growth factor, or IL-3 variant with or without a linker, used to obtain a pharmaceutical composition, which is administered to increase the production of hematopoietic cell, in a mammal.

They are known from WO 91/02754 and WO 92/04455 fusion proteins, but do not exhibit any specific mutation. WO 91/02754 describes a fusion protein, composed of GM-CSF and IL-3, which has biological activity, increased compared to GM-CSF or to IL-3 alone. Also, non-glycosylated IL-3 and GMCSF protein analogues are described as components of the fusion. In WO 92/04455, fusion proteins composed of IL-3 fused to a lymphokine selected from the group consisting of IL-3, IL-6, IL-7, IL-9, IL-11, EPO and G-CSF are described. .

It is also known that colony-stimulating factors (CSFs), which stimulate bone marrow cell differentiation and / or proliferation, generate great interest, due to their therapeutic potential for restoring low levels of hematopoietic cells derived from the cell. breastbone. CSFs were identified in both human and murine systems and separated according to their activities. For example, CSF-granulocyte (G-CSF) and CSF-macrophage (M-CSF) stimulate the in vitro formation of neutrophil granulocyte and macrophage colonies, respectively, while GM-CSF and interleukin-3 (IL-3) have broader activities and stimulate the formation of both neutrophilic granulocyte macrophage colonies and eosinophilic granulocytes. IL-3 also stimulates the formation of mast cells, megakaryocytes and pure or mixed erythroid colonies.

Due to its ability to stimulate the proliferation of many different cell types and to support the growth and proliferation of progenitor cells, IL-3 has potential for therapeutic use in restoring hematopoietic cells, to normal amounts, in those situations where cell numbers have decreased, due to diseases or therapeutic treatments, such as irradiation and / or chemotherapy.

Interleukin-3 (IL-3) is a hematopoietic growth factor, which has the property of being able to initiate survival, growth and differentiation of hematopoietic cells. Among the biological properties of IL-3 are (a) the ability to support growth and differentiation of progenitor cells, from which all or indeed all blood cell lines are formed, (b) to interact with multipotential early stem cells; (c) to support the growth of pluripotent precursor cells, (d) to stimulate the proliferation of myelogenous, chronic (CML) leukemia cells, (e) to stimulate the proliferation of mast cells, eosinophils and basophils, (f) to stimulate DNA synthesis. of acute myelogenous leukemia (AML) cells, (g) to initiate cells to produce leukotriene and histamine, (h) to induce leukocyte chemotaxis, and (i) inducing the molecules on the surface of the cell required for attachment of the leukocyte.

Mature human interleukin-3 (hlL) -3) consists of 133 amino acids. It has a disulfide bridge and 2 potential glycosylation sites (Yang. Et al., Cell 47: 3 (1986)).

Murine IL-3 (mlL-3) was initially identified by Ihle et al., J.Immunol 126: 2184 (1981), as a factor inducing the expression of a 20-hydroxysteroid dehydrogenase enzyme associated with T cell. purified to homogeneity and has been shown to regulate the growth and differentiation of numerous subclasses of early hematopoietic and lymphoid progenitor cells.

In 1984, cDNA clones encoding murine IL-3 were isolated (Fung et al., Nature, 307: 233 (1984) and Yokota, et al., Proc. Natl. Acad. Sci. USA 81: 1070 ( 1984) The murine DNA sequence encoded a 166 amino acid polypeptide, including an initiating signal peptide.

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The gibbon IL-3 sequence was obtained, using a gibbon cDNA expression bank, 50 sequences which were subsequently used as a probe against a human genomic bank to obtain the human IL-3 sequence.

Homologues of gibbon and human genomic DNA of murine IL-3 sequence have been described by Yang et al., In Cell 47: 3 (1986). The human sequence reported by Yang et al., Included a serine residue, at position 8 of the mature protein sequence. After this discovery, others reported the isolation of Pro cDNAs⁸ hlL-3, which have proline at position 8 of the protein sequence. Thus, it appears that there may be 2 allelic forms of hlL-3.

Dorssers et al., In Gene 55: 115 (1987), found a clone from a human cDNA bank, which hybridized with mlL-3. This hybridization was the result of the high degree of homology between the non-coding regions 3 'of mlL-3 and hlL-3. This cDNA encoded for 60 hlL-3 sequences (Pro⁸).

US Patent Nos. 4877729 and US 4959454 describe human IL-3 and gibbon IL-3 cDNAs and the protein sequences they encode. The described hlL-3 has, rather, serine than proline at position 8 in the protein sequence.

Clark-Lewis, et al., Science 231: 134 (1986) performed a functional analysis of murine IL-3 analogues synthesized with an automatic peptide synthesizer. The authors concluded that, for a total activity, the stable tertiary structure of the complete molecule was required. A study of the role of disulfide bridges showed that the replacement of all 4 Cys with Ala gives a molecule with 1/500 of the activity of the native molecule. replacement of two of the Cys residues by Ala (Cys⁷⁹, Cys¹⁴⁰ - Alas⁷⁹, Allah¹⁴⁰) led to increased activity. The authors concluded that a single disulfide bridge between cysteines 17 and 80 is required in murine IL-3 to give biological activity, which approximates the physiological levels and that this structure probably stabilizes the tertiary structure of the protein to give a conformation. which is optimal for the function (Clark-Lewis, et al., in Proc. Atlantic Academy USA 85: 7897 (1988). 75

International publication WO 88/00598 describes IL-3, similar to gibbon and human-like. hlL-3 contains a replacement, namely, Ser⁸ - Pro⁸. Suggestions have been made for the replacement of Cys by Ser, thereby breaking the disulfide bridge and for replacing one or more amino acids at the glycosylation sites.

EP-A-0275598 (WO 88/04691) illustrates that Ala¹ it can be deleted, while maintaining the biological activity in 80. Several hlL-3 mutant sequences are given, for example, two double mutants, Ala¹ - Asp¹, Trp¹³ - Arg¹³ (pGB / IL-302) and Ala¹ - Asp¹, Met³ - Thr³(pGB / IL-304) and a triple Ala mutant¹ - Asp¹, Leo⁹ - Pro⁹, Trp¹³ - Arg¹³ (PGB / IL-303).

WO 88/05469 describes how deglycosylation mutants can be obtained and suggests Arg mutants⁵⁴Arg⁵⁵ and Arg¹⁰⁸Arg¹⁰⁹Lys¹¹⁰ to avoid proteolysis to expression in 85 Saccharomyces cerevisiae by KEX2 protease. No mutant protein is described, in this context, glycosylation and KEX2 protease activity are important only in yeast expression.

WO 88/06161 mentions various mutants that, theoretically, may be conformationally and antigenically neutral. The mutations obtained at present are only Met² - him² and lle¹³¹ - Leo¹³¹. No 90 is described if, for these two mutations, the envisaged neutralities were obtained.

WO 91/00350 describes non-glycosylated hlL-3 analog proteins, for example, hlL3 (Pro⁸Asp¹⁵Asp⁷⁰), MefrhulL-3 (Pro⁸Asp¹⁵Asf7⁰) Thi⁴ rhulL-3 (Prcf Asp¹⁵I | i⁰) and Thf rhuIL3 (Pro⁸Asp¹⁵Asp⁷⁰). It is claimed that these protein compositions do not exhibit certain adverse side effects, associated with native hlL-3, such as urticaria resulting from the infiltration of 95 mast cells and lymphocytes into the dermis. The described hlL-3 protein analog may have the N-terminus at Met³, Thr⁴, or Thr⁶.

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WO 90/12874 discloses variants of IL-3, which have added cysteine ​​(CAVs), which have at least one Cys residue substituted for a naturally occurring amino acid residue.

U.S. Patent No. 48,10643 discloses the DNA sequence encoding human G-CSF.

J

The problem solved by the invention is a fusion protein, which contains a multisubstituted IL-3 variant, administered to a mammal, to increase the production of hematopoietic cell.

The fusion protein, according to the invention, has the structure corresponding to formula (I): X- (L)_e-Y (I) wherein X is R₁ or R₂, Y is or R₂, L is a linker capable of binding to X and Y radicals, a is 0 or 1 and R is a human interleukin-3 mutant polypeptide having an improved activity profile of the formula

Ala Pro Met Thr Gin ThrThrSerLeu Lys Thr Ser Trp Val Asn

1015

Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

2530

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

4045

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

5560

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

7080

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

9095

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

100 105110

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

115 120125

Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala lle Phe

130135

Sequence no .: 1 in which:

Xaa at position 17 is Ser, Lys, Gly, Asp, Met, Gin or Arg;

Xaa at position 18 is Asn, His, Leo, lle, Phe, Arg or Gin;

Xaa at position 19 is Met, Phe, lle, Arg, Gly, Ala or Cys;

Xaa at position 20 is lle, Cys, Gin, Glu, Arg, Pro or Ala;

Xaa at position 21 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gin,

Asn, Thr, Ser or Val;

Xaa at position 22 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn,

Gin, Leo, Val or Gly;

Xaa at position 23 is lle, Val, Ala, Leo, Gly, Trp, Lys, Phe,

Leo, Serum or Arg;

Xaa at position 24 is lle, Gly, Val, Arg, Ser, Phe or Leo;

Xaa at position 25 is Thr, His, Gly, Gin, Arg, Pro or Ala;

Xaa at position 26 is His, Thr, Phe, Gly, Arg, Ala or Trp;

Xaa at position 27 is Leo, Gly, Arg, Thr, Ser or Ala;

Xaa at position 28 is Lys, Arg, Leu, Gin, Gly, Pro, Val or Trp;

Xaa at position 29 is Gin, Asn, Leo, Pro, Arg or Val;

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Xaa at position 30 is Pro, His, Thr, Gly, Asp, Gin, Ser, Leo or Lys;

Xaa at position 31 is Pro, Asp, Gly, Ala, Arg, Leo or Gin;

Xaa at position 32 is Val, Arg, Gin, Asn, Gly, Ala or Glu;

Xaa at position 33 is Pro, Leo, Gin, Ala, Thr or Glu;

Xaa at position 34 is Leo, Val, Gly, Ser, Lys, Glu, Gin, Thr, 150

Arg, Ala, Phe, lle or Met;

Xaa at position 35 is Leo, Ala, Gly, Asn, Pro, Gin or Val;

Xaa at position 36 is Asp, Leo or Val;

Xaa at position 37 is Phe, Ser, Pro, Trp or lle;

Xaa at position 38 is Asn or Ala; 155

Xaa at position 40 is Leo, Trp or Arg;

Xaa at position 41 is Asn, Cys, Arg, Leo, His, Met or Pro;

Xaa at position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leo

Val, Glu, Phe, Tyr, Lle, Met or Ala;

Xaa at position 43 is Glu, Asn, Tyr, Leo, Phe, Asp, Ala, Cys, Gin, Arg, Thr, Gly or Ser; 160

Xaa at position 44 is Asp, Serum, Leo, arg, Lys, Thr, Met, Trp, Glu, Asn, Gin, Ala or Pro;

Xaa at position 45 is Gin, Pro, Phe, Val, Met, Leo, Thr, Lys,

Trp, Asp, Asn, Arg, Ser, Ala, lle, Glu or His

Xaa at position 46 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Lys, His, Ala, Tyr, lle, Val or

Gly; 165

Xaa at position 47 is lle, Gly, Val, Ser, Arg, Pro or His;

Xaa at position 48 is Leo, Ser, Cys, Arg, lle, His, Phe, Glu, Lys, Thr, Ala, Met, Val or Asn;

Xaa at position 49 is Met, Arg, Ala, Gly, Pro, Asn, His or Asp;

Xaa at position 50 is Glu, Leo, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, lle, Val, His, Phe, Met or

Gin; 170

Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr or His;

Xaa at position 52 is Asn, His, Arg, Leo, Gly, Ser or Thr;

Xaa at position 53 is Leo, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Met;

Xaa at position 54 is Arg, Asp, lle, Ser, Val, Thr, Gin, Asn, Lys, His, Ala or Leu;

Xaa at position 55 is Arg, Thr, Val, Ser, Leo or Gly; 175

Xaa at position 56 is Pro, Gly, Cys, Ser, Gin, Glu, Arg, Arg, His, Thr, Ala, Tyr, Phe, Leo, Val or Lys;

Xaa at position 57 is Asn or Gly;

Xaa at position 58 is Leo, Serum, Asp, Arg, Gin, Val or Cys;

Xaa at position 59 is Glu, Tyr, His, Leo, Pro or Arg; 180

Xaa at position 60 is Ala, Ser, Pro, Tyr, Asn or Thr;

Xaa at position 61 is Phe, Asn, Glu, Pro, Lys, Arg su Ser;

Xaa at position 62 is Asn, His, Val, Arg, Pro, Thr, Asp or lle;

Xaa at position 63 is Arg, Tyr, Trp, Lys, Ser, His, Pro or Val;

Xaa at position 64 is Ala, Asn, Pro, Ser or Lys; 185

Xaa at position 65 is Val, Thr, Pro, His, Leo, Phe or Ser;

Xaa at position 66 is Lys, lle, Arg, Val, Asn, Glu or Ser;

Xaa at position 67 is Ser, Ala, Phe, Val, Gly, Asn, lle, Pro, or His

Xaa at position 68 is Leo, Val, Trp, Ser, lle, Phe, Thr or His; 190

Xaa at position 69 is Gin, Ala, Pro, Thr, Glu, Arg, Trp, Gly, or Leo;

Xaa at position 70 is Asn, Leo, Val, Trp, Pro or Ala;

Xaa at position 71 is Ala, Met, Leo, Pro, Arg, Glu, Thr, Gin, Trp or Asn;

Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn, Arg or Asp;

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Xaa at position 73 is Ala, Glu, Asp, Leo, Ser, Gly, Thr or Arg;

Xaa at position 74 is lle, Met, Thr, Pro, Arg, Gly or Ala;

Xaa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gin or Leo;

Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;

Xaa at position 77 is lle, Ser, Arg, Thr or Leo;

Xaa at position 78 is Leo, Ala, Ser, Glu, Phe, Gly or Arg;

Xaa at position 79 is Lys, Thr, Asn, Met, Arg, lle, Gly or Asp;

Xaa at position 80 is Asn, Trp, Val, Gly, Thr, Leo, Glu or Arg;

Xaa at position 81 is Leo, Gin, Gly, Ala, Trp, Arg, Val or Lys;

Xaa at position 82 is Leo, Gin, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser, Ala, Tyr, Phe, lle, Met or Val;

Xaa at position 83 is Pro, Ala, Thr, Trp, Arg or Met;

Xaa at position 84 is Cys, Glu, Gly, Arg, Met or Val;

Xaa at position 85 is Leo, Asn, Val or Gin;

Xaa at position 86 is Pro, Cys, Arg, Ala or Lys;

Xaa at position 87 is Leo, Ser, Trp or Gly;

Xaa at position 88 is Ala, Lys, Arg, Val or Trp;

Xaa at position 89 is Thr, Asp, Cys, Leo, Val, Glu, His, Asn, or Ser;

Xaa at position 90 is Ala, Pro, Ser, Thr, Gly, Asp, lle or Met;

Xaa at position 91 is Ala, Pro, Ser, Thr, Phe, Leo, Asp or His;

Xaa at position 92 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, lle or Leo;

Xaa at position 93 is Thr, Asp, Ser, Asn, Pro, Ala, Leo or Arg;

Xaa at position 94 is Arg, lle, Ser, Glu, Leu, Val, Gin, Lys, His, Ala or Pro;

Xaa at position 95 is His, Gin, Pro, Arg, Val, Leo, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, lle or Tyr;

Xaa at position 96 is Pro, Lys, Tyr, Gly, lle or Thr;

Xaa at position 97 is lle, Val, Lys, Ala or Asn;

Xaa at position 98 is His, lle, Asn, Leo, Asp, Ala, Thr, Glu, Gin, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;

Xaa at position 99 is lle, Leo, Arg, Asp, Val, Pro, Gin, Gly, Ser, Phe or His;

Xaa at position 100 is Lys, Tyr, Leu, His, Arg, lle, Ser, Gin, or Pro;

Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, lle, Leo or Gin;

Xaa at position 102 is Gly, Leu, Glu, Lys, Ser, Tyr or Pro;

Xaa at position 103 is Asp or Ser;

Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leo, Gin, Lys, Phe or Gly;

Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gin, Tyr, Leo, Lys, lle, Asp or His;

Xaa at position 106 is Glu, Ser, Ala, Lys, Thr, lle, Gly or Pro;

Xaa at position 108 is Arg, Lys, Asp, Leo, Thr, lle, Gin, His, Ser, Ala or Pro;

Xaa at position 109 is Arg, Thr, Pro, Glu, Tyr, Leo, Ser or Gly;

Xaa at position 110 is Lys, Ala, Asn, Thr, Leo, Arg, Gin, His, Glu, Ser, Ala or Trp;

Xaa at position 111 is Leo, lle, Arg, Asp or Met;

Xaa at position 112 is Thr, Val, Gin, Tyr, Glu, His, Ser or Phe;

Xaa at position 113 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, lle, Val or Asn;

Xaa at position 114 is Tyr, Cys, Gis, Ser, Trp, Arg or Leo;

Xaa at position 115 is Leo, Asn, Val, Pro, Arg, Ala, His, Thr, Trp or Met;

Xaa at position 116 is Lys, Leo, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala,

Tyr, Phe, Gin, or lle;

Xaa at position 117 is Thr, Ser, Asn, lle, Trp, Lys or Pro;

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Xaa at position 118 is Leo, Ser, Pro, Ala, Glu, Cys, Asp or Tyr;

Xaa at position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr or Arg; 245

Xaa at position 120 is Asn, Ala, Pro, Leo, His, Val or Gin;

Xaa at position 121 is Ala, Ser, lle, Asn, Pro, Lys, Asp or Gly;

Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, lle, Tyr or Cys;

Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr or Leo;

and which, in addition, have Met- which precedes the amino acid at position 1; 250 wherein the amino acids at positions 1 to 14 at the N-terminus can be removed and / or the amino acids at positions 1 to 15 at the C-terminus can be removed and the amino acids at positions 4 through 44 designated by Xaa are different from amino acids corresponding to native human interleukin3 (1-133),

R₂ is a colony-stimulating factor selected from GM-CSF, CSF-1, CSF-G (CSF-255 granulocyte), C-mpI ligand, M-CSF, erythropoietin (EPO), IL-1, IL-4, IL -2JL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3 / flk2, human growth hormone, growth factor of B cell, B cell differentiation factor, eosinophil differentiation factor and stem cell factor (SCF) in which the X and Y radicals are joined directly or via a linker (L), provided that

X is R₂, Y cannot be R₂. 260

By applying the invention, the following advantages are obtained:

- biological or physiological activity greater than a simple summed function of the presence of IL-3 or the second colony-stimulating factor alone;

- may provide an increased effect on activity or activity other than that expected by the presence of IL-3 or the second colony-stimulating factor or variant IL-3; 265

- an improved activity profile, which may include the reduction of unwanted biological activities associated with hlL-3.

The invention also includes mutants of hlL-3 in which deletions of 1 to 14 amino acids at the N-terminus and / or 1 to 15 amino acids have been deleted from the C-terminus, containing multiple amino acid substitutions, to which 270 a second colony-stimulating factor or IL-3 variant was fused. The fusion proteins, preferred in the present invention, are composed of hlL-3 variants, wherein amino acids 1-14 are deletioned from the N-terminus, amino acids 126 to 133 deletion from the C-terminus and contain from about 4 to about 26 amino acid substitutions, in the sequence of the polypeptide fused to the second colony-stimulating factor or IL-3 variant. 275

Also, the present invention provides fusion proteins, which may function as IL-3 antagonists or as antigenic, concrete fragments, for the production of antibodies useful in immunostaining and immunotherapy protocols.

HlL-3 antagonists would be particularly useful in blocking the growth of certain cancer cells, such as AML, CML, and certain types of lymphoid cancers B. Other conditions where 280 antagonists would be useful include those in which certain cells Blood vessels are produced in abnormally large numbers or activated by endogenous ligands. Antagonists could compete effectively for hematopoietic ligands, probably naturally occurring, including but not limited to, IL-3, GM-CSF, and IL-5, which can trigger or enhance the growth of cancer cells by virtue of their ability to it binds to the IL-3 receptor complex, in 285 at the same time diminishing the intrinsic activating properties of the ligand. Also, IL-3, GM-CSF and / or IL-S play a role in certain asthmatic responses. An IL-3 receptor antagonist may be useful in this disease by blocking the activation and recruitment of receptor-mediated inflammatory cells.

In addition to using the fusion proteins of the present invention in vivo, it is contemplated that in vitro uses would include the ability to stimulate bone marrow and to activate and grow blood cells and growth prior to infusion into the patient.

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The invention also comprises recombinant variants of human interleukin-3- (hlL-3) or mutant proteins (muteins) fused to themselves, IL-3, or a second colony-stimulating factor (CSF), including, but not limited to, without being limited to, cytokine, lymphokine, interleukin, hematopoietic growth factor or IL-3 variant with or without a linker. This invention comprises mixed-function colony-stimulating factors, formed of covalently linked polypeptides, each of which can act through a different and specific cellular receptor, to initiate complementary biological activities. Hematopoiesis requires a complete series of cellular events, in which stem cells continuously generate large populations of cells that mature in all major lines. There are currently at least 20 known regulators with proliferative hematopoietic activity. Most of these proliferative regulators can stimulate the formation of one or another type of colony in vitro, the precise image of colony formation stimulated by each regulator being clearly distinct. Neither regulator stimulates exactly the same sequence of colony formation, as assessed by the number of colonies or, more importantly, by the line and spectrum of maturation of the cells that make up the developing colonies. The proliferative responses can be easily analyzed in simplified in vitro culture systems. 3 different parameters can be clearly distinguished, namely, change of colony size, change of number of colonies and cell line. Two or more factors may act on the progenitor cell, inducing the formation of a greater number of offspring, thereby increasing the size of the colony. Two or more factors may allow a larger number of progenitor cells to proliferate, either because of distinct subsets of existing progenitor cells that respond exclusively to one factor, or because of progenitors requiring stimulation by two or more factors before be able to respond. Activation of additional receptors on a cell, by using two or more factors, is similar to the increase of mitotic signal, due to the coalescence of signal pathways, which initially differ in a common final path, reaching the nucleus (Metcalf, 1989). Other mechanisms might explain synergism. For example, if a signaling pathway is limited by a further activation of an additional signaling pathway, by a second factor, it may result in an over-response. In some cases, activation of one type of receptor may induce increased expression of other receptors (Metcalf, 1993). Two or more factors can lead to a different spectrum of cell lines, than from a single factor. The use of fusion molecules may have the potential clinical advantage, due to a proliferative response, which is not possible by a single factor.

Hematopoietic factors and other growth factors can be grouped into two distinct families of related receptors: (1) tyrosine kinase receptors, including those for epidermal growth factor, M-CSF (Sherr, 1990) and SCF (Yarden et al., 1987). ) and (2) hematopoietic receptors, which do not contain a tyrosine kinase domain, but which have obvious homology in their extracellular domain (Bazan, 1990). The latter group includes erythropoietin (EPO) (D'Adrea et al., 1989), GM-CSF (Gearing et al., 1989), IL-3 (Kitamura et al., 1991), G-CSF (Fukunaga et al., 1990), IL-4 (Harada et al., 199 =), IL-5 (Takaki et al.,

1990), IL-6 (Yamasaki et al., 1988), IL-7 (Goodwin et al., 1990), LIF (Gearing et al., 1991), and IL-2 (Cosman et al., 1987).

Most of the receptors of the latter group exist in the form of high affinity, as heterodimers. After ligand binding, α-specific chains become associated with at least one other receptor chain (β-chain, γ-chain). Many of these factors share a receptor subunit. The chains a, for GM-CSF IL-3, IL-5 share the same β chain (Kitamura et al.,

1991) Takaki et al., 1991) and receptor complexes for IL-6, LIF, and IL-11 share the common β chain (gp130) (Taga et al., 1989; Gearing et al., 1992). The IL-2, IL-4 and IL-7 receptor complexes share a common γ chain (Londo et al., 1993; Russell et al., 1993; Nogochi et al., 1993).

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345

The use of multiple factors can also have the potential advantage by lowering the demands placed on cells that produce their factors and induction systems. If there is a limit on the ability of a cell to produce a factor, then by decreasing the concentrations required by each of the factors by using them in combination, the demands on the cells that produce the factor can be useful reduced. Using multiple factors can reduce the number of factors that will be needed, possibly reducing the likelihood of adverse responses.

Complementary activity is the activity that increases or changes the response for another cellular modeler. The R1 polypeptide is fused either directly or via a linker segment to the R2 polypeptide. The term "direct" defines fusions in which the polypeptides are bound without a linker peptide. Thus, L represents a chemical bond or polypeptide segment, in which both R1 and R2 are fused together, most often L is a linear peptide to which R1 and R2 are linked by amide bonds, which bind the C-terminal end of of R1 at the N-terminus of L and the C-terminus of L at the N-terminus of R2. By "merged within the framework", it is understood that there is no translation of termination or interruption between the reading frames of R1 and R2. A non-exclusive list of other growth factors, colony-stimulating factors (CSFs), cytokine, lymphokine, interleukin, hematopoietic growth factor within the definition of R2, which may be fused to a hlL-3 variant of the present invention, include GM-CSF, CSF-1, G-CSF, Meg-CSF (more recently known as c-mp1 ligand), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-5 , IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3 ligand, human growth hormone, B cell growth factor, B cell differentiation factor, eusenophil differentiation factor, stem cell factor (SCF) also known as steel factor or kit c ligand. Additionally, this invention comprises the use of modified or mutated R2 molecules or modified DNA sequences, which encodes these R2 molecules. Also disclosed herein is the fusion of molecules wherein R 2 is a hlL-3 variant which means an IL-3 in which an amino acid is substituted and which portions of the removed hlL-3 molecule can be removed as described in WO. 94/12638 and WO 94/12639 as well as other variants known in the art.

The binding group (L) is generally a polypeptide with a length between 1 and 500 amino acids. The linkers linking the two molecules are preferably designated for: (1) allow the two molecules to fold and act independently of each other, (2) they do not have a predilection for the development of an ordered secondary structure, which could interfere with the functional domains of the two proteins, (3) minimal hydrophobicity or loading characteristics, which could interact with the functional protein domains and (4) ensure the historical separation of R1 and R2, so that R1 and R2 could interact, simultaneously, with their corresponding receptors, on a single cell. Typically, the surface area of ​​the amino acids in the flexible regions of the protein includes Gly, Asn, and Ser. Indeed, any permutation of the amino acid sequences containing Gly, Asn, and Ser would be expected to meet the above criteria for a linker sequence. Other neutral amino acids such as Thr, and Ala can also be used in the linker sequence. Additionally, additional amino acids may be included in the linkers, due to the addition of unique restriction sites in the linker sequence, to facilitate the construction of fusions.

Preferred linkers of the present invention include sequences selected from the formula group: (Gly3Ser)_n, (Gly4Ser)_n, (Gly5Ser)_n, (Gly_nSerum)_n or (AlaGlySer)_n.

An example of a high flexibility linker is the rich spacer region (GlySer), present in the pili protein of filamentous bacteriophages, for example, bacteriophages M13 or fd (Schaller et al., 1975). This region provides a long, flexible spacing region between the two domains of the pili protein surface.

The spacer region consists of the amino acid sequence:

350

355

360

365

370

375

380

385

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GlyGlyGlySerGIyFlyGlySerGIyGlySergluGlyGlyGlySergluGlyGlyGlySer GluGlyGlyGlySerGluGlyGlyGlySerGlyGlyGlySer (SEQ. No. 50).

The present invention also includes linkers in which an endopeptidase recognition sequence is included. Such a cleavage site may be useful for separating the individual components of the fusion, to determine whether they are properly folded and active in vitro. Examples of various endopeptidases include, but are not limited to, plasmin, enterokinase, kalikrein, urokinase, tissue plasminogen activator, clostripaine, chemosine, collagenase, Russell's venom protease, postproline cleavage enzyme, V8 protease, thrombin, and factor X8. .

Linker peptide segments from the base region of the heavy chain immunoglobulin IgG, IgA, IgM, IgD or IgE provide a rigid relationship between the attached polypeptides. Particularly useful are those core regions, where the cysteines are replaced by serines. Preferred linkers of the present invention include sequences derived from the murine IgG gamma 2b base region, in which the cysteines were changed to serines. These linkers may also include an endopeptidase cleavage site. Examples of such linkers include the following sequences chosen from the sequence group.

IleSerGIuProSerGIyProlleSerThrlIeAsnProSerProProSerLys GluSerHisLysSerPro (SEQ.51)

IleGluGlyArgIleSerGIuProSerGIyProlleSerThrIleAsnProSer ProProSerLysGluSerHisLysSerPro (SECV.Nr.52)

However, the present invention is not limited by the form, size or number of the linker sequences used, and there is only a requirement that the linker does not interfere, in a harmful manner, with the folding and function of the individual molecules of the fusion.

An alternative method for connecting two hematopoietic growth factors is through non-covalent interaction. Such complex proteins can be described by one of the formulas:

R1-C1 + R2-C2; or C1-R1 + C2-R2; C1-R1 + R2-C2; or C1-R1 + R2-C2, where R1 is a hlL-3 variant, which contains multiple amino acid substitutions and may have distant portions of the hlL-3 molecule, R2 is a colony-stimulating factor with different but complementary activity. A non-exclusive list of other growth hormones, colony-stimulating factors (CSFs), cytokine, lymphokine, interleukin, hematopoietic growth factor, within the definition of R2, which may be fused to an hlL-3 variant of the invention. front, include GM-CSF, CSF-1, G-CSF, Meg-CSF (more recently known as c-mpl ligand), M-CSF, erythropoietin (EPO), IL-1, IL-4, IL-2, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3 ligand, human growth hormone, B cell growth factor, B cell differentiation factor, eusenophil differentiation factor and stem cell factor (SCF) also known as steel factor or kit-c ligand. Domains C1 and C2 are chemical structures, either identical or different, usually protein, which can form a specific non-covalent association. The complex between C1 and C2 results in a stoichiometric relationship between R1 and R2 for each complex. Examples of the domains that are associated are the "zipper leucine" domains of transcription factors, the dimerization domains of bacterial transcription repressors and the constant immunoglobulin domains. Covalent bonds link R1 and C1 and R2 to C2 respectively. As indicated in the formula, the C1 and C2 domains may be present at both the N-terminal and C-terminus of the corresponding hematopoietic growth factor (R). These domains of multimerization (C1 and C2) include those derived from the bZIP family of proteins (Abel et al., 1989; Landshulz et al., 1988; Pu et al., 1993; Kozarides et al., 1988) as well as multimerization domains of the helix-loop-helix family of proteins (Abel et al., 1989; Murre et al., 1989; Tapscott et al., 1988; Fischer et al., 1991). Preferred fusions of the present invention include dimerized colony-stimulating factors for

RO 118016 Β1

440 their incorporation as translational fusions to the leucine zipper dimerization domains of the bZIP Fos and Jun protein families. The leucine zipper domain of Jun is able to interact with identical domains. On the other hand, the Fos leucine zipper domain interacts with the Jun leucine zipper domain, but does not interact with other Fos leucine zipper domains. The mixtures of Fos and Jun result predominantly from the formation of Fos-Jun heterodimers. As a result, when fused to the colony-stimulating factor, the Jun domain can be used to direct the formation of either homo- or heterodimers. The preferential formation of heterodimers can be achieved if one of the colony-stimulating factor partners is processed to possess the Jun zipper leucine domain, while another is processed to possess the Fos zipper.

Peptides may also be added to facilitate the purification or identification of fusion proteins (eg, poly-His).

Also, a strongly antigenic peptide can be added, which will allow rapid analysis and easy purification of the fusion protein by a specific monoclonal antibody.

The present invention relates to novel fusion molecules, composed of novel variants of human interleukin-3 (hiL-3), in which amino acid substitutions have been made, at four or more positions in the amino acid sequence of the polypeptide fused to one. the second colony-stimulating factor or IL-3 variant. Preferred fusion molecules of the present invention are deletion mutants (15-125) hlL-3, which have deletions of 1 to 14 amino acids at the N-terminus and 126 to 133 at the C-terminus C and which also have , 4 or more amino acid substitutions, in the polypeptide fused to a second colony-stimulating factor or IL-3 variant. The present invention includes mutant polypeptides, comprising at least 15 to 118 amino acid residues of hlL-3 with or without additional amino acid extensions at the N-terminus and / or C-terminus, which additionally contain 4 or more amino acid substitutions in the amino acid sequence. of the polypeptide fused to another colony-stimulating factor or IL-3 variant.

As used herein, human interleukin-3 corresponds to the amino acid sequence (1-133), as illustrated in Figs. 1 and (15-125) hlL-3 and corresponds to the amino acid sequence 15 to 125 of the hlL- polypeptide. 3. Naturally encountered variants of the amino acids of the hlL-3 polypeptide are also included in the present invention (for example, the allele in which proline is rather than serine at position 8 in the sequence of the hlL-3 polypeptide) such as molecule variants. hlL-3, which are post-translationally modified (eg, glycosylation).

"Mutant amino acid sequence," mutant protein "or" mutant polypeptide "refers to a polypeptide having an amino acid sequence, which varies from the native sequence or is encoded by a nucleotide sequence, made, intentionally, variant from the native sequence. . "Mutant protein", "variant protein" or "mutein" means a protein that comprises a mutant amino acid sequence and includes polypeptides that differ from the native hlL-3 amino acid sequence due to amino acid deletions, substitutions or both. "Native sequence" refers to an amino acid or nucleic acid sequence, which is identical to a wild or native form of a gene or protein.

Human IL-3 can be characterized by its ability to stimulate colony formation by human hematopoietic progenitor cells. Formed colonies include erythroid, granulocyte, megakaryocyte, granulocytic macrophages and combinations thereof. Human IL-3 has a capacity to restore bone marrow function and peripheral blood cell populations to therapeutically useful levels, in studies performed initially in primates and subsequently in humans (Gillio, PA et al., (1990); Ganser, A. et al., (1990); Falk S. et al. (1991). Additional activities of hlL-3 include the ability to stimulate leukocyte migration and chemotaxis; the ability to initiate human leukocytes to produce high levels of

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RO 118016 Β1 inflammatory mediators, such as leukotrienes and histamine; the ability to induce expression on the cell surface of the molecules required for leukocyte adhesion; and the ability to trigger inflammatory dermal and fever responses. Many or all of these biological activities of hlL-3 involve signal transduction and high affinity for receptor binding. The fusion molecules of the present invention may have useful properties, having similar or greater biological activity, compared to native hlL-3 or having an enhanced half-life or side effects, adverse, low, or a combination of these properties. They can also be useful as antagonists. Fusion proteins that have little or no activity, compared to native hlL-3, may still be useful as antagonists, as antigens for producing antibodies used in immunology or immunotherapy, as genetic probes, or as intermediates used to build other hlL muteins. -3 useful.

The novel fusion proteins of the present invention will preferably have at least one biological property of human IL-3 and another colony-stimulating factor or other IL-3 variant, to which it is fused and may have more than a biological property, such as IL-3 or an improved property, or a reduction of an undesirable biological property, of human IL-3. Some mutant polypeptides of the present invention may also have an enhanced side effect profile. For example, they may exhibit a decrease in leucotrein release or histamine release compared with native hlL-3 or (15125) hlL-3. Such hlL-3 or similar hlL-3 biological properties may include one or more of the following biological characteristics and in vivo and in vitro activities.

Such a property is to support the growth and differentiation of the progenitor cells, passed to the erythroid, lymphoid and myeloid lines. For example, in a standard human bone marrow assay, a biological property such as IL-3 is the stimulation of granulocyte-like colonies, megakaryocytic-type colonies, monocyte / macrophage colonies, and erythroid occurrences. Other properties such as IL-3 are the interaction with early multipotent stem cells, support the growth of pluripotent precursor cells, the ability to stimulate chronic myelogenous leukemia (CML) cell proliferation, stimulate mast cell proliferation, the ability to support the growth of various cell lines. and the ability to trigger the immature, bone marrow progenitors. Other biological properties of IL-3 have been described in the literature. Human IL-3 also has some biological activities, which in some cases may be undesirable, for example, the ability to stimulate leukotriene release and the ability to stimulate increased histamine synthesis in spleen and bone marrow and bone marrow cultures. vivo.

The biological activity of hlL-3 and hlL-3 fusion proteins of the present invention is determined by DNA synthesis from human acute myelogenous leukemia (AML) cells. The factor-dependent AML 193 cell line was adapted for use in biological assay activity. The biological activity of hlL-3 and hlL-3 fusion proteins of the present invention is also determined by counting colony forming units in a bone marrow test.

Other in vitro cell-based assays may also be useful for determining the activity of fusion molecules, depending on the colony-stimulating factors that the fusion comprises.

It is an object of the present invention to provide the hlL-3 variant with four or more amino acids substituted in the sequence of the polypeptide fused to a second colony-stimulating factor with IL-3 variant, which has biological activity, similar or enhanced to native hlL-3. , or the second colony-stimulating factor or IL-3 variant.

The hlL-3 variant fusion proteins of the present invention may have hlL-3 activity or similar hlL-3 activity. For example, they may possess one or more of the biological activities of hlL-3 and may be useful in stimulating the production of hematopoietic cells,

RO 118016 Β1 by primate or human progenitor cells. The fusion molecules of the present invention and the pharmaceutical compositions containing them may be useful in the treatment of reducing or destroying hematopoietic cell populations due to disease or treatments, such as irradiation or chemotherapy. Pharmaceutical compositions containing the fusion molecules of the present invention may be administered parenterally, intravenously or subcutaneously.

The native HIL-3 possesses considerable inflammatory activity and has been shown to stimulate synthesis of the metabolites of arhidonic acid LTC4, LTD4 and LTE4, histamine synthesis and histamine release. Human clinical studies with native hlL-3 have substantiated inflammatory responses (Biesma et al., Blood, 80: 1141-1148 (1992) and Postmus et al., J.CIin.Oncol. 10: 11311140 (1992)). A recent study has shown that leukotrienes are involved in IL-3 actions in vivo, and can significantly contribute to the biological effects of IL-3 treatment (Denzlinger C. et al., Blood, 81: 2466-2470 (1993)).

Some of the fusion proteins of the present invention may have an improved therapeutic profile compared to native hlL-3. For example, some fusion molecules of the present invention may have similar or stronger growth factor activity relative to hlL-3, without having similar or appropriate growth in leukotriene or histamine stimulation. These fusion molecules will be expected to have a more favorable therapeutic profile, because the amount of the polypeptide that is required to be given the desired growth factor activity (eg, cell proliferation) will have a leukotriene or histamine stimulation effect. smaller. In studies with native hlL-3, stimulation of inflammatory factors was an undesirable side effect of treatment. Reducing or releasing the stimulation of inflammation mediators will provide an advantage over native hlL-3 use.

The novel fusion proteins of the present invention may also be useful as antagonists that block the hlL-3 receptor by specifically binding to it and preventing agonist binding.

A potential advantage of the new fusion products, of the present invention, in particular, those that retain similar or better acidity than native hlL-3, is that it may be possible to use a lower amount of biologically active mutein, for producing the desired therapeutic effect. The use of smaller quantities may also reduce the possibility of any potential antigenic effects or other possible undesirable side effects. For example, if a desired therapeutic effect can be achieved with a smaller amount of polypeptide, it may be possible to reduce or eliminate the side effects associated with the administration of native IL-3, such as leukotene stimulation and / or histamine release. The novel fusion molecules of the present invention may also be useful in activating stem or progenitor cells, which have low receptor numbers.

Also included in the present invention are DNA sequences, which encode fusion proteins, DNA sequences that are substantially similar, and perform substantially the same function and DNA sequences, which differ from the DNAs that encode fusion proteins. of the invention, only due to the degeneracy of the genetic code. Also included in the present invention are oligonucleotide intermediates used for the construction of mutant DNAs and polypeptides encoded by these oligonucleotides. These polypeptides may be useful as antagonists or with fragments for the production of antibodies useful in immunotherapy and immunotherapy protocols.

The compounds of this invention are preferably made by genetic engineering techniques, henceforth referred to in the art, US Pat. No. 4935233 and Sambrook et al., “Molecular Cloning. The Laboratory Manual, Cold Spring Harbor Laboratory (1989). One method of creating the preferred hlL-3 mutant genes (15-125) is the mutagenesis cassette (Wells et al., 1989) in which a portion of the hlL-3 coding sequence of a plasmid is replaced by oligonucleotides. synthetic, which encodes the desired amino acid substitutions in a portion of the gene

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RO 118016 Β1 of 2 restriction sites. Similarly, amino acid substitutions can be made in the whole hlL-3 gene or genes encoding variants of hlL-3 in which from 1 to 14 amino acids have been removed from the N-terminus and / or from the 1-terminus. up to 15 amino acids were removed from the C-terminus. When properly assembled, these oligonucleotides will modify the hlL-3 variant with the desired amino acid substitutions and / or deletions at the N-terminal and / or C-terminal end. These and other mutations can be created by those skilled in the art by other methods of mutagenesis, including oligonucleotide, oriented mutagenesis / Zoller and Smith (1982, 1983, 1984), Smith (1985), Kunkel (1985), Taylor et al. , (1985), Geng and Nickoloff (1992)) or polypeptide chain reaction (PCR) techniques (Seiki, (1985)).

Synthetic, complementary oligonucleotide pairs encoding the desired gene can be obtained and normalized. The DNA sequence of the oligonucleotide will encode the sequence for the amino acids of the desired gene, except those substituted and / or removed from the sequence.

Plasmid DNA can be treated with restriction endonucleases, chosen, and then bind to normalized oligonucleotides. The ligated mixtures can be used to transform JM101 cells competent for resistance to a suitable antibiotic. Single colonies can also be collected and the plasmid DNA examined by restriction analysis and / or DNA sequencing to identify the plasmids with the desired genes.

By fusing the DNA sequences of the hlL3 variant with the DNA sequence of another factor that

J 1 stimulates colony or IL-3 variant, can be obtained by using intermediate vectors. Alternatively, a gene can be cloned directly into a vector containing another gene. For linking DNA sequences as well as replacing lost sequences, linkers or adapters may be used when a restriction site has been internal to the region of interest. Thus, genetic material (DNA) encoding a polypeptide, linker peptide and other polypeptide is introduced into an appropriate expression vector, which is used to transform bacteria, yeasts, insect cells or mammalian cells. The transformed organism grows and the protein is isolated by standard techniques. The resultant product is therefore a novel protein, which has a hlL-3 variant bound by a linker region to a second colony-stimulating factor or IL-3 variant.

Another aspect of the present invention provides plasmid DNA vectors for use in the expression of these novel fusion molecules. These vectors contain novel DNA sequences, described above, which code for novel polypeptides of the invention. Suitable vectors, which can transform microorganisms capable of expressing fusion molecules, include expression vectors, comprising nucleotide sequences, which code for the fusion molecules linked to the transcriptional and translational regulatory sequence, which are chosen according to the host cells used.

Vectors incorporating modified sequences, as described above, are included in the present invention and are useful in the production of fusion polypeptides. The vector used in the method also contains regulatory sequences, selected in functional association with the coding DNA sequences, of the invention and capable of directing their replication and expression in the chosen host cells.

As another aspect of the present invention, there is provided a method for producing novel fusion molecules. The method of the present invention involves culturing a corresponding cell or cell line, which has been transformed with a vector containing a DNA sequence, which encodes the expression of a variant of the novel hlL-3 fusion molecule. Suitable cells or cell lines may be bacterial cells, for example, various strains of E.coli are well known as host cells in the field of biotechnology. Examples of such strains include E.coli strains GM101 (Yanish-Perron et al. (1985)) and MON105 (Obukowicz et al. (1992)). Also included in the present invention is the expression of the fusion protein, which uses an E.coli chromosomal expression vector, based on the bacteriophage Mu (Weinberg et al., (1993)). Also, in this method, various strains can be used

RO 118016 Β1 of B. subtilis. Numerous yeast cell strains, known to those skilled in the art 635, are also accessible as host cells, for expression of the polypeptides of the present invention. When expressed in the cytoplasm of the E.coli cell, the mutant variants of the hlL-3 fusion protein mentioned above can be constructed with Met-Ala- at the N-terminus, so that upon expression, Met cleaves leaving Ala at the N-terminal end. The fusion proteins of the present invention may include fusion polypeptides, having Met-, Ala- or Met-640 Al-attached at the N-terminus. When the fusion molecules are expressed in the cytoplasm of the E.coli cell, polypeptides are obtained with and without Met attached to the N-terminus. The N-terminal ends of the protein in the cytoplasm of the E.coli cell are affected by posttranslational methionine-amino-peptidase processing (Sen-Bassat et al., 1987) and possibly by other peptidases. These mutant fusion proteins may also be expressed in E.coli by 645 fusion of a signal peptide at the N-terminus. This signal peptide is cleaved from the polypeptide as part of the secretion process. Secretion in E.coli can be used to obtain the correct amino acid at the N-terminus (eg, Asn¹⁵ in polypeptide (15125) (hlL-3), due to the precise nature of the signal peptidase. This is distinct from the heterogeneity often observed, at the N-terminus, of proteins expressed in the 650c cytoplasm of the E.coli cell.

Also suitable for use in the present invention are mammalian cells, such as Chinese hamster ovary (CHO) cells. General methods for the expression of foreign genes in mammalian cells are provided by Kaufman, RJ (1987) in High levelproduction ofproteins in mammalian cells, in Genetic engineering, Principles and 655 Methods, vol.9, JKSetlow, publisher, Plenum Press, New York. An expression vector is constructed, in which a strong promoter capable of functioning, in mammalian cells, directs the transcription of a coding region of the eukaryotic secretion signal peptide, which fused translationally to the coding region of the fusion molecule. For example, plasmids such as pcDNAI / Neo, pRc / RSV and pRc / aCMV (obtained from Invitrogen Corp., San 660 Diego, California) can be used. The coding region of the eukaryotic secretion signal peptide may be from the hlL-3 gene or may be from another mammalian secreted protein (Bayne, ML et al., (1987) Proc. Natl. Acad. Sci. USA, 84 2638-2542). After constructing the vector containing the hlL-3 variant gene, the DNA vector is transfected into mammalian cells. Such cells may be, for example, COS7, HeLa, BHK, CHO or mouse lines L. The cells may be cultured, for example, in DMEM (DRH Scientific) media. The hlL-3 variant secreted in media can be recovered by standard biochemistry, after transient expression, at 24-72 h, after transfection of cells or after establishing stable cell lines, following selection, for neomycin resistance. The selection of host cells, mammals, suitable and methods for transformation, culture, amplification, sorting and production of the product and purification are known in the art. See, for example, Gething and Sambrook Nature, 293: 620-625 (1981) or alternatively, Kaufman et al., Mol.Cell.Biol., 5 (7): 1750-1759 (1985) or Howley et al., US 4419446. Another suitable mammalian cell line is the COS-1 monkey cell line. A similarly useful mammalian cell line is the CV-1 cell line.

When desired in the method of the present invention, 675 insect cells can be used as host cells. See for example, Miller et al., Genetic engineering, 8: 277-298 (Plenum Press 1986) and references cited here. Additionally, general methods for the expression of foreign genes in the insect cell using Baculovirus vectors are described in Summers, MD and Smith G. E., (1987) A manual of methods for Baculivirus vectors and insect cell culture procedures, Texas Agricultural Experiment Station Bulletin No. 1555. A 680 expression vector, including a Baculovirus transfer vector, is constructed, in which a strong Baculovirus promoter (as the polyhedron promoter) drives the transcription of the coding region of the eukaryotic secretion peptide, which is translationally fused, to the region of

RO 118016 Β1 coding of the fusion polypeptide. For example, plasmid pVL1392 (obtained from Invitrogen Corp., San Diego, California) can be used. After constructing the vector carrying the coding gene of the fusion polypeptide, 2 / zg of this DNA is counter-infected with 1 μg Baculovirus DNA (see Summers & Smith, 1989) in insect cells, strain SF9. Pure recombinant Baculovirus, which carries the fusion protein, is used to infect cultured cells, for example, in serum-free Excell 401 (JRN Biosciences, Lenexa Kansas). The fusion protein, secreted into the environment, can be recovered by standard biochemical approaches. Supernatants from mammalian or insect cells, which express the fusion protein, can initially be concentrated using any of the numerous commercial concentration units.

The fusion proteins of the present invention may be useful in the treatment of diseases characterized by a low level of either myeloid, erythroid, lymphoid, or megakaryocyte cells of the hematopoietic system or combinations thereof. In addition, they can be used to activate myeloid and / or lymphoid mature cells. Among the conditions susceptible to treatment with the polypeptides of the present invention is leukopenia, a reduction in the number of circulating leukocytes (white cells) in peripheral blood. Leukopenia can be induced by exposure to certain viruses or radiation. It is often a side effect of various forms of cancer therapy, such as exposure to chemotherapeutic drugs, radiation and infection or hemorrhage. The therapeutic treatment of leukopenia with these fusion molecules of the present invention may avoid the undesirable side effects produced by treatment with currently accessible drugs.

The fusion proteins of the present invention may be useful in the treatment of neutropenia and, for example, in the treatment of conditions such as aplastic anemia, cyclic neutropenia, idiopathic neutropenia, Chediak-Higashi syndrome, systemic lupus erythromatosus (SLE), leukemia, myelodysplastic syndrome myelofibrosis.

The fusion protein of the present invention may be useful in the treatment or prevention of thrombocytopenia. Currently, thrombocytopenia therapy is only platelet transfusion, which is costly and has significant risks of infection (HIV, HBV) and immunization. The fusion protein can ease or lessen the need for platelet transfusions. Severe thrombocytopenia can result from genetic defects, such as Fanconi's anemia, Wiscott-AIdrich or May-Hegglin's syndromes. Acquired thrombocytopenia may result from auto- or allo-antibodies, such as in immune thrombocytopenic purpura, systemic lupus erythromatosis, hemolytic anemia or fetal, maternal incompatibilities. In addition, they may lead to splenomegaly thrombocytopenia, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, infection, or cardiac protection valves. Severe thrombocytopenia may also result from cancer chemotherapy and / or radiation therapy. Thrombocytopenia may also result from marrow invasion through carcinomas, lymphomas, leukemia or fibrosis.

The fusion proteins of the present invention may be useful in mobilizing hematopoietic and sternal progenitor cells, such as peripheral ones. The progenitors derived from peripheral blood have been shown to be effective in restoring patients, in stabilizing the autologous marrow transplant. Autologous growth factors including G-CSF and GM-CSF have been shown to increase the number of circulating systemic progenitor cells in peripheral blood. This simplified the procedure for collecting peripheral stem cells and dramatically lowered the cost of the procedure by decreasing the number of decks needed. The fusion protein may be useful in mobilizing stem cells and further enhancing the efficiency of peripheral stem cell transplantation.

Another clinically designed use of growth factors was in vitro activation of hematopoietic progenitors and stem cells for gene therapy. in order to have the gene of interest embedded in the genome of the hematopoietic progenitor or stem cell,

111 it is necessary to stimulate cell division and DNA replication. The cycle of hematopoietic stem cells is a very low frequency, which means that growth factors may be useful for initiating gene transduction and, thus, increasing clinical prospects, for gene therapy.

Many drugs can cause bone marrow suppression or hematopoietic deficiencies. Examples of such drugs are AZT, DDI, alkylating agents, and antimetabolites used in chemotherapy, antibiotics, such as chloramphenicol, penicillin, ganciclovir, daunomycin, and sulfa, phenothiazone, tranquilizer such as meprobamate, analgesics like aminopyronev, carbinevazine or , antithyroid like propylouracil and metimazole and diuretics. The fusion molecules of the present invention may be useful in the prevention or treatment of bone marrow suppression or hematopoietic deficiencies, which are often encountered in patients treated with these drugs.

Hematopoietic deficiencies may also occur as a result of viral, microbial or parasitic infections and as a result of the treatment of kidney disease or renal failure, for example, dialysis. The fusion molecules of the present invention may be useful in treating such hematopoietic deficiencies.

Treatment of hematopoietic deficiency may include administration of a pharmaceutical composition, which contains fusion molecules, to a patient. The fusion molecules of the present invention may also be useful for activating and amplifying hematopoietic cells, precursors by treating, in vitro, these cells with the fusion proteins of the present invention before injecting the cells into a patient.

Various immunodeficiencies, for example, in T and / or B lymphocytes or immune disorders, for example, rheumatoid arthritis, may also be beneficially influenced by treatment with the fusion molecules of the present invention. Immunodeficiencies may be the result of viral infections, for example, HTLVI, HTLVII, HTLVIII, severe radiation exposure, cancer therapy, or other medical treatment. The fusion proteins of the present invention may also be used alone or in combination with other hematopoietics, in the treatment of other blood cell deficiencies, including thrombocytopenia (platelet deficiency) or anemia. Other uses of these novel polypeptides are in the recovery of patients from in vivo and ex vivo bone marrow transplants, and in the development of monoclonal and polyclonal antibodies, generated by standard method, for diagnosis or therapeutic use.

Other aspects of the present invention are therapeutic methods and compositions for treating the conditions described above. Such compositions comprise a therapeutically effective amount of one or more of the fusion molecules of the present invention in admixture with a pharmaceutically acceptable carrier. This composition can be administered both parenterally, intravenously and subcutaneously.

When administered, the therapeutic composition for use in this invention is preferably in the form of an aqueous solution, parenterally acceptable and free of pyrogens. The preparation of such a parenterally acceptable protein solution, having the appropriate pH, isotony, stability and the like can be found in the prior art.

The dosage regimen, involved in a method for treating the conditions described above, will be established by the doctor, considering various factors that modify the action of the medicines, for example, the condition, body weight, sex and diet of the patient, the severity of any infection, the time of administration and other clinical factors. Generally, a daily regimen will be in the range of 0.2-150 / zg / kg of fusion protein per kg. This dosage regimen is for a standard level of biological activity, which recognizes that, in general, native IL-3 possesses an EC₅₀ at or about 10 µM to 100 µM in the AML proliferation assay described herein.

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RO 118016 Β1

Therefore, the doses will be adjusted based on the activity of the fusion protein against the native IL-3 activity (reference) and it will not be incredible, to note that the dosing regimen may include low doses, up to 0 , 1 and as high as 1 mg / kg hours / day. In addition, there may be specific circumstances where the doses of the fusion molecule could be adjusted above or below the 10-200 / ^ g / kg range. These include administration with another colony-stimulating factor or IL-3 variant or growth factors, administration with chemotherapeutic drugs and / or irradiation, use of glycosylated fusion protein, and various patient-related issues mentioned earlier in this section. As indicated above, the therapeutic method and compositions may also include administration with other human factors. A non-exclusive list of other suitable hematopoietics, cytokine CSFs, lymphokines, hematopoietic growth factors and interleukins for simultaneous or alternate administration with the polypeptides of this invention, includes GM-CSF, CSF-1, G-CSF, Meg-CSF (known, more recently, as ligand c-mpl), MCSF, erythropoietin, (EPO), IL-1, IL-4, IL-2, IL-5, IL-6, IL-7, IL-8, IL-9 , IL-10, IL-11, IL-12, IL13, LIF, fit 3 ligands, B cell growth factors, B cell differentiation factors, eusenophil differentiation factor, stem cell factor (SCF), also known as steel factor or kit-c ligand, or combinations thereof. The dosage listed above will be corrected, to compensate for such additional components in the therapeutic composition. The progress of the treated patient can be controlled by periodic analysis of the hematological profile, for example, the counting differentiate by cells and the like.

A preferred embodiment of the invention is a fusion protein of the structural formula defined in claim 1 wherein

Rf is Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn

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Cys Xaa Xaa Xaa li Xaa Glu Xaa Xaa Xaa Xaa Leu Lys Xaa Xaa 20 2530

Xaa Xaa Xaa Xaa Xaa Asp Xaa Xaa Asn Leu Asn Xaa Glu Xaa Xaa

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Xaa Leu Met Xaa Xaa Asn Leu Xaa Xaa Xaa Asn Leu Glu Xaa

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Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa li Glu

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Xaa Xaa Leu Xaa Xaa Leu Xaa Xaa Cys Xaa Pro Xaa Xaa Thr Ala

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Xaa Pro Xaa Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Asp Xaa Xaa 95 100105

Xaa Phe Xaa Xaa Lys Leu Xaa Phe Xaa Xaa Xaa Xaa Leu Glu Xaa

110 115120

Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala lle Phe

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Sequence no .: 2 in which:

Xaa at position 17 is Ser, Gly, Asp, Met or Gin;

Xaa at position 18 is Asn, His or lle;

Xaa at position 19 is Met or lle; Xaa at position 21 is Asp or Glu;

Xaa at position 23 is lle, Ala, Leo or Gly;

Xaa at position 24 is lle, Val or Leu;

RO 118016 Β1

Xaa at position 25 is Thr, His, Gin or Ala;

Xaa at position 26 is His or Ala;

Xaa at position 29 is Gin, Asn or Val;

Xaa at position 30 is Pro, Gly or Gin;

Xaa at position 31 is Pro, Asp, Gly or Gin;

Xaa at position 32 is Leo, Arg, Gin, Asn, Gly, Ala or Glu;

Xaa at position 33 is Pro or Glu;

Xaa at position 34 is Leo, Val, Gly, Ser, Lys, Ala, Arg, Gin, Glu, lle, Phe, Thr or Met;

Xaa at position 35 is Leo, Ala, Asn, Pro, Gin or Val;

Xaa at position 37 is Phe, Ser, Pro or Trp;

Xaa at position 38 is Asn or Ala;

Xaa at position 42 is Gly, Asp, Ser, Cys, Ala, Asn, lle, Leo, Met, Tyr or Arg;

Xaa at position 44 is Asp or Glu;

Xaa at position 45 is Gin, Val, Met, Leo, Thr, Ala, Asn, Glu, Ser or Lys;

Xaa at position 46 is Asp, Phe, Ser, Thr, Ala, Asn, Gin, Glu, His, lle, Lys, Tyr, Val or Cys;

Xaa at position 50 is Glu, Ala, Asn, Ser or Asp;

Xaa at position 51 is Asn, Arg, Met, Pro, Ser, Thr or His;

Xaa at position 54 is Arg or Ala;

Xaa at position 55 is Arg, Thr, Val, Leo or Gly;

Xaa at position 56 is Pro, Gly, Ser, Gin, Ala, Arg, Asn, Glu, Leo, Thr, Val or Lys;

Xaa at position 60 is Ala or Ser;

Xaa at position 62 is Asn, Pro, Thr or lle;

Xaa at position 63 is Arg or Lys;

Xaa at position 64 is Ala or Asn;

Xaa at position 65 is Val or Thr;

Xaa at position 66 is Lys or Arg;

Xaa at position 67 is Ser, Phe or His;

Xaa at position 68 is Leo, lle, Phe or His;

Xaa at position 69 is Gin, Ala, Pro, Thr, Glu, Arg or Gly;

Xaa at position 71 is Ala, Pro or Arg;

Xaa at position 72 is Ser, Glu, Arg or Asp;

Xaa at position 73 is Ala or Leo;

Xaa at position 76 is Ser, Val, Ala, Asn, Trp, Glu, Pro or Gly;

Xaa at position 77 is lle or Leo;

Xaa at position 79 is Lys, Thr, Gly, Asn, Met, Arg, lle, Gly, or Asp;

Xaa at position 80 is Asn, Gly, Glu or Arg;

Xaa at position 82 is Leo, Gin, Trp, Arg, Asp, Ala, Asn, Glu, His, lle, Met, Phe, Ser, Thr, Tyr or Val;

Xaa at position 83 is Pro or Thr;

Xaa at position 85 is Leo or Val;

Xaa at position 87 is Leo or Ser;

Xaa at position 88 is Ala or Trp;

Xaa at position 91 is Ala or Pro;

Xaa at position 93 is Thr, Asp, Ser, Pro, Ala, Leo or Arg;

Xaa at position 95 is His, Pro, Arg, Val, Leo, Gly, Asn, Phe, Ser or Tyr;

Xaa at position 96 is Pro or Tyr;

Xaa at position 97 is lle or Val;

Xaa at position 98 is His, lle, Asn, Leu, Ala, Thr, Leu, Arg, Gin, Leu, Lys, Met, Ser, Tyr, Val or Pro;

830

835

840

845

850

855

860

865

870

875

RO 118016 Β1

Xaa at position 99 is lle, Leo or Val;

Xaa at position 100 is Lys, Arg, lle, Gin, Pro or Ser;

Xaa at position 101 is Asp, Pro, Met, Lys, His, Thr, Pro, Asn, lle, Leo or Tyr;

Xaa at position 104 is Trp or Leo;

Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gin, Tyr, Leo, Lys, lle, Asp or His; Xaa at position 106 is Glu or Gly;

Xaa at position 108 is Arg, Ala or Ser;

Xaa at position 109 is Arg, Thr, Glu, Leo or Ser;

Xaa at position 112 is Thr, Val or Gin;

Xaa at position 114 is Tyr or Trp;

Xaa at position 115 is Leo or Ala;

Xaa at position 116 is Lys, Thr, Val, Trp, Ser, Ala, His, Met, Phe, Tyr or lle;

Xaa at position 117 is Thr or Ser;

Xaa at position 120 is Asn, Pro, Leo, His, Val or Gin;

Xaa at position 121 is Ala, Ser, lle, Asn, Pro, Asp or Gly;

Xaa at position 122 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, lle, Tyr or Cys;

Xaa at position 123 is Ala, Met, Glu, His, Ser, Pro, Tyr or Leo;

and which, in addition, have Met- which precedes the amino acid at position 1;

wherein the amino acids at positions 1 to 14 from the N-terminus can be removed and / or the amino acids from positions 1 to 15 from the C-terminus can also be removed from the amino acids at positions 4 to 35, designated by Xaa, are different from the amino acids corresponding to native human interleukin-3 (1-133).

Another preferred aspect of the invention is a fusion protein, of structural formula, as defined in claim 1, wherein R₂ It is

Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn

1015

Cys Xaa Xaa Met him Asp Glu Xaa lle Xaa Xaa Leu Lys Xaa Xaa

2530

Pro Xaa Pro Xaa Xaa Asp Phe Xaa Asn Leu Asn Xaa Glu Asp Xaa

4045

Xaa him Leu Met Xaa Xaa Asn Leu Arg Xaa Xaa Asn Leu Glu Ala

5560

Phe Xaa Arg Xaa Xaa Lys Xaa Xaa Xaa Asn Ala Ser Ala lle Glu

7075

Xaa Xaa Leu Xaa Xaa Leu Xaa Pro Cys Leu Pro Xaa Xaa Thr Ala

8590

Xaa Pro Xaa Arg Xaa Pro le Xaa Xaa Xaa Xaa Gly Asp Trp Xaa

100105

Glu Phe Xaa Xaa Lys Leu Xaa Phe Tyr Leu Xaa Xaa Leu Glu Xaa

110 115120

Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Ala lle Phe

125130

Sequence no .; 3 in which:

Xaa at position 17 is Ser, Gly, Asp, Met or Gin;

Xaa at position 18 is Asn, His or lle;

Xaa at position 23 is lle, Ala, Leo or Gly;

Xaa at position 25 is Thr, His or Gin;

Xaa at position 26 is His or Ala;

RO 118016 Β1

Xaa at position 29 is Gin or Val;

Xaa at position 30 is Pro or Gly;

Xaa at position 32 is Leo, Arg, Asn or Ala; 930

Xaa at position 34 is Leo, Val, Ser, Ala, Arg, Gin, Glu, lle, Phe, Thr or Met;

Xaa at position 35 is Leo, Ala, Asn or Pro;

Xaa at position 38 is Asn or Ala;

Xaa at position 42 is Gly, Asp, Ser, Ala, Asn, lle, Leo, Met, Tyr or Arg;

Xaa at position 45 is Gin, Val, Met, Leo, Thr, Ala, Asn, Glu, or Lys; 935

Xaa at position 46 is Asp, Phe, Ser, Gin, Glu, His, Val or Thr;

Xaa at position 50 is Glu, Asn, Ser or Asp;

Xaa at position 51 is Asn, Arg, Pro, Thr or His;

Xaa at position 55 is Arg, Leo or Gly;

Xaa at position 56 is Pro, Gly, Ser, Ala, Asn, Val, Leo or Gin; 940

Xaa at position 62 is Asn, Pro or Thr;

Xaa at position 64 is Ala or Asn;

Xaa at position 65 is Val or Thr;

Xaa at position 67 is Ser or Phe;

Xaa at position 68 is Leo or Phe; 945

Xaa at position 69 is Gin, Ala, Glu or Arg;

Xaa at position 76 is Ser, Val, Asn, Pro or Gly;

Xaa at position 77 is lle or Leo;

Xaa at position 79 is Lys, Asn, Met, Arg, lle or Gly;

Xaa at position 80 is Asn, Gly, Glu, or Arg; 950

Xaa at position 82 is Leo, Gin, Trp, Arg, Asp, Asn, Glu, His, Met, Phe, Ser, Thr, Tyr or Val; Xaa at position 87 is Leo or Ser;

Xaa at position 88 is Ala or Trp;

Xaa at position 91 is Ala or Pro;

Xaa at position 93 is Thr, Asp or Ala; 955

Xaa at position 95 is His, Pro, Arg, Val, Gly, Asn, Ser or Tyr;

Xaa at position 98 is His, lle, Asn, Ala, Thr, Leo, Gin, Glu, Lys, Met, Ser, Tyr, Val or Pro; Xaa at position 99 is lle or Leo;

Xaa at position 100 is Lys or Arg;

Xaa at position 101 is Asp, Pro, Met, Lys, Thr, His, Pro, Asn, lle, Leo or Tyr; 960

Xaa at position 105 is Asn, Pro, Ser, lle or Asp;

Xaa at position 108 is Arg, Ala or Ser;

Xaa at position 109 is Arg, Thr, Glu, Leo or Ser;

Xaa at position 112 is Thr or Gin;

Xaa at position 116 is Lys, Val, Trp, Ala, His, Phe, Tyr or lle; 965

Xaa at position 117 is Thr or Ser;

Xaa at position 120 is Asn, Pro, Leo, His, Val or Gin;

Xaa at position 121 is Ala, Ser, lle, Pro or Asp;

Xaa at position 122 is Gin, Met, Trp, Phe, Pro, His, lle or Tyr;

Xaa at position 123 is Ala, Met, Glu, Ser or Leo; 970

Another preferred aspect is the fusion protein wherein R, are amino acids that differ from the corresponding residue of native human IL-3 are selected from the group consisting of: Xaa at position 42 is Gly, Asp, Ser, lle, Leu, Met, Tyr or Arg; Xaa at position 45 is Gin, Val, Met or Asn; Xaa at position 46 is Asp, Ser, Gin, His or Val;

Xaa at position 50 is Glu or Asp;

975

RO 118016 Β1

Xaa at position 51 is Asn, Pro or Thr;

Xaa at position 62 is Asn or Pro;

Xaa at position 76 is Ser or Pro;

Xaa at position 82 is Leo, Trp, Asp, Asn, Glu, His, Phe, Ser, Tyr or Val;

Xaa at position 95 is His, Arg, Thr, Asn or Ser;

Xaa at position 98 is His, lle, Leo, Ala, Gin, Lys, Met, Ser, Tyr or Val;

Xaa at position 100 is Lys or Arg;

Xaa at position 101 is Asp, Pro, His, Asn, lle or Leo;

Xaa at position 105 is Asn or Pro;

Xaa at position 108 is Arg, Ala or Ser;

Xaa at position 116 is Lys, Val, Trp, Ala, His, Phe or Tyr;

Xaa at position 121 is Ala or lle;

Xaa at position 122 is Gin, lle and

Xaa at position 123 is Ala, Met or Glu;

Another preferred aspect is a fusion protein of the structural formula defined in claim wherein R, is

Asn Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1015

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa

2530

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

4045

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

5560

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

7075

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

8590

Xaa Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

100105

Xaa Xaa Xaa Xaa Gin Gin

110

Sequence no .: 4 in which:

Xaa at position 3 is Ser, Lys, Gly, Asp, Met, Gin or Arg;

Xaa at position 4 is Asn, His, Leo, lle, Phe, Arg or Gin;

Xaa at position 5 is Met, Phe, lle, Arg, Gly, Ala or Cys;

Xaa at position 6 is lle, Cys, Gin, Glu, Arg, Pro or Ala;

Xaa at position 7 is Asp, Phe, Lys, Arg, Ala, Gly, Glu, Gin, Asn, Thr, Ser or Val;

Xaa at position 8 is Glu, Trp, Pro, Ser, Ala, His, Asp, Asn, Gin, Leo, Val or Gly;

Xaa at position 9 is lle, Val, Ala, Leu, Gly, Trp, Lys, Phe, Leu, Ser or Arg;

Xaa at position 10 is lle, Gly, Val, Arg, Ser, Phe or Leo;

Xaa at position 11 is Thr, His, Gly, Gin, Arg, Pro or Ala;

Xaa at position 12 is Thr, Phe, Gly, Arg, Ala or Trp;

Xaa at position 13 is Leo, Gly, Arg, Thr, Ser or Ala;

Xaa at position 14 is Lys, Arg, Leo, Gin, Gly, Pro, Val or Trp;

Xaa at position 15 is Gin, Asn, Leo, Pro, Arg or Val;

Xaa at position 16 is Pro, His, Thr, Gly, Asp, Gin, Ser, Leo, or Lys;

Xaa at position 17 is Pro, Asp, Gly, Ala, Arg, Leo or Gin;

RO 118016 Β1

Xaa at position 18 is Leo, Val, Arg, Gin, Asn, Gly, Ala or Glu;

Xaa at position 19 is Pro, Leo, Gin, Ala, Thr or Glu;

Xaa at position 20 is Leo, Val, Gly, Ser, Lys, Glu, Gin, Thr, Arg, Ala, Phe, lle or Met;

Xaa at position 21 is Leo, Ala, Gly, Asn, Pro, Gin or Val;

Xaa at position 22 is Asp, Leo or Val;

Xaa at position 23 is Phe, Ser, Pro, Trp or lle;

Xaa at position 24 is Asn or Ala;

Xaa at position 26 is Leo, Trp or Arg;

Xaa at position 27 is Asn, Cys, Arg, Leo, His, Met or Pro;

Xaa at position 28 is Gly, Asp, Ser, Cys, Asn, Lys, Thr, Leu, Val, Glu, Phe, Tyr, lle or Met;

Xaa at position 29 is Glu, Asn, Tyr, Leo, Phe, Asp, Ala, Cys, Gin, Arg, Gly or Ser;

Xaa at position 30 is Asp, Serum, Leo, arg, Lys, Thr, Met, Trp, Glu, Asn, Gin, Ala or Pro;

Xaa at position 31 is Gin, Pro, Phe, Val, Met, Leo, Thr, Lys, Asp, Asn, Arg, Ser, Ala, lle, Glu, His or Trp.

Xaa at position 32 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Lys, His, Ala, Tyr, lle, Val or Gly;

Xaa at position 33 is lle, Gly, Val, Ser, Arg, Pro or His;

Xaa at position 34 is Leo, Ser, Cys, Arg, lle, His, Phe, Glu, Lys, Thr, Ala, Met, Val or Asn;

Xaa at position 35 is Met, Arg, Ala, Gly, Pro, Asn, His or Asp;

Xaa at position 36 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Ser, Ala, lle, Val, His, Phe, Met or Gin;

Xaa at position 37 is Asn, Arg, Met, Pro, Ser, Thr or His;

Xaa at position 38 is Asn, His, Arg, Leo, Gly, Ser or Thr;

Xaa at position 39 is Leo, Thr, Ala, Gly, Glu, Pro, Lys, Ser or Met;

Xaa at position 40 is Arg, Asp, lle, Ser, Val, Thr, Gin, Asn, Lys, His, Ala or Leu;

Xaa at position 41 is Arg, Thr, Val, Ser, Leo or Gly;

Xaa at position 42 is Pro, Gly, Cys, Ser, Gin, Glu, Arg, Arg, His, Thr, Ala, Tyr, Phe, Leo, Val or Lys;

Xaa at position 43 is Asn or Gly;

Xaa at position 44 is Leo, Serum, Asp, Arg, Gin, Val or Cys;

Xaa at position 45 is Glu, Tyr, His, Leo, Pro or Arg;

Xaa at position 46 is Ala, Ser, Pro, Tyr, Asn or Thr;

Xaa at position 47 is Phe, Asn, Glu, Pro, Lys, Arg or Ser;

Xaa at position 48 is Asn, His, Val, Arg, Pro, Thr, Asp or lle;

Xaa at position 49 is Arg, Tyr, Trp, Lys, Ser, His, Pro or Val;

Xaa at position 50 is Ala, Asn, Pro, Ser or Lys;

Xaa at position 51 is Val, Thr, Pro, His, Leo, Phe or Ser;

Xaa at position 52 is Lys, lle, Arg, Val, Asn, Glu or Ser;

Xaa at position 53 is Ser, Ala, Phe, Val, Gly, Asn, lle, Pro, or His;

Xaa at position 54 is Leo, Val, Trp, Ser, lle, Phe, Thr or His;

Xaa at position 55 is Gin, Ala, Pro, Thr, Glu, Arg, Trpn Gly or Leo;

Xaa at position 56 is Asn, Leo, Val, Trp, Pro or Ala;

Xaa at position 57 is Ala, Met, Leo, Pro, Arg, Glu, Thr, Gin, Trp or Asn;

Xaa at position 58 is Ser, Glu, Met, Ala, His, Asn, Arg or Asp;

Xaa at position 59 is Ala, Glu, Asp, Leo, Ser, Gly, Thr or Arg;

Xaa at position 60 is lle, Met, Thr, Pro, Arg, Gly or Ala;

Xaa at position 61 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gin or Leo;

Xaa at position 62 is Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly, or Asp;

Xaa at position 63 is lle, Ser, Arg, Thr or Leo;

1030

1035

1040

1045

1050

1055

1060

1065

1070

RO 118016 Β1

Xaa at position 64 is Leo, Ala, Ser, Glu, Phe, Gly or Arg;

Xaa at position 65 is Lys, Thr, Asn, Met, Arg, lle, Gly or Asp;

Xaa at position 66 is Asn, Trp, Val, Gly, Thr, Leo, Glu or Arg;

Xaa at position 67 is Leo, Gin, Gly, Ala, Trp, Arg, Val or Lys;

Xaa at position 68 is Leo, Gin, Lys, Trp, Arg, Asp, Glu, Asn, His, Thr, Ser, Ala, Tyr, Phe, lle, Met or Val;

Xaa at position 69 is Pro, Ala, Thr, Trp, Arg or Met;

Xaa at position 70 is Cys, Glu, Gly, Arg, Met or Val;

Xaa at position 71 is Leo, Asn, Val or Gin;

Xaa at position 72 is pro, Cys, Arg, Ala or Lys;

Xaa at position 73 is Leo, Ser, Trp or Gly;

Xaa at position 74 is Ala, Lys, Arg, Val or Trp;

Xaa at position 75 is Thr, Asp, Cys, Leo, Val, Glu, His, Asn, or Ser;

Xaa at position 76 is Ala, Pro, Ser, Thr, Gly, Asp, lle or Met;

Xaa at position 77 is Ala, Pro, Ser, Thr, Phe, Leo, Asp or His;

Xaa at position 78 is Pro, Phe, Arg, Ser, Lys, His, Ala, Gly, lle or Leo;

Xaa at position 79 is Thr, Asp, Ser, Asn, Pro, Ala, Leo or Arg;

Xaa at position 80 is Arg, lle, Ser, Glu, Leu, Val, Gin, Lys, His, Ala or Pro;

Xaa at position 81 is His, Gin, Pro, Arg, Val, Leo, Gly, Thr, Asn, Lys, Ser, Ala, Trp, Phe, lle or Tyr;

Xaa at position 82 is Pro, Lys, Tyr, Gly, lle or Thr;

Xaa at position 83 is lle, Val, Lys, Ala or Asn;

Xaa at position 84 is His, lle, Asn, Leo, Asp, Ala, Thr, Glu, Gin, Ser, Phe, Met, Val, Lys, Arg, Tyr or Pro;

Xaa at position 85 is lle, Leo, Arg, Asp, Val, Pro, Gin, Gly, Ser, Phe or His;

Xaa at position 86 is Lys, Tyr, Leo, His, Arg, lle, Ser, Gin, or Pro;

Xaa at position 87 is Asp, Pro, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, Gly, lle, Leo or Gin;

Xaa at position 88 is Gly, Leu, Glu, Lys, Ser, Tyr or Pro;

Xaa at position 89 is Asp or Ser;

Xaa at position 90 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leo, Gin, Lys, Ala, Phe or Gly;

Xaa at position 91 is Asn, Pro, Ala, Phe, Ser, Trp, Gin, Tyr, Leo, Lys, lle, Asp or His;

Xaa at position 92 is Glu, Ser, Ala, Lys, Thr, lle, Gly or Pro;

Xaa at position 94 is Arg, Lys, Asp, Leo, Thr, lle, Gin, His, Ser, Ala or Pro;

Xaa at position 95 is Arg, Thr, Pro, Glu, Tyr, Leo, Ser or Gly;

Xaa at position 96 is Lys, Ala, Asn, Thr, Leo, Arg, Gin, His, Glu, Ser, Ala or Trp;

Xaa at position 97 is Leo, lle, Arg, Asp or Met;

Xaa at position 98 is Thr, Val, Gin, Tyr, Glu, His, Ser or Phe;

Xaa at position 99 is Phe, Ser, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu, lle, Val or Asn;

Xaa at position 100 is Tyr, Cys, His, Ser, Trp, Arg or Leo;

Xaa at position 101 is Leo, Asn, Val, Pro, Arg, Ala, His, Thr, Trp or Met;

Xaa at position 102 is Lys, Leu, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, Ser, Asn, His, Ala, Tyr, Phe, Gin, or lle;

Xaa at position 103 is Thr, Ser, Asn, lle, Trp, Lys or Pro;

Xaa at position 104 is Leo, Ser, Pro, Ala, Glu, Cys, Asp or Tyr;

Xaa at position 105 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr or Arg;

Xaa at position 106 is Asn, Ala, Pro, Leo, His, Val or Gin;

Xaa at position 107 is Ala, Ser, lle, Asn, Pro, Lys, Asp or Gly;

Xaa at position 108 is Gin, Ser, Met, Trp, Arg, Phe, Pro, His, lle, Tyr or Cys;

RO 118016 Β1

Xaa at position 109 is Ala, Met, Glu, His, Ser, Pro, Tyr or Leo;

and which additionally have Met- or Met-Ala- which precedes the amino acid at position 1;

wherein the amino acids at positions 1 to 14 from the N-terminal end and / or the amino acids from positions 1 to 15 from the C-terminal end can be removed and the amino acids from positions 4 to 44 designated by Xaa are different from the corresponding amino acids native human interleukin-3 (1-133),

R₂ is II-3, a variant II-3 or a colony-stimulating factor selected from GM-CSF, CSF-1, CSF-G (CSF-granulocyte), C-mpI ligand, M-CSF, erythropoietin (EPO), IL -1, IL-4, IL-2.IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, LIF, flt3 / flk2, human growth hormone, B cell growth factor, B cell differentiation factor, eosinophil differentiation factor, and stem cell factor (SCF);

and L is a linker capable of binding the radical X to Y.

Another preferred aspect of the invention is the fusion protein of the structural formula defined in claim 1 wherein R, is

Asn Cys Xaa Xaa Xaa le Xaa Glu Xaa Xaa Xaa Xaa Leu Lys Xaa

1015

Xaa Xaa Xaa Xaa Xaa Xaa Asp Xaa Xaa Asn Leu Asn Xaa Glu Xaa

2530

Xaa Xaa Leu Met Xaa Xaa Asn Leu Xaa Xaa Xaa Asn Leu Glu

4045

Xaa Phe Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa Xaa Xaa li

5560

Glu Xaa Xaa Leu Xaa Xaa Leu Xaa Xaa Cys Xaa Pro Xaa Xaa Thr

7075

Ala Xaa Pro Xaa Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Gly Asp Xaa

8590

Xaa Xaa Phe Xaa Xaa Lys Leu Xaa Phe Xaa Xaa Xaa Xaa Leu Glu

100105

Xaa Xaa Xaa Xaa Gin Gin

110

Sequence no .: 5 in which:

Xaa at position 3 is Ser, Lys, Gly, Asp, Met or Gin;

Xaa at position 4 is Asn, His or lle;

Xaa at position 5 is Met or lle;

Xaa at position 7 is Asp or Glu;

Xaa at position 9 is lle, Ala, Leo or Gly;

Xaa at position 10 is lle, Val or Leu;

Xaa at position 11 is Thr, His, Gin or Ala;

Xaa at position 12 is His or Ala;

Xaa at position 15 is Gin, Asn or Val;

Xaa at position 16 is Pro, Gly or Gin;

Xaa at position 17 is Pro, Asp, Gly or Gin;

Xaa at position 18 is Leo, Arg, Gin, Asn, Gly, Ala or Glu;

Xaa at position 19 is Pro or Glu;

Xaa at position 20 is Leo, Val, Gly, Ser, Lys, Ala, Arg, Gin, Glu, lle, Phe, Thr or Met;

Xaa at position 21 is Leo, Ala, Asn, Pro, Gin or Val;

Xaa at position 23 is Phe, Ser, Pro or Trp;

Xaa at position 24 is Asn or Ala;

1125

1130

1135

1140

1145

1150

1155

1160

1165

1170

RO 118016 Β1

Xaa at position 28 is Gly, Asp, Ser, Cys, Ala, Asn, lle, Leo, Met, Tyr, lle or Met;

Xaa at position 30 is Asp or Glu;

Xaa at position 31 is Gin, Val, Met, Leo, Thr, Ala, Asp, Glu, Ser or Lys;

Xaa at position 32 is Asp, Phe, Ser, Thr, Ala, Asn, Gin, Glu, His, lle, Lys, Tyr, Val or Cys;

Xaa at position 36 is Glu, Ala, Asn, Ser or Asp;

Xaa at position 40 is Arg or Ala;

Xaa at position 41 is Arg, Thr, Val, Leo or Gly;

Xaa at position 42 is Pro, Gly, Ser, Gin, Ala, Arg, Asn, Glu, Leo, Thr, Val or Lys;

Xaa at position 46 is Ala or Ser;

Xaa at position 48 is Asn, Pro, Thr or lle;

Xaa at position 49 is Arg or Lys;

Xaa at position 50 is Ala or Asn;

Xaa at position 51 is Val or Thr;

Xaa at position 52 is Lys or Arg;

Xaa at position 53 is Ser, Phe or His;

Xaa at position 54 is Leo, lle, Phe or His;

Xaa at position 55 is Gin, Ala, Pro, Thr, Glu, Arg or Gly;

Xaa at position 57 is Ala, Pro or Arg;

Xaa at position 58 is Ser, Glu, Arg or Asp;

Xaa at position 59 is Ala or Leo;

Xaa at position 62 is Ser, Val, Ala, Asn, Glu, Pro or Gly;

Xaa at position 63 is lle or Leo;

Xaa at position 65 is Lys, Thr, Gly, Asn, Met, Arg, lle, or Asp;

Xaa at position 66 is Asn, Gly, Glu or Arg;

Xaa at position 68 is Leo, Gin, Trp, Arg, Asp, Ala, Asn, Glu, His, lle, Met, Phe, Ser, Thr, Tyr or Val;

Xaa at position 69 is Pro or Thr;

Xaa at position 71 is Leo or Val;

Xaa at position 73 is Leo or Ser;

Xaa at position 74 is Ala or Trp;

Xaa at position 77 is Ala or Pro;

Xaa at position 79 is Thr, Asp, Ser, Pro, Ala, Leo or Arg;

Xaa at position 81 is His, Pro, Arg, Val, Leo, Gly, Asn, Phe, Ser or Thr;

Xaa at position 82 is Pro or Tyr;

Xaa at position 83 is lle or Val;

Xaa at position 84 is His, lle, Asn, Leo, Ala, Thr, Arg, Gin, Lys, Met, Ser, Tyr, Val or Pro;

Xaa at position 85 is lle, Leo or Val;

Xaa at position 86 is Lys, Arg, lle, Gin, Pro or Ser;

Xaa at position 87 is Asp, Pro, Met, Lys, His, Thr, Asn, lle, Leo or Tyr;

Xaa at position 90 is Trp or Leo;

Xaa at position 91 is Asn, Pro, Ala, Ser, Trp, Gin, Tyr, Leo, Lys, lle, Asp or His;

Xaa at position 92 is Glu or Gly;

Xaa at position 94 is Arg, Ala or Ser;

Xaa at position 96 is Arg, Thr, Glu, Leo or Ser;

Xaa at position 98 is Thr, Val or Gin;

Xaa at position 100 is Tyr or Trp;

Xaa at position 101 is Leo or Ala;

Xaa at position 102 is Lys, Thr, Val, trp, Ser, Ala, His, Met, Phe, Tyr or lle;

Xaa at position 103 is Thr or Ser;

RO 118016 Β1

Xaa at position 106 is Asn, Pro, Leo, His, Val or Gin;

Xaa at position 107 is Ala, Ser, lle, Asn, Pro, Asp or Gly;

Xaa at position 108 is Gin, Ser, Met, Trp, Arg, Phe, Pro or His, lle, Tyr, Cys;

Xaa at position 109 is Ala, Met, Glu, His, Ser, Pro, Tyr or Leo;

and which additionally have Met- or Met-Ala- which precedes the amino acid at position 1;

wherein the amino acids at positions 1 to 14 at the N-terminus can be removed and / or the amino acids at positions 1 to 15 at the C-terminus can be removed and the amino acids at positions 4 to 35 designated by Xaa are different from the amino acids corresponding to native human interleukin-3 (1-133).

Another preferred aspect of the invention is a fusion protein of the structural formula defined in claim 1 wherein R, is

Asn Cys Xaa Xaa Xaa le Asp Glu Xaa le Xaa Xaa Leu Lys Xaa

1015

Xaa Pro Xaa Pro Xaa Xaa Asp Phe Xaa Asn Leu Asn Xaa Glu Asp

2530

Xaa Xaa Leu Met Xaa Xaa Asn Leu Arg Xaa Xaa Asn Leu Glu

4045

Ala Phe Xaa Arg Xaa Xaa Lys Xaa Xaa Xaa Asn Ala Ser Ala lle

5560

Glu Xaa Xaa Leu Xaa Xaa Leu Xaa Pro Cys Leu Pro Xaa Xaa Thr

7075

Ala Xaa Pro Xaa Arg Xaa Pro le Phe Xaa Xaa Xaa Gly Asp Trp

8590

Xaa Glu Phe Xaa Xaa Lys Leu Xaa Phe Tyr Leu Xaa Xaa Leu Glu

100105

Xaa Xaa Xaa Xaa Gin Gin

110

Sequence no .: 6 in which:

Xaa at position 3 is Ser, Gly, Asn or Gin;

Xaa at position 4 is Asn, His or lle;

Xaa at position 9 is lle, Ala, Leo or Gly;

Xaa at position 11 is Thr, His or Gin;

Xaa at position 12 is His or Ala;

Xaa at position 15 is Gin or Asn;

Xaa at position 16 is Pro or Gly;

Xaa at position 18 is Leo, Arg, Asn or Ala;

Xaa at position 20 is Leo, Val, Ser, Ala, Arg, Gin, Glu, lle, Phe, Thr or Met;

Xaa at position 21 is Leo, Ala, Asn or Pro;

Xaa at position 24 is Asn or Ala;

Xaa at position 28 is Gly, Asp, Ser, Ala, Asn, lle, Leo, Met, Tyr or Arg;

Xaa at position 31 is Gin, Val, Met, Leo, Ala, Asn, Glu or Lys;

Xaa at position 32 is Asp, Phe, Ser, Ala, Gin, Glu, His, Val, or Thr;

Xaa at position 36 is Glu, Asn, Ser or Asp;

Xaa at position 37 is Asn, Arg, Pro, Thr or His;

Xaa at position 41 is Arg, Leo or Gly;

Xaa at position 42 is Pro, Gly, Ser, Ala, Asn, Val, Leo or Gin;

Xaa at position 48 is Asn, Pro or Thr;

1225

1230

1235

1240

1245

1250

1255

1260

1265

1270

RO 118016 Β1

Xaa at position 50 is Ala or Asn;

Xaa at position 51 is Val or Thr;

Xaa at position 53 is Ser or Phe;

Xaa at position 54 is Leo or Phe;

Xaa at position 55 is Gin, Ala, Glu or Arg;

Xaa at position 62 is Ser, Val, Asn, Pro or Gly;

Xaa at position 63 is lle or Leo;

Xaa at position 65 is Lys, Asn, Met, Arg, lle or Gly;

Xaa at position 66 is Asn, Gly, Glu or Arg;

Xaa at position 68 is Leo, Gin, Trp, Arg, Asp, Asn, Glu, His, Met, Phe, Ser, Thr, Tyr or Val; Xaa at position 73 is Leo or Ser;

Xaa at position 74 is Ala or Trp;

Xaa at position 77 is Ala or Pro;

Xaa at position 79 is Thr, Asp or Ala;

Xaa at position 81 is His, Pro, Arg, Val, Gly, Asn, Ser or Thr;

Xaa at position 84 is His, lle, Asn, Ala, Thr, Arg, Gin, Glu, Lys, Met, Ser, Tyr, Val or Leo; Xaa at position 85 is lle or Leo;

Xaa at position 86 is Lys or Arg;

Xaa at position 87 is Asp, Pro, Met, Lys, His, Asn, lle, Leu, or Tyr;

Xaa at position 91 is Asn, Pro, Ser, lle or Asp;

Xaa at position 94 is Arg, Ala or Ser;

Xaa at position 95 is Arg, Thr, Glu, Leo or Ser;

Xaa at position 98 is Thr or Gin;

Xaa at position 102 is Lys, Val, Trp or lle;

Xaa at position 103 is Thr, Ala, His, Phe or Ser;

Xaa at position 106 is Asn, Pro, Leo, His, Val or Gin;

Xaa at position 107 is Ala, Ser, lle, Pro or Asp;

Xaa at position 108 is Gin, Met, Trp, Phe, Pro, His, lle or Tyr;

Xaa at position 109 is Ala, Met, Glu, Ser or Leo;

which additionally have Met- or Met-Ala- which precedes the amino acid at position 1; wherein the amino acids from positions 1 to 14, from the N-terminal end, can be removed and / or the amino acids from positions 1 to 15, from the C-terminal end, the amino acids from positions 4 to 26 may also be removed, designated by Xaa, are different from amino acids corresponding to native human interleukin-3 (1-133)

Another preferred aspect of the invention is the fusion protein of the structural formula as defined in claim 1, wherein R is (Met)_m-Ala Pro Met Thr Gin Thr Thr Ser Leu Lys Thr

510

Ser Trp Val Asn Cys Ser Xaa Xaa Xaa Asp Glu Xaa him

1520

Xaa His Leu Lys Xaa Pro Pro Xaa Pro Xaa Leu Asp Xaa

3035

Xaa Asn Leu Asn Xaa Glu Asp Xaa Asp lle Leu Xaa Glu

4550

Xaa Asn Leu Arg Xaa Xaa Asn Leu Xaa Xaa Phe Xaa Xaa

5560

Ala Xaa Lys Xaa Leu Xaa Asn Ala Ser Xaa li Glu Xaa

7075

RO 118016 Β1 Leu Xaa Asn Leu Xaa Pro Cys Xaa Pro Xaa Xaa Thr 8085

Ala Xaa Pro Xaa Arg Xaa Pro le Xaa le Xaa Xaa Gly

95100

Asp Thr Xaa Glu Phe Arg Xaa Lys Leu Xaa Phe Tyr Leu

105 110115

Xaa Xaa Leu Glu Xaa Ala Gin Xaa Gin Gin Thr Thr Leu 120125

Be Leu Ala le Phe

130 wherein m is 0 or 1

Xaa at position 18 is Asn, lle;

Xaa at position 19 is Met, Ala or lle;

Xaa at position 20 is lle, Pro or Ser;

Xaa at position 23 is lle, Ala or Leo;

Xaa at position 25 is Thr or His;

Xaa at position 29 is Gin, Arg, Val or lle;

Xaa at position 32 is Leo, Ala, Asn or Arg;

Xaa at position 34 is Leo or Ser;

Xaa at position 37 is Phe, Pro or Ser;

Xaa at position 38 is Asn or Ala;

Xaa at position 42 is Gly, Ala, Ser, Asp or Asn;

Xaa at position 45 is Gin, Val or Met;

Xaa at position 46 is Asp or Ser;

Xaa at position 49 is Met, lle, Leo or Asp;

Xaa at position 50 is Glu or Asp;

Xaa at position 51 is Asn, Arg or Ser;

Xaa at position 55 is Arg, Leo or Thr;

Xaa at position 56 is Pro or Ser;

Xaa at position 59 is Glu or Leo;

Xaa at position 60 is Ala or Ser;

Xaa at position 62 is Asn, Val or Pro;

Xaa at position 63 is Arg or His;

Xaa at position 65 is Wave or Ser;

Xaa at position 67 is Ser, Asn, His or Gin;

Xaa at position 69 is Gin or Glu;

Xaa at position 73 is Ala or Gly;

Xaa at position 76 is Ser, Ala or Pro;

Xaa at position 79 is Lys, Arg or Ser;

Xaa at position 82 is Leo, Glu, Val or Trp;

Xaa at position 85 is Leo or Val;

Xaa at position 87 is Leo, Ser or Tyr;

Xaa at position 88 is Ala or Trp;

Xaa at position 91 is Ala or Pro;

Xaa at position 93 is Pro or Ser;

Xaa at position 95 is His or Thr;

Xaa at position 98 is His, lle or Thr;

Xaa at position 100 is Lys or Arg;

Xaa at position 101 is Asp, Ala or Met;

1320

1325 (Sequence no. 7)

1330

1335

1340

1345

1350

1355

1360

1365

RO 118016 Β1

Xaa at position 105 is Asn or Glu;

Xaa at position 109 is Arg, Glu or Leo;

Xaa at position 112 is Thr or Gin;

Xaa at position 116 is Lys, Val, Trp or Ser;

Xaa at position 117 is Thr or Ser;

Xaa at position 120 is Asn, Gin or His;

Xaa at position 123 is Ala or Glu;

provided that the amino acids at positions 4 to 44, designated by Xaa, are different from the amino acids corresponding to native human interleukin-3 (1-133).

Another preferred aspect of the invention is a fusion protein of the structural formula as defined in claim 1, wherein it is (Met_m-That_n)_p-Asn Cys Ser Xaa Xaa Xaa Asp Glu Xaa him

510

Xaa His Leu Lys Xaa Pro Pro Xaa Pro Xaa Leu Asp Xaa

1520

Xaa Asn Leu Asn Xaa Glu Asp Xaa Xaa leu Xaa Glu

3035

Xaa Asn Leu Arg Xaa Xaa Asn Leu Xaa Xaa Phe Xaa Xaa

4550

Ala Xaa Lys Xaa Leu Xaa Asn Ala Ser Xaa li Glu Xaa

5560 you read Xaa Asn Xaa Xaa Pro Cys Xaa Pro Xaa Xaa Thr

7075

Ala Xaa Pro Xaa Arg Xaa Pro le Xaa le Xaa Xaa Gly

8085

Asp Thr Xaa Glu Phe Arg Xaa Lys Leu Xaa Phe Tyr Leu

95100

Xaa Xaa Leu Glu Xaa Ala Gin Xaa Gin Gin

105 110 (Sequence Nr .: 8) where m is 0 or 1; n is 0 or 1; P is 0 or 1;

Xaa at position 4 is Asn or lle;

Xaa at position 5 is Met, Ala or lle;

Xaa at position 6 is lle, Pro or Leo;

Xaa at position 9 is lle, Ala or Leo;

Xaa at position 11 is Thr or His;

Xaa at position 15 is Gin, Arg, Val or lle;

Xaa at position 18 is Leo, Ala, Asn or Arg;

Xaa at position 20 is Leo or Ser;

Xaa at position 23 is Phe, Pro or Ser;

Xaa at position 24 is Asn or Ala;

Xaa at position 28 is Gly, Ala, Ser, Asp or Asn;

Xaa at position 31 is Gin, Val or Met;

Xaa at position 32 is Asp or Ser;

Xaa at position 35 is Met, lle, Leo or Asp;

Xaa at position 36 is Glu or Asp;

Xaa at position 37 is Asn, Arg or Ser;

Xaa at position 41 is Arg, Leo or Thr;

Xaa at position 42 is Pro or Ser;

Xaa at position 45 is Glu or Leo;

RO 118016 Β1

Xaa at position 46 is Ala or Ser;

Xaa at position 48 is Asn, Val or Pro;

Xaa at position 49 is Arg or His,

Xaa at position 51 is Wave or Ser;

Xaa at position 53 is Ser, Asn, His or Gin;

Xaa at position 55 is Gin or Glu;

Xaa at position 59 is Ala or Gly

Xaa at position 62 is Ser, Ala or Pro;

Xaa at position 65 is Lys, Arg or Ser;

Xaa at position 67 is Leo, Gin or Val;

Xaa at position 68 is Leo, Glu, Val or Trp;

Xaa at position 71 is Leo or Val;

Xaa at position 73 is Leo, Ser or Tyr;

Xaa at position 74 is Ala or Trp;

Xaa at position 77 is Ala or Pro;

Xaa at position 79 is Pro or Ser;

Xaa at position 81 is His or Thr;

Xaa at position 84 is His, lle or Thr;

Xaa at position 86 is Lys or Arg;

Xaa at position 87 is Asp, Ala or Met;

Xaa at position 91 is Asn or Glu;

Xaa at position 95 is Arg, Glu or Leo;

Xaa at position 98 is Thr or Gin;

Xaa at position 102 is Lys, Val, Trp or Ser;

Xaa at position 103 is Thr or Ser;

Xaa at position 106 is Asn, Gin or His;

Xaa at position 109 is Ala or Glu;

cu condiția că aminoacizii de la pozițiile 4 la 44, desemnați prin Xaa, sunt diferiți de aminoacizii corespunzători interleukinei-3 umane native (15-125).

Un alt aspect preferat este proteina de fuziune, în care R, este

1420

1425

1430

1435

1440

1445

Asn Cys Ser lle Met lle Asp Glu lle lle His His Leu

<td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Ala</td><td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>lle</td><td>Glu</td><td>Ser</td><td>lle</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td>

<td>His</td><td>lle</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

<td colspan="3">[Secv. nr.:9]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Asn Cys Ser lle Met lle Asp Glu lle lle His His Leu

<td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td></td>

<td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td><td></td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td><td> 1460</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>lle</td><td>Glu</td><td>Ser</td><td>lle</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td><td></td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td></td>

<td>His</td><td>lle</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td><td></td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td><td></td>

<td colspan="3">[Secv. nr.:10]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 1465</td>

RO 118016 Β1

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu

<td>Lys</td><td>Val</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Ser</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

<td colspan="3">[Secv. nr.:11]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Leu</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin.</td><td>Gin</td>

[Secv. nr.:12]

Asn Cys Ser Asn Met Ile Asp Glu ile ile Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Leu</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

[Secv. nr.:13]

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td>

<td>pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

RO 118016 Β1

Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala Gin Ala Gin Gin [Secv. nr.:14]

1515

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

<td colspan="3">[Secv. nr.:15]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

1520

1525

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>Thr</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

1530

1535 [secv. nr.:16]

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu

1540

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td>

<td colspan="3">[Secv. nr.:17]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

1545

1550

Asn Cys Ser Asn Met Ile Asp Glu Ile Ile Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

1555

RO 118016 Β1

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>lle</td><td>Glu</td><td>Ser</td><td>lle</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td>

<td>His</td><td>lle</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Ser</td><td>Leu</td><td>Glu</td><td>His</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td>

<td colspan="3">[Secv. nr.:18]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Asn Cys Ser Asn Met lle Asp Glu lle lle Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td>

<td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td>

[Secv. nr.: 19]

Asn Cys Ser Asn Met lle Asp Glu lle lle Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td>

<td>Thr</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td>

[Secv. nr.: 20]

Asn Cys Ser Asn Met lle Asp Glu lle lle Thr His Leu

<td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Arg</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Gin</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>C-lu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td>

<td>Thr</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Ser</td><td>Leu</td><td>Glu</td><td>His</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td>

[Secv. nr.: 21]

Asn Cys Ser lle Met lle Asp Glu lle lle His His Leu

RO 118016 Β1

1605

<td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Ala</td><td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Leu</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td colspan="2">Gly Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td colspan="2">Lys Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

<td colspan="2">[Secv. nr.</td><td> : 22]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="13">Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Lei</td>

<td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

[Secv. nr.: 23]

1610

<img file="RO118016B1_D0001.tif" />

1620

1625

Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu

<td>Lys</td><td>Val</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Ser</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td>

<td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Leu</td>

<td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>ser</td><td>Ala</td><td>Ile</td><td>Glu</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Pro</td>

<td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td>

<td>His</td><td>Ile</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td>Leu</td>

<td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Gin</td>

[Secv. nr.: 24]

1630

1635

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>Thr</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Arg</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td>

<td>Gin</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

1640

1645

RO 118016 Β1

Gin [Secv. nr.: 25]

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Asn</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>Thr</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Arg</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td>

<td>Gin</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>Thr</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td colspan="3">Gin [Secv. nr.:</td><td> 26]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Asn</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>Thr</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Phe</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Gly</td><td>Glu</td><td>Asp</td><td>Gin</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Arg</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ala</td><td>Phe</td><td>Asn</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Ser</td><td>Leu</td>

<td>Gin</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>Thr</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Ser</td><td>Leu</td><td>Glu</td><td>His</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

Gin [Secv. nr.: 27]

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ala</td><td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>lle</td><td>Glu</td><td>Ser</td><td>lle</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>His</td><td>lle</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 28]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>lle</td><td>Glu</td><td>Ser</td><td>lle</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td>

RO 118016 Β1

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td> 1695</td>

<td>lle</td><td>His</td><td>lle</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td></td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td></td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 29]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 1700</td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td><td></td>

<td>Leu</td><td>Lys</td><td>Val</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Ser</td><td>Asn</td><td>Asn</td><td>Leu</td><td></td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td></td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td><td rowspan="2"> 1705</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Ala</td><td>lle</td><td>Glu</td><td>Ser</td><td>lle</td><td>Leu</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Leu</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Leu</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Thr</td><td>Arg</td><td>His</td><td>Pro</td><td></td>

<td>lle</td><td>His</td><td>lle</td><td>Lys</td><td>Asp</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Asn</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Arg</td><td>Lys</td><td></td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td rowspan="2">Lys</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Gin</td><td>Ala</td><td>Gin</td><td></td>

<td colspan="3">Gin [Secv. nr.:</td><td> 30]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 1710</td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ala</td><td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 31]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

Gin [Secv. nr.: 32]

1715

1720

1725

1730

<td>Met</td><td>Ala</td><td>Asn Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Val Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Ser</td><td>Asn</td><td>Asn</td><td>Leu</td>

1735

RO 118016 Β1

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 33]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ala</td><td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td colspan="2">Arg Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Thr</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 34]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Val</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Ser</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Thr</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

Gin [Secv. nr.: 35]

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Thr</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Ser</td><td>Leu</td><td>Glu</td><td>His</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 36]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

RO 118016 Β1

1785

<td>Met</td><td>Ala</td><td>Asn</td><td>cys</td><td>Ser</td><td>lle :</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Val</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>ASP</td><td>Ser</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>G1U</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>Thr</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Ser</td><td>Leu</td><td>Glu</td><td>His</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 37]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>Thr</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 38]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ala</td><td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Zle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Val</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>Thr</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Ser</td><td>Leu</td><td>. Glu</td><td>His</td><td>Ala</td><td>Gin</td><td>. Glu</td><td>Gin</td>

Gin [Secv. nr.: 39]

1790

1795

1800

1805

1810

1815

1820

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser Tle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ala</td><td>Glu</td><td>Asp</td><td>Val Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Asp</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Ser</td><td>Asn</td><td>Leu</td><td>Glu Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

1825

RO 118016 Β1

<td colspan="6">Ile Ile Ile Lys Ala Gly</td><td colspan="8">Asp Trp Gin Glu Phe Arg Glu Lys</td>

<td colspan="4">Leu Thr Phe Tyr</td><td rowspan="2">Leu</td><td rowspan="2">Val</td><td rowspan="2">Thr</td><td colspan="3" rowspan="2">Leu Glu Gin</td><td rowspan="2">Ala</td><td rowspan="2">Gin</td><td colspan="2" rowspan="2">Glu Gin</td>

<td>Gin</td><td colspan="3">[Secv. nr.: 40]</td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ala</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Met</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 41]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Met</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="3">[Secv. nr.: 42]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ala</td><td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Asp</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

Gin [Secv. nr.: 43]

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

RO 118016 Β1

1875

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Val</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="3">[Secv. nr.: 44]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

1880

1885

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>ASp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Met</td><td>Ser</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 45]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Tyr</td><td>Pro</td><td>Glu</td><td>Thr</td><td>Asp</td><td>Tyr</td><td>Lys</td><td>Asp</td><td>Asp</td><td>Asp</td><td>Asp</td><td>Lys</td>

<td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td>

<td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Ala</td>

<td>Glu</td><td>Asp</td><td>Val</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Pro</td>

<td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Asn</td>

<td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td>

<td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>Ile</td><td>Ile</td>

<td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td>

<td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td></td>

[Secv. nr.: 46]

1890

1895

1900

1905

1910

<td>Met</td><td>Ala</td><td>Tyr</td><td>Pro</td><td>Glu</td><td>Thr</td><td>ASp</td><td>Tyr</td><td>Lys</td><td>Asp</td><td>Asp</td><td>Asp</td><td>Asp</td><td>Lys</td>

<td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td>

<td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Ser</td>

<td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td><td>Pro</td>

<td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td><td>Asn</td>

<td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td>

1915

RO 118016 Β1

<td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td>lle</td>

<td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td>

<td colspan="2">Phe Tyr [Secv, nr.:</td><td colspan="2">Leu Val 47] și</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>Leu</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>lle</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Leu</td><td>Asp</td><td>Ser</td><td>Ala</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Val</td><td>Ser</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 48].</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

în continuare sunt date exemple de proteine de fuziune în conformitate cu prezenta invenție

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>ile</td><td>Met</td><td>lle</td><td>ASp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td><td>Ser</td>

<td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Cys</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Val</td>

<td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td><td>Leu</td>

<td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td><td>Ser</td>

<td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td><td>Gin</td>

<td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td>Ala</td>

<td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td><td>Thr</td>

<td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td>Gin</td>

<td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Thr</td>

RO 118016 Β1

<td>Gin</td><td colspan="2">Gly Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td>Arg</td><td>Arg</td><td> 1965</td>

<td>Ala</td><td colspan="2">Gly Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td></td>

<td>Glu</td><td>Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>Arg</td><td>His</td><td>Leu</td><td>Ala</td><td>Gin</td><td>Pro</td><td></td><td></td>

<td colspan="2">[Secv. nr.:</td><td> 121]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 1970</td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td><td></td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td></td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td></td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td> 1975</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td></td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td></td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td></td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td rowspan="2"> 1980</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td colspan="2">Gly Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td><td>Ser</td><td></td>

<td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Val</td><td></td>

<td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td><td>Leu</td><td rowspan="2"> 1985</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td><td>Leu</td>

<td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td><td>Ser</td><td></td>

<td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td><td>Gin</td><td></td>

<td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td>Ala</td><td></td>

<td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td><td>Thr</td><td> 1990</td>

<td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td>Gin</td><td></td>

<td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Thr</td><td></td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td>Arg</td><td>Arg</td><td></td>

<td>Ala</td><td>Gly</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td> 1995</td>

<td>Glu</td><td>Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>Arg</td><td>His</td><td>Leu</td><td>Ala</td><td>Gin</td><td>Pro</td><td></td><td></td>

<td colspan="2">[Secv. nr.</td><td> : 122]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

2000

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

2005

RO 118016 Β1

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Lys</td><td>lle</td><td>Ser</td><td>Pro</td><td colspan="3">Gly Gly Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td><td>Ser</td>

<td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Val</td>

<td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td><td>Leu</td>

<td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td><td>Ser</td>

<td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td><td>Gin</td>

<td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td>Ala</td>

<td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td><td>Thr</td>

<td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td>Gin</td>

<td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Thr</td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td colspan="2">Arg Arg</td>

<td>Ala</td><td>Gly</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td>

<td>Glu</td><td>Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>Arg</td><td>His</td><td>Leu</td><td>Ala</td><td>Gin</td><td>Pro</td><td></td>

<td colspan="2">[Secv. nr.</td><td> : 123]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Mec</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td><td>Ser</td>

<td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Val</td>

<td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td><td>Leu</td>

<td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td><td>Ser</td>

<td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td><td>Gin</td>

<td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td>Ala</td>

<td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td><td>Thr</td>

<td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td>Gin</td>

<td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Thr</td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td>Arg</td><td>Arg</td>

<td>Ala</td><td>Gly</td><td>Gly</td><td>val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td>

RO 118016 Β1

Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro [Secv. nr.: 124]

2055

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td colspan="2">Gly Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td>

<td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td>

<td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td>

<td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td>

<td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td>

<td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td>

<td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td>

<td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td>

<td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 125]</td><td></td><td></td><td></td><td></td><td></td>

2060

2065

2070

2075

2080

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro .-.sn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Mec Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu C-lv</td><td>Lys</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn l-lec</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td>

<td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td>

<td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td>

<td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td>

<td>Ala</td><td>val</td><td>Lys</td><td>His</td><td>Leu Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td>

<td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td>

2085

2090

2095

RO 118016 Β1

Pro Ser Arg His Pro lle lle lle Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin [Secv. nr.: 126]

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td>

<td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td>

<td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td>

<td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td>

<td>Ala</td><td>val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td>

<td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td>

<td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td>

<td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>val</td><td>Thr</td><td>Leu</td><td>Glu</td>

<td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv. nr.</td><td> : 127]</td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Ser</td>

<td>Gly</td><td>Pro</td><td>lle</td><td>Ser</td><td>Thr</td><td>lle</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Pro</td><td>Pro</td><td>Ser</td><td>Lys</td><td>Glu</td>

<td>Ser</td><td>His</td><td>Lys</td><td>Ser</td><td>Pro</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td>

<td>Ser</td><td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Cys</td><td>Leu</td><td>Glu</td><td>Gin</td>

<td>Val</td><td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td>

RO 118016 Β1

<td>Leu</td><td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Șer</td><td> 2145</td>

<td>Ser</td><td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td colspan="2">Gly Cys</td><td>Leu</td><td>Ser</td><td></td>

<td>Gin</td><td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td></td>

<td>Ala</td><td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td><td></td>

<td>Thr</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td> 2150</td>

<td>Gin</td><td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td></td>

<td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td>Arg</td><td></td>

<td>Arg</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td><td></td>

<td>Leu</td><td>Glu</td><td>Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>Arg</td><td>His</td><td>Leu</td><td>Ala</td><td>Gin</td><td>Pro</td><td> 2155</td>

[Secv. nr.: 128]

Met Ala Asn Cys

Ser lle Met lle Asp Glu lle lle His His

<td colspan="3" rowspan="2">Leu Lys Arg</td><td colspan="5" rowspan="2">Pro Pro Asn Pro Leu</td><td colspan="7">Leu Asp Pro Asn Asn Leu</td>

<td rowspan="2">Met</td><td rowspan="2">Glu</td><td rowspan="2">Arg</td><td colspan="3" rowspan="2">Asn Leu Arg</td><td rowspan="2"> 2160</td>

<td colspan="2">Asn Ser</td><td>Glu</td><td>Asp</td><td colspan="2">Met Asp</td><td colspan="2">lle Leu</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td></td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td></td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td></td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td> 2165</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td></td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Lys</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Ser</td><td></td>

<td>Gly</td><td>Pro</td><td>lle</td><td>Ser</td><td>Thr</td><td>lle</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Pro</td><td>Pro</td><td>Ser</td><td>Lys</td><td>Glu</td><td></td>

<td>Ser</td><td>His</td><td>Lys</td><td>Ser</td><td>Pro</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td><td> 2170</td>

<td>Ser</td><td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Cys</td><td>Leu</td><td>Glu</td><td>Gin</td><td></td>

<td>Val</td><td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td><td></td>

<td>Leu</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td><td></td>

<td>Leu</td><td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td><td> 2175</td>

<td>Ser</td><td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td><td></td>

<td>Gin</td><td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td></td>

<td>Ala</td><td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td><td></td>

<td>Thr</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td> 2180</td>

<td>Gin</td><td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td></td>

<td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td>Arg</td><td></td>

<td>Arg</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td><td></td>

<td>Leu</td><td>Glu</td><td>Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>Arg</td><td>His</td><td>Leu</td><td>. Ala</td><td>. Gin</td><td>Pro</td><td></td>

[Secv. nr.: 129]

Met Ala Asn Cys Ser lle Met lle Asp Glu lle lle His His

RO 118016 Β1

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Ser</td>

<td>Gly</td><td>Pro</td><td>Ile</td><td>Ser</td><td>Thr</td><td>Ile</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Pro</td><td>Pro</td><td>Ser</td><td>Lys</td><td>Glu</td>

<td>Ser</td><td>His</td><td>Lys</td><td>Ser</td><td>Pro</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td>

<td>Ser</td><td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>cys</td><td>Leu</td><td>Glu</td><td>Gin</td>

<td>Val</td><td>Arg</td><td>Lys</td><td>Ile</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td>

<td>Leu</td><td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>Ile</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td>

<td>Ser</td><td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td>

<td>Gin</td><td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td>

<td>Ala</td><td>Leu</td><td>Glu</td><td>Gly</td><td>Ile</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td>

<td>Thr</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>Ile</td><td>Trp</td>

<td>Gin</td><td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td>

<td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td>Arg</td>

<td>Arg</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td>

<td>Leu</td><td>Glu</td><td>Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>Arg</td><td>His</td><td>Leu</td><td>Ala</td><td>Gin</td><td>Pro</td>

[Secv. nr.: 130]

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>Ile</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>Ile</td><td>Glu</td><td>Ala</td><td>Ile</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>Ile</td><td>Ile</td><td>Ile</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>Ile</td><td>Glu</td><td>Gly</td><td>Arg</td><td>Ile</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Ser</td>

<td>Gly</td><td>Pro</td><td>Ile</td><td>Ser</td><td>Thr</td><td>Ile</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Pro</td><td>Pro</td><td>Ser</td><td>Lys</td><td>Glu</td>

<td>Ser</td><td>His</td><td>Lys</td><td>Ser</td><td>Pro</td><td>Asn</td><td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>Ile</td><td>Met</td><td>Ile</td>

<td>Asp</td><td>Glu</td><td>Ile</td><td>Ile</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td>

RO 118016 Β1

2235

<td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td>

<td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td>

<td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td>

<td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td>

<td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td>

<td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td>

2240

<td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 131]</td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Lys</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Ser</td>

<td>Gly</td><td>Pro</td><td>lle</td><td>Ser</td><td>Thr</td><td>lle</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Pro</td><td>Pro</td><td>Ser</td><td>Lys</td><td>Glu</td>

<td>Ser</td><td>His</td><td>Lys</td><td>Ser</td><td>Pro</td><td>Asn</td><td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td>

<td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td>

<td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td>

<td>Met</td><td>Glu</td><td>Arg.</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td>

<td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td>

<td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td>

<td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td>

<td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td>

<td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv. nr.</td><td> : 132]</td><td></td><td></td><td></td><td></td>

2245

2250

2255

2260

2265

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td><td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Ser</td>

2270

2275

RO 118016 Β1

<td>Gly</td><td>Pro</td><td>lle</td><td>Ser</td><td>Thr</td><td>lle</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Pro</td><td>Pro</td><td>Ser</td><td>Lys</td><td>Glu</td>

<td>Ser</td><td>His</td><td>Lys</td><td>Ser</td><td>Pro</td><td>Asn</td><td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td>

<td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Leu</td>

<td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Ser</td><td>Glu</td><td>Asp</td><td>Met</td><td>Asp</td><td>lle</td><td>Leu</td>

<td>Met</td><td>Glu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Thr</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Leu</td><td>Ala</td><td>Phe</td><td>Val</td>

<td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>His</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td>

<td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td>

<td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td>

<td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td>

<td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv. nr.</td><td colspan="2"> : 133]</td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle l</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Val</td><td>Ser</td><td>lle</td><td>Leu</td><td>Met</td><td>ASp</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td><td>Ser</td>

<td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Cys</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Val</td>

<td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td><td>Leu</td>

<td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td><td>Ser</td>

<td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td><td>Gin</td>

<td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td>Ala</td>

<td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>ASp</td><td>Thr</td>

<td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td>Gin</td>

<td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Thr</td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td></td><td>Phe</td><td>Gin</td><td>Arg</td><td>Arg</td>

<td>Ala</td><td>Gly</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>l Ser</td><td>Phe</td><td>Leu</td>

<td>Glu</td><td>. Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>; Arg</td><td>His</td><td colspan="5">Leu Ala Gin Pro</td>

[Secv. nr.: 134]

Met Ala Asn Cys Ser lle Met lle Asp Glu lle lle His His

RO 118016 Β1

2325

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Val</td><td>Ser</td><td>lle</td><td>Leu</td><td>Met</td><td>Asp</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td><td>Ser</td>

<td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Val</td>

<td>Arg</td><td>Lys</td><td>lle</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td><td>Leu</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td><td>Leu</td>

<td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>lle</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td><td>Ser</td>

<td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>ser</td><td>Gin</td>

<td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td><td>Ala</td>

<td>Leu</td><td>Glu</td><td>Gly</td><td>lle</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td><td>Thr</td>

<td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>lle</td><td>Trp</td><td>Gin</td>

<td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Thr</td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Phe</td><td>Gin</td><td>Arg</td><td>Arg</td>

<td>Ala</td><td>Gly</td><td>Gly</td><td>Val</td><td>Leu</td><td>Val</td><td>Ala</td><td>Ser</td><td>His</td><td>Leu</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td>

<td>Glu</td><td>Val</td><td>Ser</td><td>Tyr</td><td>Arg</td><td>Val</td><td>Leu</td><td>Arg</td><td>His</td><td>Leu</td><td>Ala</td><td>Gin</td><td>Pro</td><td></td>

[Secv. nr.: 135]

2330

2335

2340

2345

2350

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Val</td><td>Ser</td><td>lle</td><td>Leu</td><td>Met</td><td>Asp</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu</td><td>Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>Ser</td><td>Asn</td><td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td>

<td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td><td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td>

<td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td><td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Val</td><td>Ser</td><td>lle</td><td>Leu</td><td>Met</td>

<td>Asp</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Ser</td><td>Phe</td><td>G.1</td><td>Arg</td>

2355

2360

2365

RO 118016 Β1

<td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td><td>lle</td>

<td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td>

<td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td><td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td>

<td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td><td>Glu</td>

<td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 136]</td><td></td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser</td><td>lle</td><td>Met</td><td>lle</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

Asn Asp Glu Asp Val Ser lle Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly lle Glu Ala lle Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro lle lle lle Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr Val lle Glu Gly Arg lle Ser Pro Gly Glu Pro Ser Gly Pro lle Ser Thr lle Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Asn Cys Ser lle Met lle Asp Glu lle lle His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser lle Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val

<td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn Leu</td><td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly</td><td>lle</td><td>Glu</td><td>Ala</td>

<td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu Gin</td><td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser</td><td>Ala</td><td>Thr</td><td>Ala</td>

<td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His Pro</td><td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td>

<td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu Lys</td><td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu</td><td>Val</td><td>Thr</td><td>Leu</td>

<td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu Gin</td><td>Gin</td><td colspan="2">[Secv. nr.:</td><td> 137]</td><td></td><td></td><td></td><td></td>

<td>Met</td><td>Ala</td><td>Asn</td><td>Cys</td><td>Ser lle</td><td>Met</td><td>Ile</td><td>Asp</td><td>Glu</td><td>lle</td><td>lle</td><td>His</td><td>His</td>

<td>Leu</td><td>Lys</td><td>Arg</td><td>Pro</td><td>Pro Ala</td><td>Pro</td><td>Leu</td><td>Leu</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Leu</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Val Ser</td><td>lle</td><td>Leu</td><td>Met</td><td>Asp</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Arg</td>

<td>Leu</td><td>Pro</td><td>Asn</td><td>Leu</td><td>Glu Ser</td><td>Phe</td><td>Val</td><td>Arg</td><td>Ala</td><td>Val</td><td>Lys</td><td>Asn</td><td>Leu</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>Ser</td><td>Gly lle</td><td>Glu</td><td>Ala</td><td>lle</td><td>Leu</td><td>Arg</td><td>Asn</td><td>Leu</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Leu</td><td>Pro</td><td>Ser Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>Ser</td><td>Arg</td><td>His</td><td>Pro</td>

<td>lle</td><td>lle</td><td>lle</td><td>Lys</td><td>Ala Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Phe</td><td>Arg</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Thr</td><td>Phe</td><td>Tyr</td><td>Leu Val</td><td>Thr</td><td>Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Val</td><td>lle</td><td>Glu Gly</td><td>Arg</td><td>lle</td><td>Ser</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>Ser</td>

<td>Gly</td><td>Pro</td><td>lle</td><td>Ser</td><td>Thr lle</td><td>Asn</td><td>Pro</td><td>Ser</td><td>Pro</td><td>Pro</td><td>Ser</td><td>Lys</td><td>Glu</td>

<td>Ser</td><td>His</td><td>Lys</td><td>Ser</td><td>Pro Asn</td><td>Met</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Ala</td>

RO 118016 Β1

2415

<td>Ser</td><td>Ser</td><td>Leu</td><td>Pro</td><td>Gin</td><td>Ser</td><td>Phe</td><td>Leu</td><td>Leu</td><td>Lys</td><td>Ser</td><td>Leu</td><td>Glu</td><td>Gin</td>

<td>Val</td><td>Arg</td><td>Lys</td><td>Ile</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Glu</td><td>Lys</td>

<td>Leu</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>Lys</td><td>Leu</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Val</td>

<td>Leu</td><td>Leu</td><td>Gly</td><td>His</td><td>Ser</td><td>Leu</td><td>Gly</td><td>Ile</td><td>Pro</td><td>Tip</td><td>Ala</td><td>Pro</td><td>Leu</td><td>Ser</td>

<td>Ser</td><td>Cys</td><td>Pro</td><td>Ser</td><td>Gin</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Leu</td><td>Ser</td>

<td>Gin</td><td>Leu</td><td>His</td><td>Ser</td><td>Gly</td><td>Leu</td><td>Phe</td><td>Leu</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Leu</td><td>Gin</td>

<td>Ala</td><td>Leu</td><td>Glu</td><td>Gly</td><td>Ile</td><td>Ser</td><td>Pro</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Leu</td><td>Asp</td>

<td>Thr</td><td>Leu</td><td>Gin</td><td>Leu</td><td>Asp</td><td>Val</td><td>Ala</td><td>Asp</td><td>Phe</td><td>Ala</td><td>Thr</td><td>Thr</td><td>Ile</td><td>Trp</td>

<td>Gin</td><td>Gin</td><td>Met</td><td>Glu</td><td>Glu</td><td>Leu</td><td>Gly</td><td>Met</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Leu</td><td>Gin</td><td>Pro</td>

<td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>Met</td><td>Pro</td><td>Ala</td><td>Phe</td><td>Ala</td><td>Ser</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td>

<td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td><td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td>

<td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td><td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td>

<td colspan="2">[Secv. No..</td><td> : 138]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td><td>Asp</td><td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td>

2420

2425

2430

Leu Lys Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser Glu Aisp Met Asp Ile Leu Met Glu Arg Asn Leu Arg Thr Pro Asn Leu Leu Ala Phe Val Arg Ala Val Lys His Leu

2435

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>with</td><td>with</td><td>with</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td><td>with</td><td>To be</td><td>Pro</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Hours</td>

<td>Asn</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td>

<td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>To be</td><td>Gly</td><td>Asp</td>

<td>Faction</td><td>Asp</td><td>Tyr</td><td>Glu</td><td>Asn</td><td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td>

<td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>To be</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td>

<td>Angry</td><td>list</td><td>with</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td><td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>hour</td><td>Lion</td>

<td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td><td>Gly</td><td>with</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td>

<td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gin</td>

<td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td><td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Glu</td><td>Gly</td><td>with</td><td>To be</td><td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td><td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>with</td><td>Trp</td><td>Gin</td>

<td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td><td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td>

2440

2445

2450

2455

RO 118016 Β1

2460 Ala Gly Gly Val Leu Val

Glu Val Ser Tyr Arg Val [Secv. no .: 139]

Ala Ser His Leu Gin Ser Phe Leu

Leu Arg His Leu Ala Gin Pro

2465

2470

2475

2480

2485

<td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td><td>Asp</td><td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td>

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>with</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>with</td><td>with</td><td>with</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td><td>with</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Angry</td><td>To be</td><td>Pro</td><td>To be</td><td>Pro</td>

<td>To be</td><td>Thr</td><td>Gin</td><td>Pro</td><td>Trp</td><td>Glu</td><td>His</td><td>Hours</td><td>Asn</td><td>Ala</td><td>with</td><td>Gin</td><td>Glu</td><td>Ala</td>

<td>Angry</td><td>Angry</td><td>Lion</td><td>Lion</td><td>Asn</td><td>Lion</td><td>To be</td><td>Angry</td><td>Asp</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Glu</td><td>With</td>

<td>Asn</td><td>Glu</td><td>Thr</td><td>Hours</td><td>Glu</td><td>Hours</td><td>with</td><td>To be</td><td>Glu</td><td>With</td><td>Faction</td><td>Asp</td><td>Lion</td><td>Gin</td>

<td>Glu</td><td>Pro</td><td>Thr</td><td>Cys</td><td>Lion</td><td>Gin</td><td>Thr</td><td>Angry</td><td>Lion</td><td>Glu</td><td>Lion</td><td>Tyr</td><td>list</td><td>Gin</td>

<td>Gly</td><td>Lion</td><td>Angry</td><td>Gly</td><td>To be</td><td>Lion</td><td>Thr</td><td>list</td><td>Lion</td><td>list</td><td>Gly</td><td>Pro</td><td>Lion</td><td>Thr</td>

<td>With</td><td>With</td><td>Ala</td><td>To be</td><td>His</td><td>Tyr</td><td>list</td><td>Gin</td><td>His</td><td>Cys</td><td>Pro</td><td>Pro</td><td>Thr</td><td>Pro</td>

<td>Glu</td><td>Thr</td><td>To be</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Gin</td><td>with</td><td>with</td><td>Thr</td><td>Faction</td><td>Glu</td><td>To be</td><td>Faction</td>

<td>list</td><td>Glu</td><td>Asn</td><td>Lion</td><td>list</td><td>Asp</td><td>Faction</td><td>Lion</td><td>Lion</td><td>Hours</td><td>with</td><td>Pro</td><td>Faction</td><td>Asp</td>

2490

2495

<td>Cys</td><td>Trp</td><td>Glu</td><td>Pro</td><td>Hours</td><td>Gin</td><td>Glu</td><td colspan="2">[Secv. no .:</td><td> 141]</td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td><td>Asp</td><td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td>

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>with</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>with</td><td>with</td><td>with</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td><td>with</td><td>To be</td><td>Pro</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Hours</td>

<td>Asn</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td>

<td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>To be</td><td>Gly</td><td>Asp</td>

<td>Faction</td><td>Asp</td><td>Tyr</td><td>Glu</td><td>Asn</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Angry</td><td>to be</td><td>Pro</td><td>To be</td><td>Pro</td>

2500

RO 118016 Β1

2505

<td>To be</td><td>Thr</td><td>Gin</td><td>Pro</td><td>Trp</td><td>Glu</td><td>His</td><td>Hours</td><td>Asn</td><td>Ala</td><td>with</td><td>Gin</td><td>Glu</td><td>Ala</td>

<td>Angry</td><td>Angry</td><td>Lion</td><td>Lion</td><td>Asn</td><td>Lion</td><td>To be</td><td>Angry</td><td>Asp</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Glu</td><td>With</td>

<td>Asn</td><td>Glu</td><td>Thr</td><td>Hours</td><td>Glu</td><td>Hours</td><td>with</td><td>To be</td><td>Glu</td><td>With</td><td>Faction</td><td>Asp</td><td>Lion</td><td>Gin</td>

<td>Glu</td><td>Pro</td><td>Thr</td><td>Cys</td><td>Lion</td><td>Gin</td><td>Thr</td><td>Angry</td><td>Lion</td><td>Glu</td><td>Lion</td><td>Tyr</td><td>list</td><td>Gin</td>

<td>Gly</td><td>Lion</td><td>Angry</td><td>Gly</td><td>To be</td><td>Lion</td><td>Thr</td><td>list</td><td>Lion</td><td>list</td><td>Gly</td><td>Pro</td><td>Lion</td><td>Thr</td>

<td>With</td><td>With</td><td>Ala</td><td>To be</td><td>His</td><td>Tyr</td><td>list</td><td>Gin</td><td>His</td><td>cys</td><td>Pro</td><td>Pro</td><td>Thr</td><td>Pro</td>

<td>Glu</td><td>Thr</td><td>To be</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Gin</td><td>with</td><td>with</td><td>Thr</td><td>Faction</td><td>Glu</td><td>To be</td><td>Faction</td>

<td>list</td><td>Glu</td><td>Asn</td><td>Lion</td><td>list</td><td>Asp</td><td>Faction</td><td>Lion</td><td>Lion</td><td>Hours</td><td>with</td><td>Pro</td><td>Faction</td><td>Asp</td>

<td>cys</td><td>Trp</td><td>Glu</td><td>Pro</td><td>Hours</td><td>Gin</td><td>Glu</td><td colspan="2">[Secv. no .:</td><td> : 142]</td><td></td><td></td><td></td><td></td>

2510

2515

<td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td><td>Asp</td><td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td>

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>with</td><td>Lion</td><td>With</td><td>G1U</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>with</td><td>with</td><td>with</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>Pro</td><td>Hours</td><td>Asn</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>To be</td><td>Gly</td><td colspan="2">Gly Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>To be</td><td>Gly</td><td>To be</td><td>Gly</td><td>Asn</td><td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td>

<td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>Cys</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td>

<td>Angry</td><td>list</td><td>with</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td><td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td>

<td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td><td>Gly</td><td>with</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td>

<td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gin</td>

<td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td><td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Glu</td><td>Gly</td><td>with</td><td>To be</td><td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td>

2520

2525

2530

2535

<td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td><td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>with</td><td>Trp</td><td>Gin</td>

<td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td><td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td>

<td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td><td>hour</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td>

<td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td><td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td></td>

[Secv. no .: 143]

2540

2545

Met Ala Asn Cys Ser With Met With Asp Glu With His His

RO 118016 Β1

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>for</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>hour</td><td>list</td><td>His</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>for</td><td>Glu</td><td>Gly</td><td>Angry</td><td>for</td><td>To be</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>To be</td>

<td>Gly</td><td>Pro</td><td>for</td><td>To be</td><td>Thr</td><td>for</td><td>Asn</td><td>Pro</td><td>To be</td><td>Pro</td><td>Pro</td><td>To be</td><td>list</td><td>Glu</td>

<td>To be</td><td>His</td><td>list</td><td>To be</td><td>Pro</td><td>Asn</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Angry</td><td>To be</td><td>Pro</td><td>To be</td>

<td>Pro</td><td>To be</td><td>Thr</td><td>Gin</td><td>Pro</td><td>Trp</td><td>Glu</td><td>His</td><td>Hours</td><td>Asn</td><td>Ala</td><td>for</td><td>Gin</td><td>Glu</td>

<td>Ala</td><td>Angry</td><td>Angry</td><td>Lion</td><td>Lion</td><td>Asn</td><td>Lion</td><td>To be</td><td>Angry</td><td>Asp</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Glu</td>

<td>With</td><td>Asn.</td><td>Glu</td><td>Thr</td><td>Hours</td><td>Glu</td><td>Hours</td><td>for</td><td>To be</td><td>Glu</td><td>With</td><td>Faction</td><td>Asp</td><td>Lion</td>

<td>Gin</td><td>Glu</td><td>Pro</td><td>Thr</td><td>Cys</td><td>Lion</td><td>Gin</td><td>Thr</td><td>Angry</td><td>Lion</td><td>Glu</td><td>Lion</td><td>Tyr</td><td>list</td>

<td>Gin</td><td>Gly</td><td>Lion</td><td>Angry</td><td>Gly</td><td>To be</td><td>Lion</td><td>Thr</td><td>list</td><td>Lion</td><td>list</td><td>Gly</td><td>Pro</td><td>Lion</td>

<td>Thr</td><td>With</td><td>With</td><td>Ala</td><td>To be</td><td>His</td><td>Tyr</td><td>list</td><td>Gin</td><td>His</td><td>Cys</td><td>Pro</td><td>Pro</td><td>Thr</td>

<td>Pro</td><td>Glu</td><td>Thr</td><td>To be</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Gin</td><td>for</td><td>for</td><td>Thr</td><td>Faction</td><td>Glu</td><td>To be</td>

<td>Faction</td><td>list</td><td>Glu</td><td>Asn</td><td>Lion</td><td>list</td><td>Asp</td><td>Faction</td><td>Lion</td><td>Lion</td><td>Hours</td><td>for</td><td>Pro</td><td>Faction</td>

<td>Asp</td><td>Cys</td><td>Trp</td><td>Glu</td><td>Pro</td><td>Hours</td><td>Gin</td><td>Glu</td><td colspan="2">[Secv. no .:</td><td> : 144]</td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td>

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>for</td><td>Lion</td><td>With</td><td>G1U</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>for</td><td>Glu</td><td>Gly</td><td>Angry</td><td>for</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>Pro</td><td>Hours</td><td>Pro</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Asp</td>

<td>To be</td><td>list</td><td>Asp</td><td>Hours</td><td>Ala</td><td>Ala</td><td>Pro</td><td>His</td><td>Angry</td><td>Gin</td><td>Pro</td><td>Lion</td><td>Thr</td><td>To be</td>

<td>To be</td><td>Glu</td><td>Angry</td><td>for</td><td>Asp</td><td>list</td><td>Gin</td><td>for</td><td>Angry</td><td>Tyr</td><td>for</td><td>Lion</td><td>Asp</td><td>Gly</td>

<td>for</td><td>To be</td><td>Ala</td><td>Lion</td><td>Angry</td><td>list</td><td>Glu</td><td>Thr</td><td>Cys</td><td>Asn</td><td>list</td><td>To be</td><td>Asn</td><td>With</td>

<td>Cys</td><td>Glu</td><td>To be</td><td>To be</td><td>list</td><td>Glu</td><td>Ala</td><td>Lion</td><td>Ala</td><td>Glu</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td>

<td>Lion</td><td>Pro</td><td>list</td><td>With</td><td>Ala</td><td>Glu</td><td>list</td><td>Asp</td><td>Gly</td><td>Cys</td><td>Faction</td><td>Gin</td><td>To be</td><td>Gly</td>

<td>Faction</td><td>Asn</td><td>Glu</td><td>Glu</td><td>Thr</td><td>Cys</td><td>Lion</td><td>Hours</td><td>list</td><td>for</td><td>for</td><td>Thr</td><td>Gly</td><td>Lion</td>

<td>Lion</td><td>Glu</td><td>Faction</td><td>Glu</td><td>Hours</td><td>Tyr</td><td>Lion</td><td>Glu</td><td>Tyr</td><td>Lion</td><td>Gin</td><td>Asn</td><td>Angry</td><td>Faction</td>

RO 118016 Β1

<td>Glu</td><td>To be</td><td>To be</td><td>Glu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Angry</td><td>Ala</td><td>Hours</td><td>Gin</td><td>With</td><td>To be</td><td>Thr</td><td> 2595</td>

<td>Lys</td><td>Hours</td><td>Lion</td><td>for</td><td>Gin</td><td>Faction</td><td>Lion</td><td>Gin</td><td>list</td><td>list</td><td>Ala</td><td>list</td><td>Asn</td><td>Lion</td><td></td>

<td>Asp</td><td>Ala</td><td>for</td><td>Thr</td><td>Thr</td><td>Pro</td><td>Asp</td><td>Pro</td><td>Thr</td><td>Thr</td><td>Asn</td><td>Ala</td><td>To be</td><td>Lion</td><td></td>

<td>Lion</td><td>Thr</td><td>list</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Asn</td><td>Gin</td><td>Trp</td><td>Lion</td><td>Gin</td><td>Asp</td><td>With</td><td></td>

<td>Thr</td><td>Thr</td><td>His</td><td>Lion</td><td>for</td><td>Lion</td><td>Angry</td><td>To be</td><td>Faction</td><td>list</td><td>Glu</td><td>Faction</td><td>Lion</td><td>Gin</td><td> 2600</td>

<td>To be</td><td>To be</td><td>Lion</td><td>Angry</td><td>Ala</td><td>Lion</td><td>Angry</td><td>Gin</td><td>With</td><td colspan="2">[Secv. no .:</td><td> 145]</td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td><td></td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>Cys</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>for</td><td>Gin</td><td>Gly</td><td> 2605</td>

<td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td><td></td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td><td></td>

<td>Gly</td><td>for</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td><td></td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td colspan="2">Gly Cys</td><td>Lion</td><td>To be</td><td>Gin</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td><td rowspan="2"> 2610</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>for</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td><td></td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>for</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td><td></td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td><td></td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td><td> 2615</td>

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td><td></td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>for</td><td>Glu</td><td>Gly</td><td>Angry</td><td></td>

<td>for</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td></td>

<td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td><td>list</td><td> 2620</td>

Arg Pro Pro Asn Pro Leu Leu Asp Pro Asn Asn Leu Asn Ser

Glu Asp Met Asp lle Leu Met Glu Arg Asn Leu Arg Thr Pro

Asn Leu Leu Ala Phe Val Arg Ala Val Lys His Leu Glu Asn

<td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Cys</td>

<td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>for</td><td>for</td>

<td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td><td>Thr</td>

<td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr Leu</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td></td>

<td colspan="2">[Secv. No..</td><td> : 146]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Read Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>Cys Lee</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>for</td><td>Gin</td><td>Gly</td>

<td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Read Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td>

<td>Gly</td><td>for</td><td>Pro</td><td>Trp</td><td>Wing Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly Cys</td><td>Lion</td><td>To be</td><td>Gin</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

RO 118016 Β1

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>with</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>with</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td colspan="2">Gly Gly</td><td>hour</td><td>Lion</td>

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td>

<td>with</td><td>To be</td><td>Pro</td><td>Gly</td><td colspan="2">Gly Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td>

<td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td><td>Asp</td><td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td><td>Lion</td><td>list</td>

<td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>Asp</td>

<td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>with</td><td>Lion</td><td>With</td><td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Lion</td><td>Pro</td>

<td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td><td>Glu</td><td>Asn</td>

<td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Cys</td>

<td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>with</td><td>with</td>

<td>with</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td><td>Thr</td>

<td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td></td>

<td colspan="2">[Secv. no .:</td><td> : 147]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>Cys</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>with</td><td>Gin</td><td>Gly</td>

<td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td>

<td>Gly</td><td>with</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gin</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>with</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>with</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td>

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>Pro</td><td>Gin</td><td>Pro</td><td>Pro</td>

<td>Hours</td><td>Asn</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td>

<td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>To be</td><td>Gly</td>

<td>Asp</td><td>Faction</td><td>Asp</td><td>Tyr</td><td>Glu</td><td>Asn</td><td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td>

<td>Asp</td><td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td><td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td>

<td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>hour</td><td>To be</td><td>with</td><td>Lion</td>

RO 118016 Β1

2685

<td colspan="5" rowspan="3">Met Asp Arg Asn Leu Glu Asn Ala Ser Gly Pro Cys Leu Pro Ser Ile Ile Ile Lys Ala</td><td colspan="9">Arg Leu Val Arg Ala Val List Asn Leu</td>

<td colspan="2" rowspan="2">Ile Glu Ala Thr Gly Asp</td><td colspan="7">Ala Hair Leu Arg Asn Leu Gin</td>

<td colspan="2">Do not start Trp Gin</td><td colspan="5">Pro Ser Arg His Pro Glu Phe Arg Glu List</td>

<td rowspan="2">Lion Gin</td><td colspan="4">Thr Phe Tyr Leu</td><td rowspan="2">Hours</td><td rowspan="2">Thr</td><td rowspan="2">Lion</td><td rowspan="2">Glu</td><td rowspan="2">Gin</td><td rowspan="2">Ala</td><td rowspan="2">Gin</td><td colspan="2" rowspan="2">Glu Gin</td>

<td colspan="2">[Secv. no .:</td><td colspan="2"> 148]</td>

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>Cys</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>with</td><td>Gin</td><td>Gly</td>

<td colspan="2">Asp Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td>

<td>Gly</td><td>with</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td colspan="2">Gly Cys</td><td>Lion</td><td>To be</td><td>Gin</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>with</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>with</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pto</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td>

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td>

<td>with</td><td>To be</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>To be</td><td>Gly</td><td>Pro</td><td>with</td><td>To be</td><td>Thr</td><td>with</td><td>Asn</td>

2690

2695

2700

2705

Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Asn Cys Ser Ile Met Ile Asp Glu Ile Ile His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser Ile Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Ile Glu Ala Ile Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Ile Ile Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin [Secv. no .: 149]

Met Ala Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu Lys Cys Leu Glu Gin Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala

2710

2715

2720

2725

RO 118016 Β1

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gin</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>with</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>with</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td>

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td>

<td>with</td><td>To be</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>To be</td><td>Gly</td><td>Pro</td><td>with</td><td>To be</td><td>Thr</td><td>with</td><td>Asn</td>

<td>Pro</td><td>To be</td><td>Pro</td><td>Pro</td><td>To be</td><td>list</td><td>Glu</td><td>To be</td><td>His</td><td>list</td><td>To be</td><td>Pro</td><td>Asn</td><td>With</td>

<td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td><td>Asp</td><td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td><td>Lion</td>

<td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td>

<td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>with</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Thr</td>

<td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td>

<td>Cys</td><td>Lion</td><td>Pro</td><td>to be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>with</td>

<td>with</td><td>with</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td>

<td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td>

<td colspan="2">[Secv. No..</td><td> : 150]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>Cys</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>with</td><td>Gin</td><td>Gly</td>

<td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td>

<td>Gly</td><td>with</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gin</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>with</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>with</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td>

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td>

<td>with</td><td>To be</td><td>Pro</td><td>Gin</td><td>Pro</td><td>Pro</td><td>Hours</td><td>Asn</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td>

<td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td>

<td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td>

<td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>To be</td><td>Gly</td><td>Asp</td><td>Faction</td><td>Asp</td><td>Tyr</td><td>Glu</td><td>Asn</td><td>With</td><td>Ala</td>

RO 118016 Β1

<td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td><td>list</td><td> 2775</td>

<td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>To be</td><td></td>

<td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>for</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Thr</td><td>Pro</td><td></td>

<td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td><td>Glu</td><td>Asn</td><td></td>

<td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Cys</td><td> 2780</td>

<td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>for</td><td>for</td><td></td>

<td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td><td>Thr</td><td></td>

<td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td></td><td></td>

[Secv. no .: 151]

2785

<td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td>

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td><td>With</td><td>ASp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Lion</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td>

<td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>To be</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td>

<td>Angry</td><td>list</td><td>for</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td> 2800</td>

<td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td><td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td></td>

<td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td><td>Gly</td><td>for</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td></td>

<td>Cys</td><td>Pro</td><td>To be</td><td>Gin.</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>to be</td><td>Gin</td><td></td>

<td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td><td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td> 2805</td>

<td>Lion</td><td>Glu</td><td>Gly</td><td>for</td><td>To be</td><td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td></td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td><td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>for</td><td>Trp</td><td>Gin</td><td></td>

<td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td></td>

<td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td><td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td rowspan="2"> 2810</td>

<td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td><td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td>

<td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td><td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td></td><td></td>

[Secv. no .: 152]

Met Ala Asn Cys Ser lle Met lle Asp Glu lle lle His His

Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu

2815

RO 118016 Β1

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td><td>With</td><td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Lion</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td>

<td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td><td>Lion</td>

<td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td><td>With</td>

<td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Lion</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td><td>Angry</td>

<td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td><td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td>

<td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td>

<td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td>

<td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td>

<td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv. No..</td><td colspan="2"> : 153]</td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Asn</td><td>cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td>

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td><td>With</td><td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Lion</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>for</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>To be</td>

<td>Gly</td><td>Pro</td><td>for</td><td>To be</td><td>Thr</td><td>for</td><td>Asn</td><td>Pro</td><td>To be</td><td>Pro</td><td>Pro</td><td>To be</td><td>list</td><td>Glu</td>

<td>To be</td><td>His</td><td>list</td><td>To be</td><td>Pro</td><td>Asn</td><td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td>

<td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>To be</td><td>Lion</td><td>Glu</td><td>Gin</td>

<td>Hours</td><td>Angry</td><td>list</td><td>for</td><td>Gin</td><td>Gly</td><td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td><td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td>

<td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td><td>Gly</td><td>for</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td>

<td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td>

<td>Gin</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td><td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td>

<td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>for</td><td>To be</td><td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td>

<td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td><td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>for</td><td>Trp</td>

RO 118016 Β1

Gin

Thr

Angry

Lion

With

Lion

Asn

Lion

Glu

Pro lle

Lion

Gin

Gly

To be

<td colspan="3">Gin Met Glu</td><td colspan="10">Glu Leu Gly Met Ala Pro Ala Leu Gin Pro</td>

<td colspan="2" rowspan="2">Gin Gly Ala Gly</td><td rowspan="3">Ala Gly To be</td><td colspan="2">With Pro</td><td colspan="4">Ala Phe Ala Ser</td><td colspan="4" rowspan="2">Ala Phe Gin Arg Leu Gin Ser Phe</td>

<td rowspan="2">Hours Tyr</td><td rowspan="2">Lion Angry</td><td rowspan="2">hour Hours</td><td colspan="3">Ala Ser His</td>

<td>Glu in. No .:</td><td>Hours 154]</td><td>Lion</td><td colspan="2">Arg His</td><td colspan="2">Read Allah</td><td colspan="2">Gin Pro</td>

<td>Ala</td><td>Asn</td><td>cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td>

<td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asp</td><td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td><td>With</td><td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Pro</td><td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>To be</td>

<td>Pro</td><td>for</td><td>To be</td><td>Thr</td><td>for</td><td>Asn</td><td>Pro</td><td>To be</td><td>Pro</td><td>Pro</td><td>To be</td><td>list</td><td>Glu</td>

<td>His</td><td>list</td><td>Set</td><td>Pro</td><td>Asn</td><td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td>

<td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td>

2865

2870

2875

2880

2885

Asp

<td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>Asp</td><td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td>

<td>With</td><td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Lion</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td>

<td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td><td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td>

<td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>c-ln</td><td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td>

<td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td>

<td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td>

<td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>C-ln</td><td>Gin</td><td colspan="2">[Secv. no .:</td><td> 155]</td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>Cys</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>for</td><td>Gin</td><td>Gly</td>

<td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td>

<td>Gly</td><td>for</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gly</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>for</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>for</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td>

2890

2895

2900

2905

RO 118016 Β1

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>To be</td><td>Gly</td><td>Pro</td><td>for</td><td>To be</td><td>Thr</td><td>for</td><td>Asn</td>

<td>Pro</td><td>To be</td><td>Pro</td><td>Pro</td><td>To be</td><td>list</td><td>Glu</td><td>To be</td><td>His</td><td>list</td><td>To be</td><td>Pro</td><td>Asn</td><td>With</td>

<td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td>

<td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td>

<td>Asp</td><td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td><td>With</td><td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Lion</td>

<td>Pro</td><td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td><td>Glu</td>

<td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td>

<td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>for</td>

<td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td>

<td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td colspan="2">Gin Glu</td><td>Gin</td><td>Gin</td>

[Secv. no .: 156]

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>To be</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>for</td><td>Gin</td><td>Gly</td>

<td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td>

<td>Gly</td><td>for</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gly</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>for</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>for</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td>

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td>Tyr</td><td>Angry</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td>

<td>Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Glu</td><td>Pro</td><td>To be</td><td>Gly</td><td>Pro</td><td>for</td><td>To be</td><td>Thr</td><td>for</td><td>Asn</td>

<td>Pro</td><td>To be</td><td>Pro</td><td>Pro</td><td>To be</td><td>list</td><td>Glu</td><td>To be</td><td>His</td><td>list</td><td>To be</td><td>Pro</td><td>Asn</td><td>With</td>

<td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td>

Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser lle Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly lle Glu Ala lle Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro lle lle lle Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin

RO 118016 Β1 [Sec. no .: 157]

Met Ala Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu Lys Cys Leu Glu Gin Val Arg Lys lle Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly lle Pro Trp Wing Pro Leu Being Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gly Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly lle Being Pro Glu Leu Gly pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr lle Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Val Leu val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Tyr Val Glu Gly Gly Gly Gly Being Pro Gly Gly Gly Being Gly Gly Gly Being Asn Met Ala Asn Cys Being Met Met Asp Glu lle lle His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp As Glu Asp Val Ser le Leu Met Asp Arg Asn Leu Arg Leu Pro

2955

2960

2965

2970

2975

<td colspan="14">Asn Leu Glu Ser Phe Val Arg Ala Val Lys Asn Leu Glu Asn</td>

<td colspan="5" rowspan="4">Ala Ser Gly lle Glu Leu Pro Ser Ala Thr lle Lys Ala Gly Asp Phe Tyr Leu Val Thr</td><td colspan="2">Come on</td><td colspan="7">Leu Arg Asn Leu Gin Pro Cys</td>

<td rowspan="4">Ala Trp Lion</td><td rowspan="4">Ala Gin Glu</td><td colspan="5">Pro Ser Arg His Pro</td><td colspan="2">lle lle</td>

<td colspan="2">Glu Phe</td><td rowspan="3">Angry Gin</td><td colspan="2">Glu Lys</td><td rowspan="3">Lion Gin</td><td rowspan="3">Thr</td>

<td rowspan="2">Gin</td><td rowspan="2">Ala</td><td rowspan="2">Glu</td><td rowspan="2">Gin</td>

<td colspan="2">[Secv. no .:</td><td colspan="3"> 158]</td>

<td>With</td><td>Ala</td><td>Thr</td><td>Pro</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Ala</td><td>To be</td><td>To be</td><td>Lion</td><td>Pro</td><td>Gin</td><td>To be</td>

<td>Faction</td><td>Lion</td><td>Lion</td><td>list</td><td>To be</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Hours</td><td>Angry</td><td>list</td><td>for</td><td>Gin</td><td>Gly</td>

<td>Asp</td><td>Gly</td><td>Ala</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Glu</td><td>list</td><td>Lion</td><td>Cys</td><td>Ala</td><td>Thr</td><td>Tyr</td><td>list</td>

<td>Lion</td><td>Cys</td><td>His</td><td>Pro</td><td>Glu</td><td>Glu</td><td>Lion</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Gly</td><td>His</td><td>To be</td><td>Lion</td>

<td>Gly</td><td>for</td><td>Pro</td><td>Trp</td><td>Ala</td><td>Pro</td><td>Lion</td><td>To be</td><td>To be</td><td>Cys</td><td>Pro</td><td>To be</td><td>Gin</td><td>Ala</td>

<td>Lion</td><td>Gin</td><td>Lion</td><td>Ala</td><td>Gly</td><td>Cys</td><td>Lion</td><td>To be</td><td>Gly</td><td>Lion</td><td>His</td><td>To be</td><td>Gly</td><td>Lion</td>

<td>Faction</td><td>Lion</td><td>Tyr</td><td>Gin</td><td>Gly</td><td>Lion</td><td>Lion</td><td>Gin</td><td>Ala</td><td>Lion</td><td>Glu</td><td>Gly</td><td>for</td><td>To be</td>

<td>Pro</td><td>Glu</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Lion</td><td>Asp</td><td>Thr</td><td>Lion</td><td>Gin</td><td>Lion</td><td>Asp</td><td>Hours</td>

<td>Ala</td><td>Asp</td><td>Faction</td><td>Ala</td><td>Thr</td><td>Thr</td><td>for</td><td>Trp</td><td>Gin</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Lion</td>

<td>Gly</td><td>With</td><td>Ala</td><td>Pro</td><td>Ala</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Thr</td><td>Gin</td><td>Gly</td><td>Ala</td><td>With</td><td>Pro</td>

<td>Ala</td><td>Faction</td><td>Ala</td><td>To be</td><td>Ala</td><td>Faction</td><td>Gin</td><td>Angry</td><td>Angry</td><td>Ala</td><td>Gly</td><td>Gly</td><td>Hours</td><td>Lion</td>

2980

2985

2990

2995

RO 118016 Β1

<td>Hours</td><td>Ala</td><td>To be</td><td>His</td><td>Lion</td><td>Gin</td><td>To be</td><td>Faction</td><td>Lion</td><td>Glu</td><td>Hours</td><td>To be</td><td colspan="2">Tyr Arg</td>

<td>Hours</td><td>Lion</td><td>Angry</td><td>His</td><td>Lion</td><td>Ala</td><td>Gin</td><td>Pro</td><td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td colspan="2">Gly Gly</td>

<td>Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td>

<td>Asn</td><td>Cys</td><td>To be</td><td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td><td>list</td>

<td>Angry</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>Asp</td>

<td>Glu</td><td>Asp</td><td>Hours</td><td>To be</td><td>for</td><td>Lion</td><td>With</td><td>Asp</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Lion</td><td>Pro</td>

<td>Asn</td><td>Lion</td><td>Glu</td><td>To be</td><td>Faction</td><td>hour</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>Asn</td><td>Lion</td><td>Glu</td><td>Asn</td>

<td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Cys</td>

<td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>for</td><td>for</td>

<td>for</td><td>list</td><td>Ala</td><td colspan="2">Gly Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td><td>Thr</td>

<td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td>Gin</td><td></td>

<td colspan="2">[Secv. no .:</td><td> : 159]</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>Asn i</td><td>Cys</td><td>To be</td><td>lle!</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td>

<td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td>

<td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>background</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td>

<td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>for</td><td>Glu</td><td>Gly</td><td>Angry</td><td>for</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>To be</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Cys</td>

<td>Asp</td><td>Lion</td><td>Angry</td><td>Hours</td><td>Lion</td><td>To be</td><td>list</td><td>Lion</td><td>Lion</td><td>Angry</td><td>Asp</td><td>To be</td><td>His</td><td>Hours</td>

<td>Lion</td><td>His</td><td>To be</td><td>Angry</td><td>Lion</td><td>To be</td><td>Gin</td><td>Cys</td><td>Pro</td><td>Glu</td><td>Hours</td><td>His</td><td>Pro</td><td>Lion</td>

<td>Pro</td><td>Thr</td><td>Pro</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Pro</td><td>Ala</td><td>Hours</td><td>Asp</td><td>Faction</td><td>To be</td><td>Lion</td><td>Gly</td>

<td>Glu</td><td>Trp</td><td>list</td><td>Thr</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Thr</td><td>list</td><td>Ala</td><td>Gin</td><td>Asp</td><td>for</td>

<td>Lion</td><td>Gly</td><td>Ala</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Lion</td><td>Lion</td><td>Glu</td><td>Gly</td><td>Hours</td><td>With</td><td>Ala</td><td>Ala</td>

<td>Angry</td><td>Gin</td><td>Gin</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Cys</td><td>Lion</td><td>To be</td><td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td>

<td>Gin</td><td>Lion</td><td>To be</td><td>Gly</td><td>Gin</td><td>Hours</td><td>Angry</td><td>Lion</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Ala</td><td>Lion</td><td>Gin</td>

<td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Thr</td><td>Gin</td><td>Lion</td><td>Pro</td><td>Pro</td><td>Gin</td><td>Gly</td><td>Angry</td><td>Thr</td><td>Thr</td>

<td>Ala</td><td>His</td><td>list</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Ala</td><td>for</td><td>Faction</td><td>Lion</td><td>To be</td><td>Faction</td><td>Gin</td><td>His</td>

<td>Lion</td><td>Lion</td><td>Angry</td><td>Gly</td><td>list</td><td>hour</td><td>Angry</td><td>Faction</td><td>Lion</td><td>With</td><td>Lion</td><td>Hours</td><td>Gly</td><td>Gly</td>

<td>To be</td><td>Thr</td><td>Lion</td><td>Cys</td><td>Hours</td><td>Angry</td><td colspan="2">[Secv. No..</td><td colspan="2"> 165]</td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>. Asn</td><td>l Cys</td><td>To be</td><td>• lle</td><td>i Met</td><td colspan="2">Asp</td><td colspan="4">to Glu place where His</td><td>; His</td>

<td colspan="2">Leu Lys</td><td>in Arg</td><td>C Pro</td><td>i Pro</td><td colspan="2">i Asn Prc</td><td>• Leo</td><td colspan="6">and Leu Asp Pro Asn Asn Leu</td>

RO 118016 Β1

<td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>with</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td> 3045</td>

<td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td><td></td>

<td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td></td>

<td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td><td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td></td>

<td>with</td><td>with</td><td>with</td><td>list</td><td>Ala</td><td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td> 3050</td>

<td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td><td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>Gin</td><td>Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td></td>

<td>Gin</td><td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td>Gly</td><td colspan="2">Gly Gly</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td></td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>To be</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Cys</td><td></td>

<td>Asp</td><td>Lion</td><td>Angry</td><td>Hours</td><td>Lion</td><td>To be</td><td>list</td><td>Lion</td><td>Lion</td><td>Angry</td><td>Asp</td><td>To be</td><td>His</td><td>Hours</td><td rowspan="2"> 3055</td>

<td>Lion</td><td>His</td><td>To be</td><td>Angry</td><td>Lion</td><td>To be</td><td>Gin</td><td>Cys</td><td>Pro</td><td>Glu</td><td>Hours</td><td>His</td><td>Pro</td><td>Lion</td>

<td>Pro</td><td>Thr</td><td>Pro</td><td>Hours</td><td>Lion</td><td>Lion</td><td>Pro</td><td>Ala</td><td>Hours</td><td>Asp</td><td>Faction</td><td>To be</td><td>Lion</td><td>Gly</td><td></td>

<td>Glu</td><td>Trp</td><td>list</td><td>Thr</td><td>Gin</td><td>With</td><td>Glu</td><td>Glu</td><td>Thr</td><td>list</td><td>Ala</td><td>Gin</td><td>Asp</td><td>with</td><td></td>

<td>Lion</td><td>Gly</td><td>Ala</td><td>hour</td><td>Thr</td><td>Lion</td><td>Lion</td><td>Lion</td><td>Glu</td><td>Gly</td><td>Hours</td><td>With</td><td>Ala</td><td>Ala</td><td rowspan="2"> 3060</td>

<td>Angry</td><td>Gin</td><td>Gin</td><td>Lion</td><td>Gly</td><td>Pro</td><td>Thr</td><td>Cys</td><td>Lion</td><td>To be</td><td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td>

<td>Gin</td><td>Lion</td><td>To be</td><td>Gly</td><td>Gin</td><td>Hours</td><td>Angry</td><td>Lion</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Ala</td><td>Lion</td><td>Gin</td><td></td>

<td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Thr</td><td>Gin</td><td>Lion</td><td>Pro</td><td>Pro</td><td>Gin</td><td>Gly</td><td>Angry</td><td>Thr</td><td>Thr</td><td></td>

<td>Ala</td><td>His</td><td>list</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Ala</td><td>with</td><td>Faction</td><td>Lion</td><td>To be</td><td>Faction</td><td>Gin</td><td>His</td><td></td>

<td>Lion</td><td>Lion</td><td>Angry</td><td>Gly</td><td>list</td><td>Hours</td><td>Angry</td><td>Faction</td><td>Lion</td><td>With</td><td>Lion</td><td>Hours</td><td>Gly</td><td>Gly</td><td> 3065</td>

<td>To be</td><td>Thr</td><td>Lion</td><td>Cys</td><td>Hours</td><td>Angry</td><td colspan="2">[Secv. No..</td><td colspan="2"> : 166]</td><td></td><td></td><td></td><td></td><td></td>

<td>With</td><td>Ala</td><td>To be</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Cys</td><td>Asp</td><td>Lion</td><td>Angry</td><td>Hours</td><td>Lion</td><td></td>

<td>To be</td><td>list</td><td>Lion</td><td>Lion</td><td>Angry</td><td>Asp</td><td>To be</td><td>His</td><td>Hours</td><td>Lion</td><td>His</td><td>To be</td><td>Angry</td><td>Lion</td><td> 3070</td>

<td>To be</td><td>Gin</td><td>Cys</td><td>Pro</td><td>Glu</td><td>Hours</td><td>His</td><td>Pro</td><td>Lion</td><td>Pro</td><td>Thr</td><td>Pro</td><td>Hours</td><td>Lion</td><td></td>

<td>Lion</td><td>Pro</td><td>Ala</td><td>Hours</td><td>Asp</td><td>Faction</td><td>To be</td><td>Lion</td><td>Gly</td><td>Glu</td><td>Trp</td><td>list</td><td>Thr</td><td>Gin</td><td></td>

<td>With</td><td>Glu</td><td>Glu</td><td>Thr</td><td>list</td><td>Ala</td><td>Gin</td><td>Asp</td><td>with</td><td>Lion</td><td>Gly</td><td>Ala</td><td>hour</td><td>Thr</td><td></td>

<td>Lion</td><td>Lion</td><td>Lion</td><td>Glu</td><td>Gly</td><td>Hours</td><td>With</td><td>Ala</td><td>Ala</td><td>Angry</td><td>Gin</td><td>Gin</td><td>Lion</td><td>Gly</td><td rowspan="2"> 3075</td>

<td>Pro</td><td>Thr</td><td>Cys</td><td>Lion</td><td>To be</td><td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Gin</td><td>Lion</td><td>To be</td><td>Gly</td><td>Gin</td>

<td>Hours</td><td>Angry</td><td>Lion</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Ala</td><td>Lion</td><td>Gin</td><td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Thr</td><td></td>

<td>Gin</td><td>Lion</td><td>Pro</td><td>Pro</td><td>Gin</td><td>Gly</td><td>Angry</td><td>Thr</td><td>Thr</td><td>Ala</td><td>His</td><td>list</td><td>Asp</td><td>Pro</td><td></td>

<td>Asn</td><td>Ala</td><td>with</td><td>Faction</td><td>Lion</td><td>To be</td><td>Faction</td><td>Gin</td><td>His</td><td>Lion</td><td>Lion</td><td>Angry</td><td>Gly</td><td>list</td><td rowspan="2"> 3080</td>

<td>Hours</td><td>Angry</td><td>Faction</td><td>Lion</td><td>With</td><td>Lion</td><td>Hours</td><td>Gly</td><td>Gly</td><td>To be</td><td>Thr</td><td>Lion</td><td>Cys</td><td>Hours</td>

<td>Angry</td><td>Tyr</td><td>Hours</td><td>with</td><td>Glu</td><td>Gly</td><td>Angry</td><td>with</td><td>To be</td><td>Pro</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td></td>

<td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td><td>with</td><td>With</td><td>with</td><td>Asp</td><td></td>

<td>Glu</td><td>with</td><td>with</td><td>His</td><td>His</td><td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td><td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td></td>

<td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td><td>Asp</td><td>with</td><td>Lion</td><td>With</td><td> 3085</td>

<td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Angry</td><td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td><td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td></td>

<td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td><td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td><td>with</td><td>Glu</td><td>Ala</td><td>with</td><td></td>

RO 118016 Β1

<td colspan="9">Leu Arg Asn Leu Gin Pro Cys Leu Pro</td><td rowspan="4">To be Ala Lion</td><td colspan="4" rowspan="2">Ala Thr Ala Ala Gly Asp Trp Gin</td>

<td colspan="3" rowspan="3">Pro Ser Arg Glu Phe Arg Gin Ala Gin</td><td colspan="5">His Pro loves you</td><td rowspan="3">list Tyr 167]</td>

<td colspan="2">Glu Lys</td><td colspan="3">Read Thr Phe</td><td rowspan="2">Hours</td><td colspan="3" rowspan="2">Thr Leu Glu</td>

<td>Glu</td><td>Gin</td><td>Gin</td><td colspan="2">[Secv, no .:</td>

<td>With</td><td>Ala</td><td>To be</td><td>Pro</td><td>Ala</td><td>Pro</td><td>Pro</td><td>Ala</td><td>Cys</td><td>Asp</td><td>Lion</td><td>Angry</td><td>Hours</td><td>Lion</td>

<td>To be</td><td>list</td><td>Lion</td><td>Lion</td><td>Angry</td><td>Asp</td><td>To be</td><td>His</td><td>Hours</td><td>Lion</td><td>His</td><td>To be</td><td>Angry</td><td>Lion</td>

<td>To be</td><td>Gin</td><td>Cys</td><td>Pro</td><td>Glu</td><td>Hours</td><td>His</td><td>Pro</td><td>Lion</td><td>Pro</td><td>Thr</td><td>Pro</td><td>Hours</td><td>Lion</td>

<td>Lion</td><td>Pro</td><td>Ala</td><td>Hours</td><td>Asp</td><td>Faction</td><td>To be</td><td>Lion</td><td>Gly</td><td>Glu</td><td>Trp</td><td>list</td><td>Thr</td><td>Gin</td>

<td>With</td><td>Glu</td><td>Glu</td><td>Thr</td><td>list</td><td>Ala</td><td>Gin</td><td>Asp</td><td>for</td><td>Lion</td><td>Gly</td><td>Ala</td><td>Hours</td><td>Thr</td>

<td>Lion</td><td>Lion</td><td>Lion</td><td>Glu</td><td>Gly</td><td>Hours</td><td>With</td><td>Ala</td><td>Ala</td><td>Angry</td><td>Gin</td><td>Gin</td><td>Lion</td><td>Gly</td>

<td>Pro</td><td>Thr</td><td>Cys</td><td>Lion</td><td>To be</td><td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Gin</td><td>Lion</td><td>To be</td><td>Gly</td><td>Gin</td>

<td>Hours</td><td>Angry</td><td>Lion</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Ala</td><td>Lion</td><td>Gin</td><td>To be</td><td>Lion</td><td>Lion</td><td>Gly</td><td>Thr</td>

<td>Gin</td><td>Lion</td><td>Pro</td><td>Pro</td><td>Gin</td><td>Gly</td><td>Angry</td><td>Thr</td><td>Thr</td><td>Ala</td><td>His</td><td>list</td><td>Asp</td><td>Pro</td>

<td>Asn</td><td>Ala</td><td>for</td><td>Faction</td><td>Lion</td><td>To be</td><td>Faction</td><td>Gin</td><td>His</td><td>Lion</td><td>Lion</td><td>Angry</td><td>Gly</td><td>list</td>

<td>Hours</td><td>Angry</td><td>Faction</td><td>Lion</td><td>With</td><td>Lion</td><td>Hours</td><td>Gly</td><td>Gly</td><td>To be</td><td>Thr</td><td>Lion</td><td>Cys</td><td>Hours</td>

<td>Angry</td><td>Glu</td><td>Faction</td><td>His</td><td>Ala</td><td>Tyr</td><td>Hours</td><td>Glu</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Pro</td>

<td colspan="2">Gly Gly</td><td>Gly</td><td>To be</td><td>Gly</td><td>Gly</td><td>Gly</td><td>To be</td><td>Asn</td><td>With</td><td>Ala</td><td>Asn</td><td>Cys</td><td>To be</td>

<td>for</td><td>With</td><td>for</td><td>Asp</td><td>Glu</td><td>for</td><td>for</td><td>His</td><td>His</td><td>Lion</td><td>list</td><td>Angry</td><td>Pro</td><td>Pro</td>

<td>Asn</td><td>Pro</td><td>Lion</td><td>Lion</td><td>Asp</td><td>Pro</td><td>Asn</td><td>Asn</td><td>Lion</td><td>Asn</td><td>To be</td><td>Glu</td><td>Asp</td><td>With</td>

<td>Asp</td><td>for</td><td>Lion</td><td>With</td><td>Glu</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Now</td><td>Thr</td><td>Pro</td><td>Asn</td><td>Lion</td><td>Lion</td>

<td>Ala</td><td>Faction</td><td>Hours</td><td>Angry</td><td>Ala</td><td>Hours</td><td>list</td><td>His</td><td>Lion</td><td>Glu</td><td>Asn</td><td>Ala</td><td>To be</td><td>Gly</td>

<td>for</td><td>Glu</td><td>Ala</td><td>for</td><td>Lion</td><td>Angry</td><td>Asn</td><td>Lion</td><td>Gin</td><td>Pro</td><td>Cys</td><td>Lion</td><td>Pro</td><td>To be</td>

<td>Ala</td><td>Thr</td><td>Ala</td><td>Ala</td><td>Pro</td><td>To be</td><td>Angry</td><td>His</td><td>Pro</td><td>for</td><td>for</td><td>for</td><td>list</td><td>Ala</td>

<td>Gly</td><td>Asp</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Faction</td><td>Angry</td><td>Glu</td><td>list</td><td>Lion</td><td>Thr</td><td>Faction</td><td>Tyr</td><td>Lion</td>

<td>Hours</td><td>Thr</td><td>Lion</td><td>Glu</td><td>. Gin</td><td>. Ala</td><td>Gin</td><td>Glu</td><td>Gin</td><td colspan="2">Gin</td><td></td><td></td><td></td>

[Secv. no .: 168]

Materials and methods for the expression of the fusion molecule in E. coli.

Except where noted, all chemical materials are obtained from Sigma Co., (St. Louis, Mo). Resting endonucleases, T4 polynucleotidinase, large fragment DNA polymerase I E. coli (Klenow) and T4 DNA ligase are obtained from New England Biolabs (Beverly, Massachusatts).

Escherichia coli strains

JM101 strain: delta (pro lac), supE, thi, F '(traD36, rpoAB, lacl-Q, LacZdeltaM15) (Messing, 1979). This strain can be obtained from the American Type Culture Collection (ATCC), 12301 Parklawn Drive, lockville, Maryland 20852, accession number 33876. MON105 (W3110 rpoH358) is a derivative of W3110 (Bachmann, 1972) and has been assigned the number access code ATCC 55204. GM48 strain: dam-3, dcn-6, gal, ara, lac, thr, leu, tonA, tsx (Marinus, 1973) is used to obtain plasmid DNA that is not methylated at the GATC sequence.

Gene and plasmids

The gene used to produce hlL-3 in E.coli is obtained from British Biotechnology Incorporated, Cambridge, England, catalog number BBG14. This gene is contained by a pUC-based plasmid designated pP0518. Many other human CSF genes can be obtained from R&amp;D Systems, Inc. (Ninn, MN) including IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, G-CSF, GM-CSF and LIF.

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Plasmids used for the production of hlL-3 in E.coli contain genetic elements whose use has been described (Olins et al., 1988; Olins and Rangwala, 1990). The replicon used is that of pBR327 (Covarrubias et al., 1981), which is maintained in a number of copies of about 100 in the cell (Soberon et al., 1980). A plasmid gene encodes the deta-lactamase protein. This protein gives the cell ampicillin resistance. This resistance serves as a selectable phenotype for the presence of the plasmid in the cell.

For cytoplasmic expression of vectors, the transcription promoter is derived from the recA gene of E.coli (Sancar et al., 1980). This promoter, designated precA, includes the RNA polymerase binding site and the lexA repressor binding site (the operator). This DNA segment provides the high level of transcription that is bound even when the recA promoter is on a plasmid with the origin of pBR327 replication (Olins et al., 1988) incorporated herein by reference).

The binding site of the ribozone used is that of gene 10 of phage 17 (Olins et al., 1988). It is encoded in a fragment of 100 base pairs (bp), placed adjacent to precA. In the plasmids used herein, the recognition sequence for the Ncol enzyme (CCATGG) follows glo-L. It is at this Ncol site, to which the hlL-3 genes are linked to the plasmid. It is expected that the nucleotide sequence at this junction is recognized in the mRNA as a functional starting site for translation (Olins et al., 1988). The hlL-3 genes were processed to have a HindiII recognition site (AAGCTT), downstream of the gene coding sequence. At this Hindlll site, there is a Rsal fragment of 514 base pairs, which contains the origin of the single-stranded phage replication fl (Dente et al., 1983; Olins et al., 1990) both incorporated herein by reference. A plasmid containing these elements is pMON2341. Another plasmid containing these elements is pMON5847, which is stored at the ATCC, under accession number 68912.

In secretion expression plasmids, the transcriptional promoter is derived from the E. coli B, A and D genes (Greenfield et al., 1978). This promoter is designated pAraBAD and is contained on a restriction fragment Sacii, Bglll of 323 base pairs. The LamB secretion leader (Wong et al., 1988, Clement et al., 1981) is fused to the Nterminal end of the hlL-3 gene in the recognition sequence for the Ncol enzyme (5'CCATGG3 '). The hlL-3 genes used were processed to have a Hindlll recognition site (5'AAGCTT3 '), which follows the gene coding sequence.

Metode DNA recombinant.

Synthetic gene assembly

The hlL-3 variant genes and other CSF genes can be constructed by assembling synthetic oligonucleotides. Synthetic oligonucleotides are designated such that they will normalize into complementary pairs with single stranded ends, which exit out and, when the pairs are properly assembled, will result in a DNA sequence, which encodes a portion of the desired gene. Amino acid substitutions, in the hlL-3 gene, are made by designating oligonucleotides to encode desired substitutions. Complementary oligonucleotides are normalized to a concentration of 1 pmol / pl in ligation buffer plus 50 mM NaCl. The samples are heated in a 100 ml laboratory vessel with hot water and allowed to cool slowly, at room temperature. From each normalized oligonucleotide pair, 1 pmol is ligated with approximately 0.2 pmol of plasmid DNA, digested with the appropriate restriction enzymes in ligation buffer (25 mM Tris pH 8.0, 10 mM MgC12, 10 mM dithiothreitol, 1 mM ATP, 2 mM spermidine) with T4 DNA ligase obtained from New England Biolabs (Beverly, Massachusetts) in a total volume of 20 µl, at room temperature, overnight.

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The polymerization chain reaction in the polymerase chain reaction techniques (hereinafter referred to as PCR) (Saiki, 1985) used the reagent kit and the thermal cycler from Perkin-Elmer Cetus (Norwalk, CT.). PCR is based on a thermostable DNA polymerase from Thermus Aquaticus. PCR technique is a method of DNA amplification, which mimics the process of natural DNA replication, in which the number of DNA molecules doubles after each cycle, in a similar way to in vivo replication. DNA polymerase, which mediates extension, is in a 5 'to 3' direction. The term "primer", as used herein, refers to an oligonucleotide sequence, which provides an end at which DNA polymerase can add the nucleotide which is complementary to a nucleotide sequence. The last nucleotide sequence is called a "matrix, where the polymers are normalized. The amplified PCR product is defined as the region between the 5 'ends of the extension primers. Because the primers have defined sequences, the product will have precise ends, which correspond to the primer sequences. The primer extension reaction is performed using 20 pmol of each oligonucleotide and 1 µg of template DNA plasmid for 35 cycles (1 cycle is defined as 94 ° C for 1 min, 50 ° C for 2 min and 72 ° C for 3 min. ). The reaction mixture is extracted with an equal volume of phenol / chloroform (50% phenol and 50% chloroform, volume by volume), for protein removal. The aqueous phase containing the amplified DNA and the solvent phase are separated by centrifugation, 5 min., In a microcentrifuge (Model 5414 Eppendorf Inc. Fremont CA.). To precipitate the amplified DNA, remove and transfer to a new tube with 1/10 volume of 3 M NaUAc (pH 5.2) and 2.5 volumes of ethanol (100%, stored at - 20 °). C). The solution is mixed and placed on dry ice, 20 min. Pellet the DNA by centrifugation, 10 minutes, in a microcentrifuge and remove the solution from the pellet. The DNA pellet was washed with 70% ethanol, the ethanol was removed and dried in a vacuum concentrator (Savant, Fermingdale, New York). The pellet was resuspended in 25 μΙ TE (20 mM Tris-HCl, pH 7.9, 1 mM EDTA). Alternatively, the DNA is precipitated by adding an equal volume of 4 M NH₄OAc and 1 volume of isopropanol (Treco et al. (1988)). The solution was mixed, incubated at room temperature, 10 min., And centrifuged. These conditions precipitate selectively DNA fragments, that is, on those larger than about 20 bases and are used for the removal of the primary oligonucleotides. One quarter of the reaction is digested with restriction enzymes (Higuchi, (1989)) on a heating supplement, up to 70 ° C, for enzyme inactivation.

Recovery of recombinant plasmids from ligand mixtures

GM101 E.coli cells are competent for DNA uptake. Usually, 20 to 100 ml of cells are grown in LB medium to a density of about 150 Klett units and then collected by centrifugation. The cells are resuspended in a culture medium of 50 mM CaCl₂ and kept at 4 ° C for 1 h. DNA was added to a volume of 150 μΙ of these cells and the samples maintained at 4 ° C for 30 min. The samples are passed at 42 ° C, for 1 min, 1 ml of LB is added and the samples are stirred at 37 ° C, 1 h. The cells in these samples are disseminated on plates containing ampicillin for selecting the transformants. The plates are incubated overnight at 37 ° C. Single colonies are collected, grown in LB supplemented with ampicillin overnight at 37 ° C with agitation. From these cultures, DNA is isolated for restriction analysis.

Culture environment