Immunotherapeutic combinations for treating cancers overexpressing gangliosides

UKRAINE

(19) and A (11) 76745 (13) C2

(51) IPC

А61К 31/7032 (2006.01) А61К 31/739 (2006.01) А61К 39/00 (2006.01) А61К 39/395 (2006.01) С07К 16/00 (2006.01) С07К 16/18 (2006.01) С07К 16/30 (2006.01) С07К 16/42 (2006.01)

MINISTRY OF EDUCATION SCIENCE OF UKRAINE

STATE DEPARTMENT OF INTELLECTUAL PROPERTY

DESCRIPTION

TO THE INVENTORY PATENT

(54) IMMUNOPERATIVE COMBINATIONS FOR THE TREATMENT OF HUMAN TREATMENTS SUFFERING GANGLIO-ZIDA

1

(21) 2003108988

(22) April 8, 2002

(24) 15.09.2006

(86) PCT / C02 / 00002 of 08.04.2002

(31) 84/2001

(32) April 6, 2001

(33) s

(46) Sep 15, 2006, Bul. No. 9, 2006

(72) Fernandez Molina Luis, C, Vazquez LopezAn, C, Perez Rodriguez Rolando, Cesi, Perez Gon-Hall Alexis, Ci Carr Peres Adrian, Ci, Diaz Rodrigues Yildian, Ci Alfonso Fernandez Mau-roo Ci Rojas Del Calvo , C

(73) CENTER FOR INMUNOLOGY MOLECULAR, C

(56) EP 0 586 002 A2, 14.06.1995.

JO 99/20656 A, 29.04.1999.

EP 0 661 061 A, 05.07.1995.

EP 0 586 002 A, 09.03.1994.

υδ 6,149,921 A, 21.11.2000.

(57) 1. An immunotherapeutic combination for tumor immunity that overexpresss gangliosides containing a gangliosidic vaccine (C) as well as an idiotype vaccine (A) containing a murine antiangialiosis-monoclonal antibody (AL1) or an idiotopovaccinol (B ) containing a specific murine anti-diotype monoclonal antibody (AL2) antiantiganglioside monoclonal antibody.

2. The immunotherapeutic combination of claim 1, which is based on the fact that the vaccine A contains mouse anti-

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ganglioside antibody MAI P3 (DEPOSITION numberESASS 94113026).

3. The immunotherapeutic combination of claim 1, which is characterized by the fact that the vaccine B contains a mouse anti-diotype antibody 1E10 (deposition number, eSASS 97112901).

4. Immunotherapeutic combination at any time. 1-3, which is characterized in that the vaccine C is a ganglioside of HeySeMM3.

5. Immunotherapeutic combination at any time. 1-3, characterized in that the vaccine C is a ganglioside of NieaAesMM3.

6. Immunotherapeutic combination at any time. 1-5, characterized in that vaccines A and Sabo vaccines B and C are administered concurrently or in turn.

7. The use of the immunotherapeutic combination for any of the items. 1 -6 for the treatment of tumors that are on-to-pump out gangliosides.

8. The use according to claim 7 for treating a tumor of the lung, lung, gastrointestinal system, genitourinary system, melanoma, and sarcoma of the neuroectodermic origin of the tumor.

A method for controlling the growth and / or proliferation of tumor cells that overexpress gangliosides, which comprises administering to a mammal an immunotherapeutic combination of any one of the preceding claims. 1 -6.

10. The method of claim 9, wherein the person is a sasseman.

iA (11) 76745 (13) C2

This invention relates to medicine, and in particular to therapeutic vaccines that induce an immune response to tumors that overexpress gangliosides.

Gangliosides are integral parts of the plasma membranes of most mammalian cells. Regardless of the fact that these glycosfingolipids are expressed in normal tissues, they are very

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attractive targets for immunotherapy after the changes in the character of expression during malignant degeneration of cells [Hakomori C (Nakotogi δ.), APP. Reu Visio 50; 1981: 733-764; Hakomori (Nakotogi), Sapzeg Reye. 45; 1985: 2405-2414; Iri R.F. (Igea RP), U: TiehareiIistoposiopai apyiСолеее. Borberk K.A.K. (VoggeBaesks A.A.K.), Larrik D.V. (Laghisk B.Sc.) (Editors). M. δ. ^ Μοη Rayge, 1990, pp. 75-94].

Gangliosides are molecules with very low immunogenicity due to saccharide nature and due to the fact that they are autoantigens. In order toincrease the immunogenicity of these antigens have gone to certain strategies. The basis of these strategies is the presentation of gangliosides to the immune system in a different molecular environment. One of these strategies was the use of conjugated vaccine, wherein the saccharide antigen is covalently bonded to the carrier protein, and said carrier is highly immunogenic for T cells. This provides a strong and sustained humoral immune response. Due to this procedure, IDS antibodies against these gangliosides can be absorbed, although the titres after revaccinations are less than those obtained in the case of a classic immune response against thymus-independent antigens [HellingF. (NeiIipd R.), Sapsig Reye. 54; 1994: 197-203; Helling Φ. (NeiIipd R.), Sapsig Reye. 55; 1995: 2783-2788; Livingstone P.O. (I_amped1op R.O.) Sapseg Ittipoi IttipoiIg. 45; 1997: 10-19].

It has been reported that new vaccine compositions induce an immune response against N-acetylated and N-glycolylated gangliazides. The basis of these vaccines is hydrophobic conjugation between gangliosides and proteolypolosomes of a very large size (UZZR), which represent a complex of external Membrane Proteins (OMRS) Gram-Bacteria Meieegiia tepipdiiiibie (ganglionis-di / UZZR) [Esteves Φ. (E. Euwei R.), Uasspep 18; 1999: 190-197; US Pat. Nos. 5,778,985 and 6,149,921]. Vaccines that include gangliosid SMV / UZZR or ganglioside-eyScSM3) / U55P produce high titers of specific IgMt-IDS antibodies against CM3 and NeiSssMz.

In other words, immunization with the vaccine ISM / UZZ significantly increased the survival time with the B16 melanoma, and also reduced the volume of tumors and increased the intensity of the transplant versus host response in the case of subcutaneous transplantation of this tumor [Alonso (AIOopoe) and others, Hyp. b. Opportunity 15; 1999: 59-66; Kara A. (Sag A.) and others, Meijopota Reeågas, published].

According to the theory of idiotypic grids, proposed by Erne in 1974 [Erne N.K. (backstage NK.), APP. Ittipoi. 125C; 1974: 373-389], the immune system is depicted as a network of antibodies with a complex hacker of interaction between these antibodies and a large number of natural antigens. These interactions take place through the variable regions or the set of idiotypic determinants (ICs), and the immune system is regulated by this interaction of an idiot-antiidiotip. Ern's theory provided the opportunity to develop new strategies for active immunotherapy (AI) cancer built on the use of anti-idiot-vaccine vaccines. For vaccination, an antibody (AL1) that recognizes a tumor antigen is used,

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which induces the formation of an anti-idiotypovichantitil (AL2) in the body. These anti-idiotypic antibodies simulate pseudo-antigen and, in turn, produce anti-thiidiotype antibodies (Aβ3) against the tumor anti-gene [Schmelling J. (Zsithioi.dd. B.) and others, Nujibotta 14; 1995: 183-186]. On the other hand, there are many reports with examples of vaccines containing anti-idiotypic antibodies (anti-IC or (A2)) that are capable of inducing immune responses of antitumor antigens [Raichoguri C (RausPaiiPihi δ.) And others, b. Ittipoi. 137; 1986: 1743-1749; Reichhores C (RausiiaIgi 3) and others, b. Ittipoi. 139; 1987: 3902-3910; Bhattakaraya-Chatterjee M. (ViyasIagua-Seyidey M.) and others, b. IttipoI.139; 1987: 1354-1360; Bhattakaraya-Chatterjee M. (ViyiasIagua-Syayede M.) and others, b. Ittipoi.141; 1988: 1398-1403; Gerlien D. (Negius, J.) and others, Ipiiegp. Reu Ittipoi. 4; 1989: 347-357; Chen Z.-J. (Siepe Z.-b.) and others, SeII. ITT Ittipoiyeg Sapseg, 1990: 351-359; Gerlin D. (Negiev Yu.) And others, Yip Uiuu5; 1991: 615-624; Furuya A. (Rigiua A.) and others, Apysapegre Ree. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. ) and others, SeII. ITT Ittipoiyeg Sapseg, 1990: 351-359; Gerlin D. (Negiev Yu.) And others, Yip Uiuu5; 1991: 615-624; Furuya A. (Rigiua A.) and others, Apysapegre Ree. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. ) and others, SeII. ITT Ittipoiyeg Sapseg, 1990: 351-359; Gerlin D. (Negiev Yu.) And others, Yip Uiuu5; 1991: 615-624; Furuya A. (Rigiua A.) and others, Apysapegre Ree. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. Ittipoiyeg Sapseg, 1990: 351-359; Gerlin D. (Negiev Yu.) And others, Yip Uiuu5; 1991: 615-624; Furuya A. (Rigiua A.) and others, Apysapegre Ree. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. Ittipoiyeg Sapseg, 1990: 351-359; Gerlin D. (Negiev Yu.) And others, Yip Uiuu5; 1991: 615-624; Furuya A. (Rigiua A.) and others, Apysapegre Ree. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. (Negiev Yu.) And others, Yip Uiuu5; 1991: 615-624; Furuya A. (Rigiua A.) and others, Apysapegre Ree. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. (Negiev Yu.) And others, Yip Uiuu5; 1991: 615-624; Furuya A. (Rigiua A.) and others, Apysapegre Ree. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. 12; 1992: 27-32; Mittelmen A. (MyeitApp A.) and others, Pogos. Nai AsA 3s iZA 89; 1992: 466-470; Durran L.G. (Oyghapus I_.S.) and others, Sapsig Reye. 54; 1994: 4837-4840; Mittelmen A. (MyeitApp A.) and others, Sapsegger Rhee. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. (MyItap A.) and others, Sapsig Reye. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. (MyItap A.) and others, Sapsig Reye. 54; 1994: 415-421; Schmitt G. (Zsitiy H.) And others, NughiSot 13; 1994: 389-396; Chacrobarty M. (SiakoGoyu M.) and others, b. Ittipoiyeg 18; 1995: 95-103; Chacrobarty M. (Siakhoboyu M.) and others, Sapsegger Rhee. 55; 1995: 1525-1530; Fun SA (Roop K.A.) and others, Sipip.Sapseg Ree. 1; 1995: 1285-1294; GerlindD (Negiev Yu.) And others, Nugirth 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. NugriSot 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76]. NugriSot 14; 1995: 159-166; Sklebusch G. (Zsichiysi H.) And others, NubrySot 14; 1995: 167-174; Berlin D. (Negiev Yu.) And others, Sapseg IttipoiIttipoIiyg. 43; 1996: 65-76].

Another use of antibodies AL2 and pi-movement of the immunogenicity of saccharide residuesincludes the possibility that such a saccharide anti-gene determinant may be representedby protein antigenic determinant on the molecule antibody. In fact, many such anti-Ig antibodies have been obtained; they immitate gangliosides that are extensively expressed in tumor cells, for example, CM3, CU3 and CU2 [Yamamoto S. (Uatatoio 3.) and others, b. ΝβίΙ. Sapsig Ipei 82; 1990: 1757-1760; Chapman P.B. (Siirtap R.V.) and others, b. SIip Ipuiye 88; 1991: 186-192; Cheung N-KV (CIIPID N-K.V.) and others, Yapi b. Sapzeg 54; 1993: 499-505; Saleh M.N. (ZayEI MM) and others, b. IttipoI 151; 1993: 3390-3398; Saint G. (Zep S.) and others, b. IttipoIiyaharu 21; 1998: 75-83].

The promising results were obtained in clinical trials, during which some of the aforementioned monoclonal antibodies (MAIAX) were used in combination with BCG or 0321, which were used for the treatment of cancer patients [McCarthy M. (M.Spage M.) and others, Ciip Sapseg Ree 2; 1996: 679-686; Fun K.A. (Roop K.A.) and others, Sipip.Sapseg Re 4; 1998: 1117-1124].

Of the prior art, a known monoclonal antibody (MAb) P3 (deposited with the European Collection of Cultured Tweening Cells (ECACS 94113026), which specifically recognizes the acidic acid in the monosyalo- and dysialloganliosis-roof, including N-glycolil, is known. This is MA (monoclonal

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nal antibody) AL1 recognizes antigens in human breast tumors and melanomas [US Patent No. 5,788,985; Vasquez AM (ναζςιΐθζΑ.Μ.) and others, NugisIota 14; 1995: 551-556; Moreno (Moegao E.) and others, Siusioioode 8; 1998: 695-705; Markina G. (Magcypa S.) and others, Sapseg Rev 56; 1996: 5165-5171; Kar A. (Sagg A.) and others, Nugisiota 19 (3); 2000: 241-247].

Antidiabetic antibody 1E10 (AL2 MAI 1E10) (ECAS 97112901 deposition number), which is absorbed by immunization with MAI P3, is an antibody of type gamma (the "internal image" has no). Al2MeA1E10 demonstrated an antitumor effect against mouse tumors of breast milk and melanoma [US Pat. No. 6,063,379; You-ces ^ ζςι ^ ζ) and others, Nu'GiSot 14; 1995: 183-186; Vasquez ^ ζςι ^ ζ) and others, OpsoIoD of the Redoubts 7; 2000: 751-756].

The prior art does not have evidence of the use of a combination of ganglion-ozid vaccines and pharmaceutical compositions containing antiangialiosid antibodies (AY) or anti-idiotyp antibodies (AL2), or recombinant variants (chimeric or humanized antibodies) of the antibodies mentioned (which are called idiotypic vaccines) ; There is also no evidence of the use of combinations of idiot vaccine ALI with idiotype AL2 vaccines.

This invention relates to the use of all possible vaccine combinations described herein in order to potentiate the effect that they cause in the case of individual application of each of them.

The present invention relates to a pharmaceutical composition or a combination of pharmaceutical compositions suitable for immunotherapy of cancer, for the immunotherapy of tumors that overexpress gangliosides containing at least two of the following components as follows:

(A) An idiotype vaccine containing an antiangial-ozid antibody (AL1);

(B) An idiotype vaccine containing an anti-idiot antibody (AB2) against antiangialiosid antibody; and

(C) Ganglioside containing vaccine.

Pharmaceutical composition or combination

pharmaceutical compositions may contain A plus B or A plus C or B plus C.

In a preferred embodiment, this invention relates to a pharmaceutical composition or a combination of pharmaceutical compositions, wherein A may be an idiotypic vaccine that mimics mouse MA3 P3 (ESASC94113026 deposition number), wherein B may be an idiopathic vaccine that contains mouse anti-idiotypic antibody 1E10 (deposition number ECAS 97112901) and where it may be a vaccine containing gangliosides of N-glycolides CM3 ^ eisCsM3) or N-acetyl CM3 (KIeiAsSMZ).

According to the present invention, A plus B or A plus C or C plus C can be introduced simultaneously or in the form of a black-and-white.

The compositions of the present invention may be suitable for the treatment of cancer, in particular, cancerous tumors that overexpress gangliosides, as well as the lung, breast, gastrointestinal system, urinary system, melanoma, sar-

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com and tumors of neuroectodermic origin.

The present invention also provides a description of the scheme of introducing a pharmaceutical composition or a combination of pharmaceutical compositions for the treatment of women.

The present invention also provides a description of a method comprising administering to a mammal a pharmaceutical composition or a combination of pharmaceutical compositions described above for the prevention or treatment of breast tumors, lungs, gastrointestinal system, urinary system, melanoma , sarcoma and tumors of neo-rocetodermic origin.

1. Receiving vaccines including ganglionicides:

Vaccines comprising gangliosides are prepared according to the technical conditions that were published [Estevez (Ενίενεζ) and staff in Vassii 18,1999: 190-197 and in U.S. Patent Nos. 5,788,985 and 6,149,921], where natural or synthetic ganglion zids are used as constituents of a proteolyum of a very small size (νδδΡ) representing a complex of outer protein membranes (OMRS) of a strain of gram-negative bacteria KieivvegyatepipidiiiSi with synthetic or natural gangliosides (νδδΡ-C). Mentioned gangliosides can be ^ eiScSM3), CU3 or ^ eiAsCM3).

2. Receiving idiotypic vaccines

Pharmaceutical compositions are obtained according to the technical conditions of US Patent Nos. 5,817,513 and 6,063,379. The vaccines include murine antigang-lioside monoclonal antibodies, for example, MABP3 or mouse anti-idiotypic monoclonal anti-bodies, for example, MAb1E10, which recognize anti-ganglioside monoclonal antibodies.

3. Immunotherapeutic combinations potentiating the immune response and antitumor efficacious ganglioside vaccines and idiopathic vaccines in wildlife models:

The procedures mentioned may be used in mice or any other mammalian species. The components of said combination are gangliosidine vaccine and an idiotype vaccine; they can be combined in different ways.

In one combination, the animals can be immunized with 3-10 doses ranging from 25 μg to 1 mg antiangialiosid monoclonal antibody; The time interval between doses may be 7 days and 14 days. During this period, the animals receive 3-10 doses ranging from 60 μg to 1 000 μg ganglioside vaccine; the time interval betweendoses can be 7-14 days.

In another combination, the animals can be immunized with 3-10 doses ranging from 25 μg to 1 μg anti-idiot antibody specific to the antiangialiosid antibody; the interval betweendoses can be 7-14 days. During this time period, animals receive 3-10 doses ranging from 60 μg to 1000 μg ganglioside vaccine, and the time interval between doses can be 7-14 days.

The introduction of vaccines of both types may be one-time or alternate. Vaccines may be prepared in the form of individual products or in the form of a vaccine composition when they are administered simultaneously. In the event that the vaccines are administered alternately, intermediate

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The time between administration of a vaccine of each type may be 3-7 days. Vaccines are administered to a uadjuvant, which may be aluminum hydroxide (62.5 mg-2.5 mg), Montanid ISL 51 (MOPIIPIPE IZL 51) (0.1-1.2 ml per dose), or any other appropriate ad ' Yuante The total volume of each dose can be equal to 10μl-2ml. Vaccines involving gangliosides can be administered intradermally, subcutaneously, intramuscularly, intraocularly, intramuscularly or combined. The same route of administration can be used for vaccines containing antibodies.

Immunotherapeutic combinations increase both gumoral and cellular immune responses to tvaryn that were treated.

The time when local tumors appeared, the volume of tumors, and the survivability of subjects undergoing treatment were compared with the same parameters of the control group in order to determine the effectiveness of the immuno-therapeutic combinations. After treatment with the above-mentioned immunotherapeutic combinations in animals, there is a reduction in the incidence of tumors, a decrease in tumor volume and an increase in survival not only compared with the group treated only with adjuvants, but also comparatively with the groups that were administered only one vaccine, and not their combinations.

4. Immunotherapeutic combinations that potentiate the immune response and the antitumor effect of gangliazide and idiotypic vaccines in human patients:

The above-mentioned procedure can be applied to patients with cancer-related illness, at various clinical stages with tumors, whichexpress gangliosides. To their number are tumors of the lungs, mammary gland, gastrointestinal system, urinary-sexual system, melanoma, sarcoma and tumors of neuroectodermic origin.

In one combination, patients can be vaccinated with 3-10 doses in the range of from 0.1 mg to 5 mg antiangialioside monoclonal antibody; The time interval between doses may be 7 days and 14 days. During this period, patients receive 3-10 doses ranging from 60 μg to 1,000 μg ganglioside vaccine; the time interval betweendoses can be 7-14 days.

In another combination, patients can be vaccinated with 3-10 doses in the range of from 0.1 mg to 5 mg anti-idiotype antibody specific against the antiangialiosid antibody; the interval betweendoses can be 7-14 days. During this period of time, patients receive 4-6 doses ranging from 60 μg to 1000 μg gangliazide vaccine; The time interval between doses can be 7-14 days.

In the third combination, patients may immunize with a murine antiganglioside monoclonal antibody; doses, frequency and time intervals may correspond to the description that was given. During this period, patients are treated with 3-10 doses in the range from 0.1 mg to 2 mg of the mouse anti-idiot antibody, a specific antibody antiangialiosid antibody.

The introduction of vaccines of both types may be one-time or alternate. Vaccines can get

8

in the form of individual products or in the form of a vaccine composition when they are administered simultaneously. In the case when the vaccines are administered alternately, the interval between the administration of each type of vaccine may be 3-7 days. Vaccines are administered to a uadjuvant, which may be aluminum hydroxide (1-5 mg per dose), Monazine IZA 51 (0.6-1.2 ml per dose), or any other suitable adjuvant. The total volume of each dose can be 10μl-2ml.

Vaccines involving gangliazides may be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intra-lysically or in combination. The same pathway can be used for vaccines containing antibodies.

During vaccination, some biochemical parameters of antibody titers are controlled by determination of blood samples. Frequency can range from 1 week to 3 months. Cell immunity is investigated by taking samples of lymphocytes from patients. Samples are taken at a frequency ranging from one week to three months.

Finally, patients are re-vaccinated with both vaccines at the concentrations mentioned above, with doses between 1 and 6 months. They can be injected simultaneously or in different ways within 1-2 years.

The vaccination scheme of the present invention induces increased antibody titres and enhanced cellular immune responses, and thus reduces the tumor's severity.

Examples

Example 1: Activation of anti-idiotypic T2 and antiantitioptic T3 cells in a syngenic model induced by immunization with mouse MAIL P3

Mouse-females of the BaII / c line and the "naked" mouse of the same genetic background, aged 6-8 weeks, were immunized 100 μg of mouse MAL P3 [anti-N-glycolidal ganglioside, deposition numberESASS 94113026; Vazquez (Waitsiei) and others, Nugisiota 14; 1995: 551-558; Moreno (Moepeo) and others, SiusioIouda 8; 1998: 695-705] and FullDown Freund (CPA). Seven days later, mice were immunized with 50 μg of the antibody in the non-Fried Freund's Adjuvant (IRA). At 10 days, samples from lymph nodes were collected and lymphocytes were collected by spraying through a syringe. Cellularsuppression was used in experiments withcellular proliferation, the level of which determinedthis inclusion³N-thymidine. The proliferation of lymphocytes in vivo was determined by cultivating a suspension of lymphocytes in the presence of higher concentrations (from 25 μg / ml to 150 μg / ml) of the mutations of MAb p3 and AB2 MAI1E10 (number ESPACE 97112901). Mouse monoclonal antibodies of the same isotype were used for control. The positive stoichiometry indices were equal to or greater than 3. Proliferation of lymphocytes that were obtained after the immunization of the Vai / s P3 MAb mice was observed, in particular, in the presence of this monoclonal antibody, and such proliferation was not observed in the case of cell cultivation in the presence of a control mice monoclonal antibody A3 (IDM) [Alfonso M. (AITopeo M.) and collaborators

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ki: Nujibota 14; 1995: 209-216]. This proliferation depended on the presence of T cells that were not received with lymph node cells from immunized P3 fetal rat mice. Mouse immunization, like mAy P3, not only induced proliferation of T cells against the idiotype of this AL1 MAb (T2), but also induced the proliferation of anti-antidiotype T-cells (T3) specific to murine AL2MBA1E10 (and CI) and not against MAIL C5 the same isotype (idI) (FIG. 1).

Example 2: Activation of antiidiotsivyh (T2) and antiantitioptic (T3) cells induced by immunization with chimeric antibody P3

The chimeric P3 antibody, the amino acid sequences of the variable regions of the heavy (OH) and light (U) chains of which are shown in FIGS. 8 and 9, respectively, were used to immunize females of the VeI / c lineage at the age of 6-8 weeks . For the first dermal dose, 100 μg of antibody emulsion was used in full Freund's adjuvant. Four days later animals were re-immunized with 50 μg of antibody embedded in incomplete Freund's adjuvant. The lymph node samples (I_N) were collected at day 10 and the lymph node-lymphoid proliferative capacity of the lymph node cells was analyzed by incubation in the presence of mouse and chimeric variants of the antibodies P3 and Aβ21E10, the sequence of variable regions of which is shown in Fig. 13 (heavy chain) and FIG. .14 ​​(light chain). The mouse monoclonal body C5 thi quasi version was used as a control roll of the same isotype [international application ShO97 / 33916 A1]. The lymphocytes of mice immunized with the ch-dimensional antibody P3 were proliferated, in particular, in cultivation in the presence of this antibody or chimeric 1E10 mAi, as well as in the case of cultivation in the presence of murine variants of these antibodies. Specificity of proliferation was demonstrated by the use of control monoclonal antibodies of the same isotype. Thus, chimeric P3 MAI supports the ability of the mouse variant to induce specific proliferation of anti-thyroid (T2) and anti-antidiotype (T3) T cells (FIG. 2). as well as in the case of cultivation in the presence of murine variants of these antibodies. Specificity of proliferation was demonstrated by the use of control monoclonal antibodies of the same isotype. Thus, chimeric P3 MAI supports the ability of the mouse variant to induce specific proliferation of anti-thyroid (T2) and anti-antidiotype (T3) T cells (FIG. 2). as well as in the case of cultivation in the presence of murine variants of these antibodies. Specificity of proliferation was demonstrated by the use of control monoclonal antibodies of the same isotype. Thus, chimeric P3 MAI supports the ability of the mouse variant to induce specific proliferation of anti-thyroid (T2) and anti-antidiotype (T3) T cells (FIG. 2).

Example 3: Strengthening the antitumor effect of the SM3-UZZR / MopIyapib & lt; RTI ID = 0.0 & gt; iZA 51 vaccine by combining it with a vaccine containing mouse ALA1E10 adsorbed with aluminum hydroxide

A group of females of the C57 / VI age group 6 to 8 weeks immunized at the bottom of 0, 14, 28, and 42 subcutaneously with 50 μg of murine monoclonal antibody 1E10 adsorbed with aluminum hydroxide. At the bottom of 7, 21, 35 and 49 mice, intramuscularly, the SMX-UZZR / MopIyapib and ISA 51 vaccine were administered intramuscularly at a dose of 120 mcg. Another group of mice was immunized in a similar manner, the same immunization was started from a vaccine containing a ganglioside CM3. In these experiments, control groups were used, which were separately immunized at the same time intervals with the same dosages of each vaccine or only by phosphate buffered physiological solution. On day 63, mice of all groups subcutaneously injected 10,000 cells of the mouse down-line B16. In all groups tumor growth was determined.

To compare the growth of tumors in all groups and in the control group, which received only zabufrhenium phosphate saline, used to analyze the statistical data for mixed lines-

10

with the model. Immunization with only 1E10 MAI did not protect the mice against the experimental administration of 10,000 cells of B16 melanoma. Vaccina UZZR-SM3 slowed tumor growth (p <0.05). The result of the combination of vaccine SM3-UZZR and 1E10 mA was the enhancement of the protective effect observed in the CM3-UZZR vaccine itself (p <0.05) (FIG. 3).

EXAMPLE 4: Immunization Scheme for Cancerous Patients, Ganglioside Vaccine, and Co-CM3 / UZZR Using MopIyapibe and AZ51 as an Adjuvant

In order to demonstrate the safety and immunogenicity of the Vaccine NeuSc-SM3 / VZZR with the use of MopIyapib iZA 51 as an adjuvant [US Pat. Nos. 5,788,985 and 6,149,921], a clinical trial was conducted, in which 20 patients vaccinated with vak-kitsin a generalized malignant melanoma, for which there was no other acceptable concomitant treatment. The mentioned patients received 9 doses of the vaccine containing 200 μg ganglioside CM3. Doses were administered at the bottom of 0.14, 28, 42, 56, 84, 112, 140, and 168. According to the criteria of the doctor, patients received additional doses every 28 days after the sixth month until the end of one year of treatment.

Blood samples for conventional biochemical analyzes and for the determination of serum titers anti-NeuCsCM3 ganglioside antibodies were taken at the bottom 0, 14, 28, 56, 112, 168, 224, 280 and 332.

Antibody titers were determined by solid phase enzyme-linked immunosorbent assay. Breeding raw cotton was considered as positive in the case when the anti-gangliazide values ​​of optical density were equal or greater than 0.1 (derived from the anti-methanol optical density).

Toxicity of the vaccine NeiScSM3-

UZZR / MopIyapib eZA51 consisted in the fact that it caused erythema, local pain, induration in the place of injection and fever; it allowed classification of toxicity as light, I / II degree according to the criteria of the World Health Organization.

Patients had titers of specific anti-neyScM3 antibodies in the range of 1:80 to 1: 2560. The detectable isotype of the antibodies included CID and IDM (all patients) and CID (75% of patients; Table I).

In a patient 01 included in the diagnosis of generalized malignant melanoma (evolutionary metastatic tumor, BMJ), the regression and stabilization of some skin lesions was observed after two months of treatment with depigmentation around these lesions, in which pathological anatomical studies of biopsies were performed inflammatory infiltrates present and necrosis occurred (FIG. 4).

In patient 02, with a diagnosis of generalized malignant melanoma, stabilization of pulmonary metastatic lesions (18-20 mm, right upper part) has been observed for at least 4 months (FIG. 5).

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Table I

Titres of anti-KyEiSsMM antibodies in patients with non-malignant malignant melanoma vaccinated with MeiSsSMZ / UZZ / Mycopi-CI IZA vaccine

51

<tr><td><p>Patients</p></td><td><p>Day</p></td><td><p>Idm</p></td><td><p>Ids</p></td><td><p>Ida</p></td></tr><tr><td><p>01</p></td><td><p>0</p></td><td><p>0</p></td><td><p>0</p></td><td><p>0</p></td></tr><tr><td><p></p></td><td><p>14</p></td><td><p>640</p></td><td><p>80</p></td><td><p>320</p></td></tr><tr><td><p></p></td><td><p>28</p></td><td><p>320</p></td><td><p>160</p></td><td><p>320</p></td></tr><tr><td><p></p></td><td><p>56</p></td><td><p>1280</p></td><td><p>160</p></td><td><p>320</p></td></tr><tr><td><p>02</p></td><td><p>0</p></td><td><p>160</p></td><td><p>160</p></td><td><p>160</p></td></tr><tr><td><p></p></td><td><p>14</p></td><td><p>160</p></td><td><p>160</p></td><td><p>320</p></td></tr><tr><td><p></p></td><td><p>28</p></td><td><p>160</p></td><td><p>160</p></td><td><p>320</p></td></tr><tr><td><p></p></td><td><p>56</p></td><td><p>1280</p></td><td><p>320</p></td><td><p>320</p></td></tr><tr><td><p>03</p></td><td><p>0</p></td><td><p>80</p></td><td><p>320</p></td><td><p>0</p></td></tr><tr><td><p></p></td><td><p>14</p></td><td><p>320</p></td><td><p>320</p></td><td><p>0</p></td></tr><tr><td><p></p></td><td><p>28</p></td><td><p>640</p></td><td><p>320</p></td><td><p>0</p></td></tr><tr><td><p></p></td><td><p>56</p></td><td><p>640</p></td><td><p>640</p></td><td><p>0</p></td></tr><tr><td><p>04</p></td><td><p>0</p></td><td><p>0</p></td><td><p>0</p></td><td><p>0</p></td></tr><tr><td><p></p></td><td><p>14</p></td><td><p>160</p></td><td><p>80</p></td><td><p>160</p></td></tr><tr><td><p></p></td><td><p>28</p></td><td><p>1280</p></td><td><p>80</p></td><td><p>160</p></td></tr><tr><td><p></p></td><td><p>56</p></td><td><p>2560</p></td><td><p>640</p></td><td><p>1560</p></td></tr>

Example 5: Vaccination scheme for patients with cancer, an idiotype vaccine containing 1E10 AI2 MAI, adsorbed aluminum hydroxide house

In order to demonstrate the safety and immunogenicity of an idiotypic vaccine containing mouse antiantiotropic MAb1E10 (patents SILA No. 5,817,513 and 6,063,379) and aluminum hydroxide adjuvant, a clinical trial was conducted in 20 patients with generalized malignant melanoma, for which there was no other Adopted onco-specific treatment.

The mentioned patients received 4 doses of the vaccine containing 2 mg of 1E10 MJ. Blood samples were taken prior to treatment and 14 days after each vaccination for conventional biochemical assays and for the determination of the serum titers of anti-1E10 mAb antibodies and the gylioside NieiSs-SMZ. TI-3 antibodies were determined by solid-phase immunoassay assay. To positive ratios, we have values ​​equal to or greater than 0.15.

The introduction of the vaccine caused patients to experience weak toxicity, which, according to the World Health Organization criteria, was related to Italy II degree.

In 16 of the 17 patients who were implicated in the study, a strong humoral immune response (IDA) appeared after 2 doses or 3 doses of the vaccine. The analysis of the specificity of this AL3 showed the predominant recognition of the chelating agents of patients 1E10 MJ compared with other monoclonal antibodies of the same isotype, suggesting the possibility of induction of the idiot-specific component in the humoral immune response on 1E10 MJ. This was confirmed by the strong serum reactivity against the fragments E (a ') 2 of this monoclonal antibody with a mean titre of 1: 15,000 (titers in me-

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horror from 1: 10000 to more than 1: 100000) with no recognition or with minor recognition of the fragments of E (a ') 2 control monoclonal antibodies used as control (FIG. 6).

Antibodies formed against KeiySsSMZ were, in most cases, IdM and IDS, with titer frame 1: 4000 and 1: 800, respectively (FIG. 7).

Before the clinical trial included a patient with a diagnosis of malignant melanoma and metastasis to the liver; after treatment was demonstrated-to stabilize the disease for 8 months and the survival time of the patient was 15 months.

Example 6: Combination vaccination with antividio-type vaccine containing alpha 2 MAI 1E10 Tagungiosis vaccine KiyiSsSMZ-UZZR

The patient who was diagnosed with melanomasis metastases and who, after diagnosis, received a monthly surgical intervention, received 6 doses of an idiotype vaccine containing AA2 MAI 1E10 and a gel of aluminum hydroxide (2 mgMab per dose) at the bottom of 0, 14, 28, 42, 56. During this period, this patient also received a ganglion-zidine vaccine containing 200 μg gangliosidium CsSMZ-UZZR and MopIyapis IZA 51 as an adjuvant, at the bottom of 7, 21, C5, 49, and 6Z. After completing this vaccination scheme, the patient was re-vaccinated with both vaccines at the same time every two months for two months. During the vaccination period, new lesions did not appear and the patient's condition was good.

Example 7: Tumor Tissue Recognition MAI 14R7

Ganglioside KeeiSsSMZ is recognized by MA14R7 [patent application SHO 99/40119]. In this example, the results of the recognition of down-linen tissues by this antibody are given.

Formalinized tissue was filled with paraffin. For histological studies, cuts from hematoxylin-eosin staining were used.

These sections were subjected to immune staining with com-plex biotin-streptavidin-peroxidase [HsuMM. (Nvi Z.M.) and Rein L. (Rape b), 1981, b.Nivioiset SuIoset, 29: 1349-1Z5Z]. Briefly, par-raffin was removed, rehydrated slices were treated with% solution H.₂AT₂ in methanol for 10 minutes to eliminate the activity of endogenous peroxidase. After incubation with MA14R7 (undiluted) for 1 hour at room temperature, biotinized antimusing immunoglobulins and com-plex streptavidin-peroxidase (firm IZakoratiz) at room temperature were added; Between incubation periods, the sections were washed with buffer solution of tris-HCl. The peroxidase reaction (RT) showed 5 ml of Tris-HCl solution, 0.005 ml of buffer solution containing Z0% H2O2 and Zml of solution of Z-3-diaminobenzidine.

After washing with contaminated hematoxi-line water (firm Maueg), the sections were filled with a histologic environment containing balm, and on-curved cover glass. Enzymatic reaction is a brownish color.

Fresh biopsy specimens of the pathological tissue were maintained 1 hour after surgical intervention. All tissues were washed with physiological

13

was immediately frozen in liquid nitrogen and stored frozen at -80 ° C.

Frozen fragments were cut on cryostat i-eis at a temperature of -25 ° С. Serially received 5 μm sections, dried in air and immediately used or stored at -20 ° C in aluminum foil; in the subsequent incisions recorded 4% solution of paraformaldehyde for 20 minutes.

Table II presents the results of immune staining of MA14-14 of several human tumors. In more than 50% of tumor cells, an intense coloration of the membrane of tacidoplasm was observed. The coloration was very intense in the case of colon, uterus, ovary, sarcoma, metastasis to the lymph nodes and brain mammary carcinoma, as well as melanoma metastasis.

Table II

Immune dyeing of MAY4R7 tumors

<tr><td><p>Tumor</p></td><td><p>Immune staining</p><p>(number of positive samples / total number of samples)</p></td></tr><tr><td><p>Carcinomas of the colon</p></td><td><p>9/9</p></td></tr><tr><td><p>Carcinoma of the uterus</p></td><td><p>2/2 *</p></td></tr><tr><td><p>Carcinoma of the ovary</p></td><td><p>2/2 *</p></td></tr><tr><td><p>Sarcoma</p></td><td><p>2/2 *</p></td></tr><tr><td><p>Tumors of the mammary gland are metastases to the lymph-evil</p></td><td><p>6/6 *</p></td></tr><tr><td><p>Melanoma metastases</p></td><td><p>2/2 *</p></td></tr>

* Intense immune coloration of the cytoplasmic membrane was observed in more than 50% of cells.

1: Euthymic mice of the BAII / c line and the non-mouse mice were immunized subcutaneously with 100 μg of MI-

76745 14

MALE P3 in full Freund's adjuvant with further immunization of 50 μg MAl emulsified in incomplete Freund's adjuvant. Thirty minutes, the lymph node cells were harvested and subjected to proliferation with different concentrations MAI P3, A3, 1E10 and S5.

FIG. 2: Mice of the VAB / c line immunized subcutaneously 100 μg of the chimeric antibody P3 in the full Friedland adjuvant followed by reimmunization of 50 μg of antibody emulsified in the incomplete Frein-da adjuvant. Three days later, lymph node cells were collected and subjected to a proliferation test with different concentrations using mushy and chimeric antibodies as controls.

3: Growth kinetics of W16 murine tumor immunized with immunotherapeutic combinations, in particular, an idiotype vaccine comprising AL2 MAI1E10 and ganglioside vaccineOM3-U55P, which is described in detail in Example 3.

FIG. 4: Evolution of skin metastases in patients with melanoma. Photographs were made for vaccination with the Neo-Oxum / V55P / I5A 51 vaccine and after 2 months and 4 months after treatment. There are depigmented areas around some lesions, stabilized lesions; there was a decrease in the size of one lesion and an increase in the size of one lesion.

FIG. 5: Evolution of pulmonary metastasis in patients with melanoma. Axial computer tomogram of the right upper lung: the size of the lesion18h 20mm before vaccination with the vaccine

NeoPosM3 / V55R / I5A 51; 4 months after vaccination, stabilization of the lesion is observed.

FIG. 6: Recognition of the fragments of P (a ') 2Al2MAI1E10 and other monoclonal antibodies of the same isotype of the serum of patients vaccinated with an idiotype vaccine containing AL2MBA1E10 and a gel of aluminum hydroxide as an adjuvant.

FIG. 7: Recognition of gangliazides OM3 (NieiOS) and OM3 (NieAAS) by serum of patients, a vaccine-free idiotype vaccine containing AL2MBA1E10 and aluminum gel hydroxide as an adjuvant.

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Computerized layout O. Гапоненко_Пиписные_Тираж 26 прим.

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