Antibody containing fc-version component (versions), pharmaceutical composition containing antibody, and method of treating mammal

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discovers an antibody containing a Fc-version component with at least one amino acid substitution in a Fc-region of initial polypeptide. Said substitution is in the amino acid position matched with that of human Fc-polypeptide amino acid sequence (the positions are presented in the patent claim). The antibody exhibits a modulated binding with FcγR. There are described versions of said antibody with increased affinity to FcγR wherein said substitution is in the amino acid position 239, 332 or 267 matched with that in human Fc-polypeptide amino acid sequence (numeration according to the EU index). The invention also describes a method of treating a mammal with an antibody-dependent disorder by using a pharmaceutical composition with the modulated linkage with FcγR and containing the antibody or its version.

EFFECT: according to the invention antibodies provide the affinity in 5 and more times higher in comparison with initial Fc-polypeptide.

43 cl, 44 dwg, 66 tbl, 12 ex

 

The text descriptions are given in facsimile form.

1. Antibody exhibiting modulated binding to FcγR compared with the antibody containing the source Fc-polypeptide, with the indicated antibody contains Fc-variant part containing at least one amino acid substitution in the Fc-region of the specified source Fc polypeptide, and this replacement is in the position of amino acids, according to cstuuyxm the position of the amino acids in the amino acid sequence of an Fc-polypeptide of the person, selected from the group consisting of 239, 243, 267, 298, 325, 328, 330, 332, 333 and 334, where the numbering is given according to the EU index.

2. The antibody according to claim 1, where the specified at least one amino acid substitution is at amino acids corresponding to amino acid position in the amino acid sequence of an Fc-polypeptide of the person selected from the group consisting of: 239, 243, 267, 328 and 332.

3. The antibody according to claim 1, where the specified Fc-variant contains at least one amino acid substitution in amino acid position corresponding to the position in the amino acid sequence of an Fc-polypeptide of the person selected from the group consisting of: 298, 333, and 334.

4. The antibody according to claim 1, where the specified Fc-variant contains at least one amino acid substitution selected from the group consisting of 239D, E, 239N, 239Q, 239F, T, N, 239Y, 243W, 243L, 243Y, 243R, 243Q, 267Q, 267L, N, 325Q, 325L, 325I, 325D, E, A, T, 325V, 325H, M, 328D, E, 328N, 328Q, 328F, 328I, 328V, 328T, N, A, 330L, 330Y, 330V POS, 330I, 330F, 330R, N, 332D, E, 332N, 332Q, T, N, 332Y, and 332A.

5. The antibody according to claim 1, where the specified Fc-variant further comprises at least one amino acid substitution selected from the group consisting of 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 283, 285, 286, 288, 290, 291, 293, 294, 295, 296, 297, 298, 299, 300, 302,313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335,336 and 428.

6. The antibody according to claim 1, where the specified Fc-variant selected from the group consisting of 243W, 243L, 241L/243L/262I/264I, 241W/243W, 241W/243W/262A/264A, 243L/264I, 243L/262I/264W, 241Y/243Y/262T/264T, 241E/243R/262E/264R, 241E/243Q/262T/264E, 241R/243Q/262T/264R, 241E/243Y/262T/264R, M, E, 328F, E, M/E, 264I/332E, 241E/243R/262E/264R/332E, 241E/243Q/262T/264E/332E, 241R/243Q/262T/264R/332E, 241E/243Y/262T/264R/332E, A/E, E/E, 239Q/332E, E, 239E/265G, 239E/265N, 239E/265Q, 267Q/327S, 267L/327S, 330L, 330Y, 332D, 297S/332E, 297D/332E, E/E, 265Y/297D/332E, 265Y/297D/299L/332E, 265F/297E/332E, 328I/332E, 328Q/332E, 332N, 332Q, 325Q, 325L, 325I, 239D, 239N, 239F, 239D/332D, 239D/332E, 239D/332N, 239D/332Q, 239E/332D, 239E/332N, 239E/332Q, 239N/332D, 239N/332E, 239N/332N, 239N/332Q, 239Q/332D, 239Q/332N, 239Q/332Q, 241Y/243Y/262T/264T/297D/332E, 330Y/332E, 264I/330Y/332E, 330L/332E, 264I/330L/332E, T, N, 239Y, N, 330V POS, 330I, 330F, 330R, N, 325D, E, A, T, 325V, 325H, 328D/332E, E/E, 328N/332E, 328Q/332E, 328V/332E, T/E, N/E, 328I/332E, A, T, N, 332Y, AND 332A, 239E/264I/332E, 239Q/264I/332E, 239E/264I/330Y/332E, 239E/264I/298A/330Y/332E, 239D/297D/332E, 239E/297D/332E, 239D/265V/297D/332E, 239D/265I/297D/332E, 239D/265L/297D/332E, 239D/265F/297D/332E, 239D/265Y/297D/332E, 239D/265H/297D/332E, 239D/265T/297D/332E, 264E/297D/332E, 296D/297D/332E, 296E/297D/332E, 296N/297D/332E, 296Q/297D/332E, 296H/297D/332E, 296T/297D/332E, 297D/299V/332E, 297D/299I/332E, 297D/299L/332E, 297D/299F/332E, 297D/299H/332E, 297D/299E/332E, 297D/330Y/332E, 297D/298A7330Y/332E, 239D/330I/332E, 239N/330Y/332E, 239D/330L/332E, 239N/330L/332E, 264I/298A/332E, 239D/298A/332E, 239N/298A/332E, 239D/264I/332E, 239D/264I/298A/332E, and 239D/264I/330L/332E.

7. Antibody exhibiting modulated binding to FcγR compared with the antibody containing the source Fc-polypeptide, with the indicated antibody contains Fc-variant part containing at least one amino acid substitution in the Fc-region of the specified source Fc-the polyp is putida, moreover, this substitution is at amino acids corresponding to amino acid position in the amino acid sequence of an Fc-polypeptide of the person selected from the group consisting of 239 and 332, where the numbering is given according to the EU index.

8. The antibody according to claim 7, where the specified Fc-variant contains at least one amino acid substitution selected from the group consisting of 239D, E, 239N, 239Q, 239F, T, N, 239Y, 332D, E, 332N, 332Q, T, N, 332Y, and 332A.

9. The antibody according to claim 7, where the specified Fc-variant further comprises at least one amino acid substitution selected from the group consisting of: 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 258, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 283, 285, 286, 288, 290, 291, 293, 294, 295, 296, 297, 298, 299, 300, 302, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336 and 428.

10. The antibody according to claim 7, where the specified Fc-variant selected from the group consisting of E, M/E, 264I/332E, 241E/243R/262E/264R/332E, 241E/243Q/262T/264E/332E, 241R/243Q/262T/264R/332E, 241E/243Y/262T/264R/332E, A/E, E/E, 239Q/332E, E, 239E/265G, 239E/265N, 239E/265Q, 332D, 297S/332E, 297D/332E, E/E, 265Y/297D/332E, 265Y/297D/299L/332E, 265F/297E/332E, 328I/332E, 328Q/332E, 332N, 332Q, 239D, 239N, 239F, 239D/332D, 239D/332E, 239D/332N, 239D/332Q, 239E/332D, 239E/332N, 239E/332Q, 239N/332D, 239N/332E, 239N/332N, 239N/332Q, 239Q/332D, 239Q/332N, 239Q/332Q, 241Y/243Y/262T/264T/297D/332E, 330Y/332E, 264I/330Y/332E, 330L/332E, 264I/330L/332E, T, N, 239Y, 328D/332E, E/E, 328N/332E, 328Q/332E, 328V/332E, T/E, N/E, 328I/332E, T, N, 332Y, and 332A, 239E/264I/332E, 239Q/264I/332E, 239/264I/330Y/332E, 239E/264I/298A/330Y/332E, 239D/297D/332E, 239E/297D/332E, 239D/265V/297D/332E, 239D/265I/297D/332E, 239D/265L/297D/332E, 239D/265F/297D/332E, 239D/265Y/297D/332E, 239D/265H/297D/332E, 239D/265T/297D/332E, 264E/297D/332E, 296D/297D/332E, 296E/297D/332E, 296N/297D/332E, 296Q/297D/332E, 296H/297D/332E, 296T/297D/332E, 297D/299V/332E, 297D/299I/332E, 297D/299L/332E, 297D/299F/332E, 297D/299H/332E, 297D/299E/332E, 297D/330Y/332E, 297D/298A/330Y/332E, 239D/330Y/332E, 239N/330Y/332E, 239D/330L/332E, 239N/330L/332E, 264I/298A/332E, 239D/298A/332E, 239N/298A/332E, 239D/264I/332E, 239D/264I/298A/332E, and 239D/264I/330L/332E.

11. Antibody exhibiting modulated binding to FcγR compared with the antibody containing the source Fc-polypeptide, with the indicated antibody contains Fc-variant part containing the amino acid replacement at a position corresponding to the position of 267 amino acids in the amino acid sequence of an Fc-polypeptide of the person, where the numbering is given according to the EU index.

12. The antibody according to claim 11, where the specified amino acid substitution selected from the group consisting of T, N, 267D, 267N, E, 267Q, K, 267R, 267V, 267L, 267I, 267F, M, 267Y, 267W and R.

13. The antibody according to claim 11, where the specified antibody further comprises amino acid substitution in a position selected from the group consisting of 221,222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 258, 262, 263, 264, 265, 266, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 283, 285, 286, 288, 290, 291, 293, 294, 295, 296, 297, 298, 299, 300, 302, 313, 317, 318, 320,322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336 and 428, where the specified antibody has an increased affinity of sunayana with FcγR compared to pointed to by the m source Fc polypeptide.

14. The antibody according to claim 11, where the specified antibody includes the amino acid substitution at position T, N, 267D, 267N, E, 267Q, K, 267R, 267V, 267L, 267I, 267F, M, 267Y, 267W and R, and the above antibody further comprises amino acid substitution in a position selected from the group consisting of 221, 222, 224, 227, 228, 230, 231, 223, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243, 244, 245, 246, 247, 249, 250, 258, 262, 263, 264, 265, 266, 268, 269, 270, 271, 272, 273, 274, 275, 276, 278, 280, 281, 283, 285, 286, 288, 290, 291, 293, 294, 295, 296, 297, 298, 299, 300, 302, 313, 317, 318, 320, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336 and 428.

15. The antibody according to 14, where the specified antibody selected from the group consisting of 267Q/327S and 267L/327A.

16. The antibody according to any one of claims 1, 7 or 11, where the specified modulation is an increase in the affinity of the specified antibodies to a specific FcγR.

17. The antibody according to any one of claims 1, 7 or 11, where the specified FcγR is FcγRIIIa.

18. The antibody according to 17, where the specified FcγRIIIa is V158 or F158-allotype FcγRIIIa.

19. The antibody according to clause 16, where the specified source Fc-polypeptide is essentially human, and this affinity is about 5 times higher than the affinity of the specified source Fc polypeptide.

20. The antibody according to claim 19, where the specified source Fc-polypeptide is essentially human, and this affinity is about 5 times approximately 300 times higher than the affinity of the specified source Fc-is peptide.

21. The antibody according to any one of claims 1, 7 or 11, where the specified source Fc-polypeptide is essentially human, essentially, mouse, essentially, mouse, or, essentially, the monkey.

22. The antibody according to any one of claims 1, 7 or 11, where the binding of one or more Fc ligands is unchanged.

23. The antibody according to item 22, where the specified Fc ligand selected from the group consisting of Clq, FcRn, protein a and protein G.

24. The antibody according to any one of claims 1, 7 or 11, where the CDC is unaffected.

25. The antibody according to any one of claims 1, 7 or 11, where the binding of one or more Fc ligands is altered.

26. The antibody according to any one of claims 1, 7 or 11, where the specified Fc-variant has a multiplicity of binding FcγRIIIa: the ratio bind FcγRIIb with greater than 1.

27. The antibody according p where the specified Fc-variant has a multiplicity of binding FcγRIIIa: the ratio bind FcγRIIb with greater than about 11:1.

28. The antibody according to item 27, where the specified Fc-variant has a multiplicity of binding FcγRIIIa: the ratio of the binding to FcγRIIb between approximately 11:1 and approximately 86:1.

29. The antibody according to any one of claims 1, 7 or 11, where the specified Fc variant binds to at least one FcγR with a reduced affinity relative to the original Fc polypeptide.

30. The antibody according to clause 29, where the specified FcγR is FcγRIIIa.

31. Antibody mu the mu one of claims 1, 7 or 11, where the specified Fc-variant exhibits modulated effector function in comparison with the antibody containing the source Fc-polypeptide.

32. The antibody according p where indicated effector function is ADCC.

33. The antibody according p where the specified Fc-variant improves ADCC compared with the specified source Fc polypeptide.

34. The antibody according p, where the aforementioned improvement in ADCC is approximately 5 times greater than the improvement caused by the specified source Fc polypeptide.

35. The antibody according to clause 34, where the aforementioned improvement in ADCC is between approximately 5-fold and 50-fold improvement in comparison with the improvement caused by the specified source Fc polypeptide.

36. The antibody according to any one of claims 1, 7 or 11, where the specified source Fc-polypeptide is essentially human, essentially, mouse, essentially, mouse, or, essentially, the monkey.

37. The antibody according p where the specified Fc-variant reduces ADCC compared with the specified source Fc polypeptide.

38. The antibody according to any one of claims 1, 7 or 11, containing Fc-fused protein containing the specified Fc-option.

39. The antibody according to any one of claims 1, 7 or 11, where the specified antibody further comprises a constructed glycoform.

40. The antibody according to § 39, where the specified designed glycoform enhances effector function.

41. The antibody according to any one of claims 1, 7 or 11, where the uke is this antibody has specificity against target antigen, selected from the group consisting of CD19, CD20, CD22, CD30, CD33, CD40, CD40L, CD52, Her2/neu, EGFR, EpCAM, MUC1, GD3, CEA, CA 125, HLA-DR, TNFα, MUC18, prostate-specific membrane antigen (PMSA) and VEGF.

42. Pharmaceutical composition having modulated by binding to FcγR containing the antibody according to any one of claims 1, 7 or 11 and a pharmaceutically acceptable carrier.

43. A method of treating a mammal having associated with antibodies violation, providing for the introduction of antibodies according to any one of claims 1, 7 or 11 specified mammal.



 

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8 cl, 5 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry. An immunomodulatory and antioxidant drug characterised by the fact that it represents Psephellus herb extract containing polyphenols in amount 8-10 mg/ml, polyacetylenes in amount 0.03-0.05 mg/ml, prepared in the relation raw material:extractant 1:5, during 7 days in absence of light, and the extractant is chosen from the group: 40% of alcohol, 5-75% of glycerine, 5-100% of honey and water. The drug can be presented as a capsule, a tablet, a powder, a pill, a dragee, granules, a sachet, gel, paste, syrup, an emulsion, a suspension, a solution, and a chewing gum. The drug can be applied for immune system correction in the patients untreatable with common medications.

EFFECT: production of the immunomodulatory and antioxidant drug.

2 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention covers a water-soluble drug based on ionic silver and methylene blue compound, and also a method for preparing thereof. Said method implies synthesis when heating to 90-95°C by mixing the following components: methylene blue - silver chloride - ammonia in the molar ratio 1.06:1:58 to be cooled; a by-product is filtered, steamed in vacuum, washed with acetone and dried in vacuum at room temperature.

EFFECT: prepared drug meets the composition C16H18CI2N3SAg and exhibits antiviral and immunomodulatory action.

2 cl, 2 dwg, 3 tbl

FIELD: medicine, veterinary science.

SUBSTANCE: invention refers to agents of veterinary medicine and can be used in fur farming and animal husbandry for improving young growth liveability and productivity of animals. A new veterinary implanted retard drug for improving productivity of farm animals contains active substances: melatonin or melatonin and ximedone, a biodegradable polymer base and processing aids; and said biodegradable polymer base is presented with interpolymer complexes of polymethacrylic acid and polyethylene glycol ("КПН"-1) or interpolymer complexes of polymethacrylic acid and polypropylene glycol ("КПН"-2) in a certain ratio. The processing aids are lactose or microcrystalline cellulose or their mixtures in the ratio (wt %) 50:50. Said "КПН"-1 or "КПН"-2 used as the polymer base allows introducing up to 25% of ximedone into a dosage form of said veterinary drugs that essentially improves their effect, and reducing their cost in 1.5-2 times in comparison with a prototype.

EFFECT: application of the veterinary drugs containing melatonin and "КПН"-1 or "КПН"-2 bases in fur farming with using an accelerated technology of mink farming ensures liveability of a mink livestock to the slaughter period with reducing farming time by 1,5-2 months and gain in fur production of the area exceeding the untreated animals by 15-20%.

8 cl, 2 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and concerns a complex containing mequitazine, cyclodextrin and a reaction agent where the molar ration within the system mequitazine/cyclodextrin/the reaction agent and mequitazine/the reaction agent is 1/1 - 1/10 and water-dissolution rate of mequitazine being a part of the complex measured for an aqueous solution with mequitazine concentration 2 g/l at 35°C after 15 minutes of stirring, makes more than 50% at pH 9, to a method for preparing said complex and a based pharmaceutical composition.

EFFECT: invention provides improved solubility of mequitazine.

20 cl, 1 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns biotechnology. There is described a method for preparing a high-concentration liquid composition containing Mab C225 (cetuximab) or Mab h425 (EMD72000), by ultrafiltration, differing by the fact that protein is concentrated under pressure control with using polyester sulfonic ultrafiltration membrane with a severance within 5-500 kDa; and this cleaning results in the fact that the high-concentration liquid composition contains Mab C225 (cetuximab) or Mab h425 (EMD72000) in amount 50-180 mg/ml. There is presented the high-concentration liquid composition for preparing a drug for treatment and/or prevention of tumours and/or the tumour metastases containing 50-180 mg/ml Mab C225 (cetuximab) or Mab h425 (EMD72000) and an aqueous solution and application of said composition.

EFFECT: invention allows preparing stable high-concentration liquid compositions.

8 cl, 5 ex

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