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1. (WO2019033087) ENGINEERED ANTIBODY FC VARIANTS FOR ENHANCED SERUM HALF LIFE
Nota: Texto obtenido mediante procedimiento automático de reconocimiento óptico de caracteres.
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WHAT IS CLAIMED IS:

1. A polypeptide comprising an mutant or variant human IgG Fc domain capable of binding human FcRn at an acidic pH, wherein the Fc domain has substitution mutations of:

(i) aspartic acid at position 309 (L/V309D);

(ii) histidine at position 311 (Q311H); and

(iii) a substitution mutation at position 434 (N434).

2. The polypeptide of claim 1 , wherein the substitution mutation at position 434 is serine (N434S) or tyrosine (N434Y).

3. The polypeptide of claim 2, wherein the substitution mutation at position 434 is serine (N434S).

4. The polypeptide of claim 2, wherein the substitution mutation at position 434 is tyrosine (N434Y).

5. The polypeptide of any one of claims 1-4, wherein the Fc domain is glycosylated.

6. The polypeptide of claim 5, wherein the Fc domain has substantially equivalent, essentially the same, about the same, or the same binding to FcyR as compared to wild-type.

7. The polypeptide of claim 5, wherein the Fc domain has a binding capacity that is substantially equivalent, essentially the same, about the same, the same as, or equivalent to 1, 2, or all of FcyRI, FcyRII, and FcyRIII, as compared to wild-type.

8. The polypeptide of any one of claims 1-7, wherein the Fc domain binds FcRn at an acidic pH with an affinity higher than the wild-type.

9. The polypeptide of claim 8, wherein the Fc domain does not detectably or selectively bind to FcRn, or exhibits no or essentially no binding to FcRn, at neutral pH.

10. The polypeptide of claim 9, wherein the Fc domain exhibits: (i) enhanced binding at pH 5.8 and (ii) reduced binding or no detectable binding at pH 7.4 for FcRn, as compared to the wild-type.

11. The polypeptide of any one of claims 1-4, wherein the Fc domain is aglycosylated.

12. The polypeptide of claim 11, wherein the Fc domain has a substitution mutation of glutamic acid at position 264 (V264E)

13. The polypeptide of any one of claims 1-12, wherein the IgG is IgGl.

14. The polypeptide of any one of claims 1-12, wherein the IgG is ¾ >G2.

15. The polypeptide of any one of claims 1-12, wherein the IgG is ¾ >G3.

16. The polypeptide of any one of claims 1-12, wherein the IgG is ¾ >G4.

17. The polypeptide of any one of claims 1-12, wherein the Fc domain comprises or consists of:

EDHS (SEQ ID NO: 5; V264E; L309D; Q311H; N434S),

EDHY (SEQ ID NO: 6; V264E; L309D; Q311H; N434Y),

DHS (SEQ ID NO: 7; L309D; Q311H; N434S),

DHY (SEQ ID NO: 8; L309D; Q311H; N434Y),

IgG2-DHS (SEQ ID NO: 9; V309D; Q311H; N434S),

IgG3-DHS (SEQ ID NO: 10; L309D; Q311H; N434S), or

IgG4-DHS (SEQ ID NO: 11; L309D; Q311H; N434S).

18. The polypeptide of claims 17, wherein the Fc domain comprises or consists of: DHS (SEQ ID NO: 7; L309D; Q311H; N434S) or DHY (SEQ ID NO: 8; L309D; Q311H; N434Y).

19. The polypeptide of any one of claims 1-18, wherein the Fc domain binds FcRn with a KD value of less than about 550 nM.

20. The polypeptide of claim 19, wherein the Fc domain binds FcRn with a KD value of less than about 250 nM.

21. The polypeptide of claim 19, wherein the Fc domain binds FcRn with a KD value of less than about 125 nM.

22. The polypeptide of any one of claims 1-21, further comprising a non-Fc receptor (non-FcR) binding domain.

23. The polypeptide of claim 22, wherein the non-FcR binding domain is an Ig variable domain.

24. The polypeptide of claim 23, wherein the polypeptide is a full-length antibody.

25. The polypeptide of claim 24, wherein the antibody is an agonistic antibody.

26. The polypeptide of claim 24, wherein the antibody is an antagonistic antibody.

27. The polypeptide of claim 24, wherein the antibody selectively binds Her2/neu, CD20, CD40, IL-10, 4-lBB, PD-1, PD-Ll, CTLA-4OX40, IL-1, IL-6, IL6R, TNFa, RANKL, EGFR, c-Met, CDlla, VEGF-A, VEGFR1, VEGFR2, C5, or Integrain-a4.

28. The polypeptide of any one of claims 1-27, wherein the antibody is chemically conjugated to or covalently bound to a toxin.

29. The polypeptide of claim 22, wherein the non-FcR binding region is not an antigen binding site of an antibody.

30. The polypeptide of claim 22, wherein the non-FcR binding region binds a cell-surface protein.

31. The polypeptide of claim 22, wherein the non-FcR binding regions binds a soluble protein.

32. A nucleic acid encoding any of the polypeptides of claim 1-31.

33. The nucleic acid of claim 32, wherein the nucleic acid is a DNA segment.

34. The nucleic acid of claim 32, wherein the nucleic acid is an expression vector.

35. A host cell comprising the nucleic acid of any one of claims 32-34.

36. The host cell of claim 35, wherein said cell expresses said nucleic acid.

37. A method for preparing a polypeptide comprising:

a) obtaining a host cell in accordance with claim 36;

b) incubating the host cell in culture under conditions to promote expression of the aglycosylated polypeptide; and

c) purifying the expressed polypeptide from the host cell.

38. The method of claim 37, wherein the host cell is a prokaryotic cell or a mammalian.

39. A pharmaceutical formulation comprising a polypeptide of any one of claims 1-31, or the nucleic acid of any one of claims 32-34 in a pharmaceutically acceptable carrier.

40. A method of binding a protein in a subject comprising providing to the subject an antibody, wherein the antibody binds the protein, and comprises an Fc domain according to any one of claims 1-31.

41. The method of claim 40, wherein the antibody is capable of specifically binding human FcRn with a KD of less than about 500 nM.

42. The method of claim 41, wherein the antibody is capable of specifically binding human FcRn with a KD of less than about 250 nM.

43. The method of claim 42, wherein the antibody is capable of specifically binding human FcRn with a KD of less than about 125 nM.

44. The method of any one of claims 40-43, wherein the antibody is glycosylated, and wherein the Fc domain has about equivalent or equivalent binding of FcyRI, FcyRII, and FcyRIII, as compared to wild-type.

45. The method of any one of claims 40-44, wherein the antibody is a glycosylated therapeutic antibody.

46. The method of any one of claims 40-44, wherein the antibody is an aglycosylated version of a therapeutic antibody.

47. A method of treating a subject having a disease comprising administering to the subject an effective amount of the formulation of claim 39.

48. The method of claim 47, wherein the method induces antibody-dependent cytotoxicity.

49. The method of claim 47, wherein the disease is a cancer, an infection, or an autoimmune disease.

50. The method of claim 47, wherein the subject is a human patient.

51. The method of claim 47, wherein the formulation is administered intratumorally, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intratracheally, intraocularly, intranasally, intravitreally, intravaginally, intrarectally, intramuscularly, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, orally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, via a catheter, or via a lavage.

52. The method of any one of claims 47-51, wherein the disease is a cancer, and wherein the method further comprises administering at least a second anticancer therapy to the subject.

53. The method of claim 52, wherein the second anticancer therapy is a surgical therapy, chemotherapy, radiation therapy, cryotherapy, hormone therapy, immunotherapy or cytokine therapy.

54. A polypeptide in accordance with any one of claims 1-31 for use in the treatment of disease.

55. The polypeptide of claim 54, wherein the disease is a cancer, an infection, or an autoimmune disease.

56. The polypeptide of claim 54, wherein the disease is a bacterial infection or a viral infection.

57. Use of a polypeptide in accordance with any one of claims 1-31 in the preparation of a medicament for the treatment of a disease such as a cancer, infection, bacterial infection, viral infection, or an autoimmune disease.

58. A pharmaceutically acceptable composition comprising a polypeptide in accordance with any one of claims 1-31 and a pharmacueu tic ally acceptable excipient.

59. A composition for use in a method of treating a disease in a subject in need thereof, said composition comprising a polypeptide in accordance with any one of claims 1-31.

60. The composition of claim 59, wherein said disease is a cancer, an infection, a bacterial infection, a viral infection, or an autoimmune disease.