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Generated: September 22, 2017

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Title:Potency assays for antibody drug substance binding to an Fc receptor
Abstract: The invention relates to a method of characterizing an antibody, which method is suitable as a potency assay for batch release of a pharmaceutical composition comprising an antibody, specifically for use when applying for marketing authorization for said pharmaceutical composition. The assay provided is a method for determining the potency of a drug product comprising an FcR binding peptide, wherein at least one mechanism of action of the FcR binding peptide of the drug product is mediated through the binding of the FcR binding peptide of the drug product to a Fc receptor, wherein said method comprises determining the binding of the FcR binding peptide of the drug product to an Fc receptor.
Inventor(s): Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL)
Assignee: GENMAB A/S (Copenhagen, DK)
Application Number:11/989,064
Patent Claims:1. A method for analyzing and selecting at least one batch of a drug product, wherein the batch comprises an antibody or antibody fragment having an Fc receptor (FcR)-binding moiety, and wherein at least one mechanism of action of the antibody or antibody fragment of the drug product is mediated through the binding of the antibody or antibody fragment of the drug product to an Fc receptor, the method comprising the steps of: (a) providing an antibody or antibody fragment of the drug product and a reference standard antibody or antibody fragment, (b) contacting the antibody or antibody fragment of the drug product with an Fc.gamma.RIII receptor, wherein the Fc.gamma.RIII receptor has been modified such that it has a reduced amount of sialic acid on the N-linked glycosylation as compared to the same Fc.gamma.RIII receptor in unmodified form, (c) contacting the reference standard to the Fc.gamma.RIII receptor, (d) measuring the binding of the antibody or antibody fragment to the Fc.gamma.RIII receptor, (e) measuring the binding of the reference standard to the Fc.gamma.RIII receptor, (f) comparing the FcR binding of the antibody or antibody fragment to the FcR binding of the reference standard, and (g) selecting the antibody or antibody fragment that has equal to or greater binding to the Fc.gamma.RIII receptor compared to the reference standard, wherein the reference standard and the antibody or antibody fragment of the drug product are two different batches of the same antibody or antibody fragment.

2. A method according to claim 1, wherein the binding of the antibody or antibody fragment to the Fc.gamma.RIII receptor is determined by (i) bringing a sample of the drug product into contact with the Fc.gamma.RIII for a time period sufficient for allowing the antibody or antibody fragment to bind to the Fc.gamma.RIII receptor, and (ii) detecting the amount of antibody or antibody fragment bound to the Fc.gamma.RIII receptor.

3. A method according to claim 2, wherein the detecting step comprises adding a detecting antibody directed at the antibody or antibody fragment.

4. A method according to claim 3, wherein the detecting antibody is a labeled antibody.

5. A method according to claim 1, wherein the binding of the antibody or antibody fragment to the Fc.gamma.RIII receptor is determined by use of an enzyme-linked immunosorbent assay (ELISA).

6. A method according to claim 1, wherein the binding of the FcR binding peptide to the Fc.gamma.RIII receptor is determined by an AlphaScreen.TM. assay.

7. A method according to claim 1, wherein the binding of the FcR binding peptide to the Fc.gamma.RIII receptor is determined by a radioimmunoassay.

8. A method according to claim 1, wherein the binding of the FcR binding peptide to the Fc.gamma.RIII receptor is determined by a Biacore assay.

9. A method according to claim 1, wherein the binding of the FcR binding peptide to the Fc.gamma.RIII receptor is determined by a fluorometric microvolume assay technology (FMAT).

10. A method according to claim 1, wherein the binding of the FcR binding peptide to the Fc.gamma.RIII receptor is determined by a dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA).

11. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through antibody dependent cell-mediated cytotoxicity (ADCC).

12. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through down modulation of target receptors.

13. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the recruitment of natural killer cells.

14. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through ADCC by natural killer cells.

15. A method according to claim 1, wherein the Fc receptor to which the antibody or antibody fragment binds is expressed on natural killer cells.

16. A method according to claim 12, wherein the Fc receptor is an Fc.gamma.RIIIa receptor which retains the ability to bind an Fc region.

17. A method according to claim 16, wherein the Fc.gamma.RIII receptor is an Fc.gamma.RIIIa176V receptor which retains the ability to bind an Fc region.

18. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the recruitment of polymorphonuclear leukocytes.

19. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the induction of ADCC by polymorphonuclear leukocytes.

20. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the induction of PMN degranulation.

21. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the induction of phagocytosis by polymorphonuclear leukocytes.

22. A method according claim 1, wherein the Fc receptor to which the antibody or antibody fragment binds is expressed on polymorphonuclear leukocytes.

23. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the induction of ADCC by monocytes or macrophages.

24. A method according claim 1, wherein the Fc receptors to which the antibody or antibody fragment binds is expressed on monocytes and/or macrophages.

25. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is further mediated through the recruitment of platelets.

26. A method according to claim 1 or claim 25, wherein the antibody or the antibody fragment also binds Fc.gamma.RII receptor expressed on platelets.

27. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is to induce cytokine production.

28. A method according to claim 27, wherein the Fc receptor to which the antibody or antibody fragment binds is expressed on natural killer cells.

29. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is to induce clearance of immune complexes.

30. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the recruitment of monocytes and/or macrophages.

31. A method according to claim 1, wherein the Fc receptor is an Fc.gamma.RIII which retains the ability to bind an Fc region.

32. A method according to claim 1, wherein the Fc receptor is an Fc.gamma.RIIIb which retains the ability to bind an Fc region.

33. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is to induce down-regulation of antibody responses.

34. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the recruitment of B cells.

35. A method according to claim 1, wherein the antibody or the antibody fragment also binds Fc.gamma.RII receptor expressed on B cells.

36. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is to induce monocyte and macrophage effector function inhibition.

37. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is to induce phagocytosis.

38. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the recruitment of polymorphonuclear leukocytes, macrophages and/or dendritic cells.

39. A method according to claim 1, wherein the Fc receptor to which the antibody or antibody fragment binds is expressed on polymorphonuclear leukocytes, macrophages and/or dendritic cells.

40. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the induction of phagocytosis by monocytes or macrophages.

41. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through cross-linking of cells and/or antibodies.

42. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is to induce positive signaling via an immunoreceptor tyrosine-based activation motif.

43. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is further mediated through the recruitment of myeloid cells and/or platelets.

44. A method according to claim 1, wherein the antibody or antibody fragment binds Fc.gamma.RII receptor expressed on myeloid cells and/or platelets.

45. A method according to claim 1, wherein a mechanism of action of the antibody or antibody fragment is to induce positive signaling via common .gamma., .beta., .zeta. chains.

46. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the recruitment of myeloid cells, polymorphonuclear leukocytes or natural killer cells.

47. A method according to claim 1, wherein the Fc receptor to which the antibody or antibody fragment binds is expressed on myeloid cells, polymorphonuclear leukocytes or natural killer cells.

48. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is to induce negative signaling through an immunoreceptor tyrosine-based inhibition motif.

49. A method according to claim 1, wherein at least one mechanism of action of the antibody or antibody fragment is mediated through the recruitment of B cells, macrophages and/or monocytes.

50. A method according to claim 1, wherein the antibody or antibody fragment further binds an Fc receptor is expressed on B cells, macrophages and/or monocytes.

51. A method according to claim 1, wherein the Fc.gamma.RIII receptor has been expressed in a host cell defective in the mechanisms responsible for sialylation.

52. A method according to claim 1, wherein the Fc.gamma.RIII receptor has been treated with sialidase.

53. A method according to claim 1, wherein the antibody or antibody fragment is a monoclonal antibody.

54. A method according to claim 1, wherein the antibody or antibody fragment is a human antibody.

55. A method according to claim 1, wherein the antibody or antibody fragment is a humanized antibody.

56. A method according to claim 1, wherein the antibody or antibody fragment is a chimeric antibody.

57. A method according to claim 1, wherein the antibody or antibody fragment is an IgG1 antibody.

58. A method according to claim 57, wherein the antibody or antibody fragment is an IgG1,A antibody.

59. A method according to claim 57, wherein the antibody or antibody fragment is an IgG1,K antibody.

60. A method according to claim 1, wherein the measuring of the binding of the antibody to an Fc.gamma.RIII receptor is combined with a method of determining the binding of the antibody to its antigen.

61. A method according to claim 60, wherein the binding of the antibody to its antigen is determined by (i) bringing a sample of the antibody into contact with the antigen for a time period sufficient for allowing the antibody to bind to the antigen, and (ii) detecting the amount of antibody bound to the antigen.

62. A method according to claim 61, wherein the detection involves adding a detecting antibody directed at the antibody of the drug product.

63. A method according to claim 62, wherein the detecting antibody is a labeled antibody.

64. A method according to 60, wherein the binding of the antibody to its antigen is determined by ELISA.

65. A method according to claim 64, wherein binding of the antibody to the Fc receptor is determined with the same ELISA.

66. A method according to claim 60, wherein the binding of the antibody to its antigen is determined by an AlphaScreen.TM. assay.

67. A method according to claim 66, wherein the binding of the antibody to the Fc receptor is also determined by the AlphaScreen.TM. assay.

68. A method according to claim 60, wherein the binding of the antibody to its antigen is determined by a radioimmunoassay.

69. A method according to claim 68, wherein the binding of the antibody to the Fc.gamma.RIII receptor is also determined by a radioimmunoassay.

70. A method according to claim 69, wherein the radioimmunoassay comprises beads conjugated with Fc.gamma.RIII receptor and radioiodonated antigen.

71. A method according to claim 1, wherein the antibody or antibody fragment is an antibody binding to human CD4.

72. A method according to claim 1, wherein the antibody is zanolimumab.

73. A method according to claim 71, wherein the antibody is keliximab.

74. A method according to claim 71, wherein the antibody is clenoliximab.

75. A method according to claim 1, wherein the antibody is an antibody that binds to human EGFR.

76. A method according to claim 75, wherein the antibody is cetuximab.

77. A method according to claim 75, wherein the antibody is zalutumumab.

78. A method according to claim 1, wherein the antibody is an antibody binding to human CD20.

79. A method according to claim 78, wherein the antibody is rituximab.

80. A method according to claim 78, wherein the antibody is ibritumomab tiuxetan.

81. A method according to claim 78, wherein the antibody is tositumomab.

82. A method according to claim 78, wherein the antibody is ofatumumab.

83. A method according to claim 1, wherein the antibody is an antibody binding to human CD25.

84. A method according to claim 1, wherein the antibody is an antibody binding to human CD3.

85. A method according to claim 84, wherein the antibody is muromonab.

86. A method according to claim 1, wherein the antibody is an antibody that binds to human GPIIb/IIIa.

87. A method according to claim 83, wherein the antibody is daclizumab.

88. A method according to claim 83, wherein the antibody is basiliximab.

89. A method according to claim 1, wherein the antibody is an antibody that binds to human TNF-.alpha..

90. A method according to claim 89, wherein the antibody is infliximab.

91. A method according to claim 89, wherein the antibody is adalimumab.

92. A method according to claim 1, wherein the antibody is an antibody that binds to human RSV.

93. A method according to claim 92, wherein the antibody is palivizumab.

94. A method according to claim 1, wherein the antibody is an antibody binding to human HER-2/neu.

95. A method according to claim 94, wherein the antibody is trastuzumab.

96. A method according to claim 94, wherein the antibody is pertuzumab.

97. A method according to claim 1, wherein the antibody is an antibody that binds to human CD33.

98. A method according to claim 1, wherein the antibody is an antibody that binds to human CD52.

99. A method according to claim 98, wherein the antibody is alemtuzumab.

100. A method according to claim 1, wherein the antibody is an antibody that binds to human VEGF.

101. A method according to claim 100, wherein the antibody is bevacizumab.

102. A method according to claim 1, wherein the antibody is an antibody binding to human CTLA4.

103. A method according to claim 102, wherein the antibody is ipilimumab.

104. A method according to claim 5, wherein the Fc.gamma.RIII receptor is his-tagged, and a his-capturing antibody coated on the ELISA plate captures the his-tagged Fc.gamma.RIII receptor.

Summary for Patent: ► Subscribe

PCT Information
PCT FiledJuly 21, 2006PCT Application Number:PCT/DK2006/000426
PCT Publication Date:January 25, 2007PCT Publication Number: WO2007/009469

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Inventors Patent Expiration Status Orphan Source
Genentech
RITUXAN
rituximab
VIAL1037050011997-11-26► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXsearch
Novartis
SIMULECT
basiliximab
VIAL; SINGLE-USE1037640011998-05-12► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXsearch
Novartis
SIMULECT
basiliximab
VIAL; SINGLE-USE1037640021998-05-12► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXsearch
Medimmune
SYNAGIS
palivizumab
VIAL1037700011998-06-19► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXsearch
Medimmune
SYNAGIS
palivizumab
VIAL1037700021998-06-19► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXsearch
Centocor Inc
REMICADE
infliximab
VIAL1037720011998-08-24► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXOrphansearch
Genentech
HERCEPTIN
trastuzumab
VIAL; INTRAVENOUS1037920011998-09-25► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXOrphansearch
Genzyme
CAMPATH
alemtuzumab
VIAL; INTRAVENOUS1039480012001-05-07► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXOrphansearch
Genzyme
CAMPATH
alemtuzumab
VIAL; INTRAVENOUS1039480022001-05-07► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXOrphansearch
Genzyme
LEMTRADA
alemtuzumab
INJECTABLE;INJECTION1039480032001-05-07► Subscribe GENMAB A/S (Copenhagen, DK) Gerarda Havenith; Catharina Emanuele (Bodegraven, NL), Vink; Tom (Alphen aan den Rijn, NL), Berkel; Patrick Van (Utrecht, NL), Parren; Paul (Odijk, NL) ► SubscribeRXOrphansearch
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