IP Library › Granted Patent US 10,329,344

Granted Patent B2

US 10,329,344 · App. 16/140,189 · Granted Jun 25, 2019

Anti-Tau Antibodies and methods of use

Inventors: Oskar Adolfsson (Bercher, CH); Gai Ayalon (Moraga, CA); Isidro Hotzel (Brisbane, CA); Danielle Marie Di Cara (South San Francisco, CA)

Assignees: Genentech, Inc.; AC Immune SA

C07K16/18 A61K39/3955 A61K45/06 G01N33/6896 A61K2039/505 A61K2039/507 C07K2317/24 C07K2317/33 C07K2317/34 C07K2317/56 C07K2317/565 C07K2317/92 G01N2333/4709 G01N2800/2821

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Quick Facts

Patent No.: US 10,329,344
App. No.: 16/140,189
Granted: Jun 25, 2019
Kind: B2

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Abstract

The invention provides anti-Tau antibodies and methods of using the same.

Claims (180)

1. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering a monoclonal antibody that binds to human Tau, wherein the antibody comprises:

a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 344; HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 345, 15, 468 to 478, 495 to 517, 522 to 534, 536 to 539, and 543 to 556; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 346; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 347;

b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 72; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 73; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 74; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 75; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 76; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 77;

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 42; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 43; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 44; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 45; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 46; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 47;

d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 62; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 63; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 65; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 66; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67;

e) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 212; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 213; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 214; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 215; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 216; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 217;

f) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37; or

g) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 52; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 53; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 54; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 56; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57.

2. A method of reducing the level of Tau protein, non-phosphorylated Tau protein, phosphorylated Tau protein, or hyperphosphorylated Tau protein in an individual, comprising administering a monoclonal antibody that binds to human Tau, wherein the antibody comprises:

3. The method of claim 1 , wherein the method comprises administering at least one additional therapy.

4. The method of claim 3 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

5. The method of claim 1 , wherein the antibody is an IgG1 or an IgG4 antibody.

6. The method of claim 5 , wherein the antibody is an IgG4 antibody.

7. The method of claim 6 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

8. The method of claim 7 , wherein the antibody comprises an S228P mutation.

9. The method of claim 1 , wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K D of less than 50 nM.

10. The method of claim 1 , wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO: 4).

11. The method of claim 1 , wherein the antibody comprises:

a) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 340, 10, and 20;

b) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 341, 11, 21, 281, 291, 561, 571, and 581;

c) a VH as in (a) and a VL as in (b);

d) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 70, 300, and 453 to 459;

e) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 71 and 460 to 467;

f) a VH as in (d) and a VL as in (e);

g) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 40;

h) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 41;

i) a VH as in (g) and a VL as in (h);

j) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 60;

k) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 61;

l) a VH as in (j) and a VL as in (k);

m) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 210;

n) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 211;

o) a VH as in (m) and a VL as in (n);

p) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 30;

q) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 31;

r) a VH as in (p) and a VL as in (q);

s) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 50;

t) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 51; or

u) a VH as in (s) and a VL as in (t).

12. The method of claim 11 , wherein the antibody is an IgG1 or an IgG4 antibody.

13. The method of claim 12 , wherein the antibody is an IgG4 antibody.

14. The method of claim 13 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

15. The method of claim 14 , wherein the antibody comprises an S228P mutation.

16. The method of claim 11 , wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K D of less than 50 nM.

17. The method of claim 11 , wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO: 4).

18. The method of claim 11 , wherein the method comprises administering at least one additional therapy.

19. The method of claim 18 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

20. The method of claim 1 , wherein the antibody comprises:

a) a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 340, 10, and 20;

b) a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 341, 11, 21, 281, 291, 561, 571, and 581;

c) a VH as in (a) and a VL as in (b);

d) a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 70, 300, and 453 to 459;

e) a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 71 and 460 to 467;

f) a VH as in (d) and a VL as in (e);

g) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 40;

h) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 41;

i) a VH as in (g) and a VL as in (h);

j) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 60;

k) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 61;

l) a VH as in (j) and a VL as in (k);

m) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 210;

n) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 211;

o) a VH as in (m) and a VL as in (n);

p) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 30;

q) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 31;

r) a VH as in (p) and a VL as in (q);

s) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 50;

t) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 51; or

u) a VH as in (s) and a VL as in (t).

21. The method of claim 20 , wherein the antibody is an IgG1 or an IgG4 antibody.

22. The method of claim 21 , wherein the antibody is an IgG4 antibody.

23. The method of claim 22 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

24. The method of claim 23 , wherein the antibody comprises an S228P mutation.

25. The method of claim 20 , wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K D of less than 50 nM.

26. The method of claim 20 , wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO: 4).

27. The method of claim 20 , wherein the method comprises administering at least one additional therapy.

28. The method of claim 27 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

29. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering a monoclonal antibody that binds to human Tau, wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 344; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 345; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 346; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 347.

30. The method of claim 29 , wherein the antibody is an IgG1 or an IgG4 antibody.

31. The method of claim 30 , wherein the antibody is an IgG4 antibody.

32. The method of claim 31 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

33. The method of claim 31 , wherein the antibody comprises an S228P mutation.

34. The method of claim 29 , wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K D of less than 50 nM.

35. The method of claim 29 , wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO: 4).

36. The method of claim 29 , wherein the method comprises administering at least one additional therapy.

37. The method of claim 36 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

38. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering monoclonal antibody that binds to human Tau, wherein the antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 340 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 341.

39. The method of claim 38 , wherein the antibody is an IgG1 or an IgG4 antibody.

40. The method of claim 39 , wherein the antibody is an IgG4 antibody.

41. The method of claim 40 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

42. The method of claim 40 , wherein the antibody comprises an S228P mutation.

43. The method of claim 38 , wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K D of less than 50 nM.

44. The method of claim 38 , wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO: 4).

45. The method of claim 38 , wherein the method comprises administering at least one additional therapy.

46. The method of claim 45 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

47. The method of claim 38 , wherein the antibody comprises:

a) a heavy chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain comprising an amino acid sequence that is at least 95% identical to the sequence of SEQ ID NO: 349; or

b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain comprising the amino acid sequence of SEQ ID NO: 349.

48. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering a monoclonal antibody that binds to human Tau, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain comprising the amino acid sequence of SEQ ID NO: 349.

49. The method of claim 48 , wherein the method comprises administering at least one additional therapy.

50. The method of claim 49 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

51. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering a monoclonal antibody that binds to human Tau, wherein the antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain consisting of the amino acid sequence of SEQ ID NO: 349.

52. The method of claim 51 , wherein the method comprises administering at least one additional therapy.

53. The method of claim 52 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

54. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering a monoclonal antibody that binds to human Tau, wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 344; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 345; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 346; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 347, wherein the antibody is an IgG4 antibody, and wherein the antibody comprises S228P, M252Y, S254T, and T256E mutations.

55. The method of claim 54 , wherein the method comprises administering at least one additional therapy.

56. The method of claim 55 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

57. A method of retaining or increasing cognitive memory capacity or slowing memory loss in an individual, comprising administering a monoclonal antibody that binds to human Tau, wherein the antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 340 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 341, wherein the antibody is an IgG4 antibody, and wherein the antibody comprises S228P, M252Y, S254T, and T256E mutations.

58. The method of claim 57 , wherein the method comprises administering at least one additional therapy.

59. The method of claim 58 , wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

60. The method of claim 2 , wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 344; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 345; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 346; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 347.

61. The method of claim 60 , wherein the antibody is an IgG1 or an IgG4 antibody.

62. The method of claim 61 , wherein the antibody is an IgG4 antibody.

63. The method of claim 62 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

64. The method of claim 63 wherein the antibody comprises an S228P mutation.

65. The method of claim 60 , wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K D of less than 50 nM.

66. The method of claim 60 , wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO: 4).

67. The method of claim 2 , wherein the antibody comprises:

a) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 340, 10, and 20;

b) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 341, 11, 21, 281, 291, 561, 571, and 581;

c) a VH as in (a) and a VL as in (b);

d) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 70, 300, and 453 to 459;

e) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 71 and 460 to 467;

f) a VH as in (d) and a VL as in (e);

g) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 40;

h) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 41;

i) a VH as in (g) and a VL as in (h);

j) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 60;

k) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 61;

l) a VH as in (j) and a VL as in (k);

m) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 210;

n) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 211;

o) a VH as in (m) and a VL as in (n);

p) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 30;

q) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 31;

r) a VH as in (p) and a VL as in (q);

s) a heavy chain variable region (VH) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 50;

t) a light chain variable region (VL) comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 51; or

u) a VH as in (s) and a VL as in (t).

68. The method of claim 2 , wherein the antibody comprises:

a) a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 340, 10, and 20;

b) a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 341, 11, 21, 281, 291, 561, 571, and 581;

c) a VH as in (a) and a VL as in (b);

d) a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 70, 300, and 453 to 459;

e) a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 71 and 460 to 467;

f) a VH as in (d) and a VL as in (e);

g) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 40;

h) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 41;

i) a VH as in (g) and a VL as in (h);

j) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 60;

k) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 61;

l) a VH as in (j) and a VL as in (k);

m) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 210;

n) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 211;

o) a VH as in (m) and a VL as in (n);

p) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 30;

q) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 31;

r) a VH as in (p) and a VL as in (q);

s) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 50;

t) a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 51; or

u) a VH as in (s) and a VL as in (t).

69. The method of claim 2 , wherein the antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 340 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 341.

70. The method of claim 69 , wherein the antibody is an IgG1 or an IgG4 antibody.

71. The method of claim 70 , wherein the antibody is an IgG4 antibody.

72. The method of claim 71 , wherein the antibody comprises M252Y, S254T, and T256E mutations.

73. The method of claim 72 wherein the antibody comprises an S228P mutation.

74. The method of claim 69 , wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K D of less than 50 nM.

75. The method of claim 69 , wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO: 4).

76. The method of claim 69 , wherein the antibody comprises:

b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain comprising the amino acid sequence of SEQ ID NO: 349.

77. The method of claim 76 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain comprising the amino acid sequence of SEQ ID NO: 349.

78. The method of claim 76 , wherein the antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain consisting of the amino acid sequence of SEQ ID NO: 349.

Continuity (3)

Division 15171143 · Jun 2, 2016

Provisional Application 62171693 · Jun 5, 2015

Related Publication 20190112362A1 · Apr 18, 2019