Anti-TIGIT antibodies
Isolated antibodies that bind to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains) are provided. In some embodiments, the antibody has a binding affinity (K D ) for human TIGIT of less than 5 nM. In some embodiments, the anti-TIGIT antibody blocks binding of CD155 and/or CD112 to TIGIT. In some embodiments, the antibodies are afucosylated.
1. An isolated antibody that binds to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains), wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
(a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or
(b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or
(c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or
(d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or
(e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.
2. The isolated antibody of claim 1 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:248, or SEQ ID NO:249 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
3. The isolated antibody of claim 1 , comprising a heavy chain comprising an amino acid sequence selected from SEQ ID NOs: 260, 262, 264, 266, 268, 270, and 272; and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
4. The isolated antibody of claim 1 , wherein the antibody is afucosylated.
5. A pharmaceutical formulation comprising the isolated antibody of claim 1 and a pharmaceutically acceptable carrier.
6. A bispecific antibody comprising the antibody of claim 1 .
7. An antibody-drug conjugate comprising the antibody of claim 1 conjugated to a cytotoxic agent.
8. An isolated polynucleotide that encodes an antibody that binds to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains), wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
(a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or
(b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or
(c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or
(d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or
(e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.
9. The isolated polynucleotide of claim 8 , wherein the polynucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 259, 261, 163, 265, 267, 269, and 271; and/or the nucleotide sequence of SEQ ID NO: 273.
10. A vector comprising the isolated polynucleotide of claim 8 .
11. A host cell comprising the isolated polynucleotide of claim 8 .
12. A host cell that expresses the antibody of claim 1 .
13. A method of producing an antibody, comprising culturing the host cell of claim 12 under conditions suitable for producing the antibody.
14. A composition comprising isolated antibodies that bind to human TIGIT, wherein at least 90% of the antibodies in the composition are afucosylated, and wherein each of the antibodies in the composition comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
(a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or
(b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or
(c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or
(d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or
(e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.
15. The composition of claim 14 , wherein each of the antibodies comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, SEQ ID NO:246, SEQ ID NO:247, SEQ ID NO:248, or SEQ ID NO:249 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
16. The composition of claim 14 , wherein each of the antibodies comprises a heavy chain comprising an amino acid sequence selected from SEQ ID NOs: 260, 262, 264, 266, 268, 270, and 272; and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
17. The composition of claim 14 , wherein each antibody is a bispecific antibody.
18. The composition of claim 14 , wherein each antibody is conjugated to a cytotoxic agent.
19. A pharmaceutical formulation comprising the composition of claim 14 and a pharmaceutically acceptable carrier.
20. A host cell that expresses an antibody that binds to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains), wherein the host cell is engineered to produce afucosylated antibodies, and wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
(a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or
(b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or
(c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or
(d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or
(e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.
21. A method of producing afucosylated antibodies that bind TIGIT, comprising culturing the host cell of claim 20 under conditions suitable for producing the afucosylated antibodies.
22. A method of producing afucosylated antibodies that bind TIGIT (T-cell immunoreceptor with Ig and ITIM domains), comprising culturing a host cell that expresses an antibody that binds human TIGIT in the presence of a fucose analogue under conditions suitable for producing afucosylated antibodies, wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of:
(a) SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively; or
(b) SEQ ID NOs: 224, 225, 62, 67, 69, and 71, respectively; or
(c) SEQ ID NOs: 226, 227, 228, 67, 69, and 71, respectively; or
(d) SEQ ID NOs: 224, 229, 230, 67, 69, and 71, respectively; or
(e) SEQ ID NOs: 224, 227, 230, 67, 69, and 71, respectively.
23. The isolated antibody of claim 1 , wherein the antibody is an IgG1 antibody, wherein the antibody is afucosylated, and wherein the antibody binds with increased affinity to FcγRIIIa and binds with decreased affinity to FcγRIIa and FcγRIIb, compared to the same antibody that is not afucosylated.
24. The composition of claim 14 , wherein each of the antibodies in the composition is an IgG1 antibody, and wherein the antibodies bind with increased affinity to FcγRIIIa and bind with decreased affinity to FcγRIIa and FcγRIIb, compared to a composition of the same antibodies that are not afucosylated.
25. The isolated antibody of claim 1 , wherein the antibody is afucosylated, and wherein the antibody has a binding affinity (K D ) for human TIGIT of less than 5 nM.
26. A composition of isolated antibodies that bind to human TIGIT, wherein the antibodies are produced by a method comprising (a) culturing a host cell in the presence of a fucose analogue under conditions suitable for producing afucosylated antibodies, or (b) culturing a host cell engineered to produce afucosylated antibodies; wherein the host cell comprises a polynucleotide comprising a nucleotide sequence encoding the antibody of claim 1 .
27. The composition of claim 26 , wherein at least 90% of the antibodies in the composition are afucosylated.
28. An isolated antibody that binds to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains), wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively.
29. The isolated antibody of claim 28 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
30. The isolated antibody of claim 28 , comprising a heavy chain comprising an amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
31. An isolated antibody that binds to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains), wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively, wherein the antibody is afucosylated.
32. The isolated antibody of claim 31 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
33. The isolated antibody of claim 32 , wherein the antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
34. A pharmaceutical formulation comprising the isolated antibody of claim 28 and a pharmaceutically acceptable carrier.
35. A pharmaceutical formulation comprising the isolated antibody of claim 29 and a pharmaceutically acceptable carrier.
36. A pharmaceutical formulation comprising the isolated antibody of claim 30 and a pharmaceutically acceptable carrier.
37. A pharmaceutical formulation comprising the isolated antibody of claim 31 and a pharmaceutically acceptable carrier.
38. A pharmaceutical formulation comprising the isolated antibody of claim 32 and a pharmaceutically acceptable carrier.
39. A pharmaceutical formulation comprising the isolated antibody of claim 33 and a pharmaceutically acceptable carrier.
40. The isolated polynucleotide of claim 8 , wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively.
41. The isolated polynucleotide of claim 40 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
42. The isolated polynucleotide of claim 40 , wherein the antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
43. The isolated polynucleotide of claim 40 , wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 259 and/or the nucleotide sequence of SEQ ID NO: 273.
44. A vector comprising the isolated polynucleotide of claim 40 .
45. A vector comprising the isolated polynucleotide of claim 41 .
46. A vector comprising the isolated polynucleotide of claim 42 .
47. A vector comprising the isolated polynucleotide of claim 43 .
48. A host cell comprising the isolated polynucleotide of claim 40 .
49. A host cell comprising the isolated polynucleotide of claim 41 .
50. A host cell comprising the isolated polynucleotide of claim 42 .
51. A host cell comprising the isolated polynucleotide of claim 43 .
52. A host cell that expresses the antibody of claim 28 .
53. A host cell that expresses the antibody of claim 29 .
54. A host cell that expresses the antibody of claim 30 .
55. A host cell that expresses the antibody of claim 31 .
56. A host cell that expresses the antibody of claim 32 .
57. A host cell that expresses the antibody of claim 33 .
58. A method of producing an antibody, comprising culturing the host cell of claim 52 under conditions suitable for producing the antibody.
59. A method of producing an antibody, comprising culturing the host cell of claim 53 under conditions suitable for producing the antibody.
60. A method of producing an antibody, comprising culturing the host cell of claim 54 under conditions suitable for producing the antibody.
61. A method of producing an antibody, comprising culturing the host cell of claim 55 under conditions suitable for producing the antibody.
62. A method of producing an antibody, comprising culturing the host cell of claim 56 under conditions suitable for producing the antibody.
63. A method of producing an antibody, comprising culturing the host cell of claim 57 under conditions suitable for producing the antibody.
64. The method of claim 13 , further comprising isolating the antibody.
65. The method of claim 58 , further comprising isolating the antibody.
66. The method of claim 59 , further comprising isolating the antibody.
67. The method of claim 60 , further comprising isolating the antibody.
68. The method of claim 61 , further comprising isolating the antibody.
69. The method of claim 62 , further comprising isolating the antibody.
70. The method of claim 63 , further comprising isolating the antibody.
71. A composition comprising isolated antibodies that bind to human TIGIT, wherein at least 90% of the antibodies in the composition are afucosylated, wherein each of the antibodies in the composition comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively.
72. The composition of claim 71 , wherein each of the antibodies in the composition comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
73. The composition of claim 71 , wherein each of the antibodies in the composition comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
74. A pharmaceutical formulation comprising the composition of claim 71 and a pharmaceutically acceptable carrier.
75. A pharmaceutical formulation comprising the composition of claim 72 and a pharmaceutically acceptable carrier.
76. A pharmaceutical formulation comprising the composition of claim 73 and a pharmaceutically acceptable carrier.
77. The host cell of claim 20 , wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively.
78. The host cell of claim 77 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
79. The host cell of claim 77 , wherein the antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
80. A method of producing afucosylated antibodies that bind TIGIT, comprising culturing the host cell of claim 77 under conditions suitable for producing the afucosylated antibodies.
81. A method of producing afucosylated antibodies that bind TIGIT, comprising culturing the host cell of claim 78 under conditions suitable for producing the afucosylated antibodies.
82. A method of producing afucosylated antibodies that bind TIGIT, comprising culturing the host cell of claim 79 under conditions suitable for producing the afucosylated antibodies.
83. The method of claim 80 , further comprising isolating the afucosylated antibodies.
84. The method of claim 81 , further comprising isolating the afucosylated antibodies.
85. The method of claim 82 , further comprising isolating the afucosylated antibodies.
86. The method of claim 22 , wherein the antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NOs: 58, 60, 62, 67, 69, and 71, respectively.
87. The method of claim 86 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:64.
88. The method of claim 86 , wherein the antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 274.
89. The method of claim 86 , further comprising isolating the afucosylated antibodies.
90. The method of claim 87 , further comprising isolating the afucosylated antibodies.
91. The method of claim 88 , further comprising isolating the afucosylated antibodies.
92. The isolated antibody of claim 28 , wherein the antibody is an IgG1 antibody, wherein the antibody is afucosylated, and wherein the antibody binds with increased affinity to FcγRIIIa and binds with decreased affinity to FcγRIIa and FcγRIIb, compared to the same antibody that is not afucosylated.
93. The isolated antibody of claim 29 , wherein the antibody is an IgG1 antibody, wherein the antibody is afucosylated, and wherein the antibody binds with increased affinity to FcγRIIIa and binds with decreased affinity to FcγRIIa and FcγRIIb, compared to the same antibody that is not afucosylated.
94. The isolated antibody of claim 30 , wherein the antibody is afucosylated, and wherein the antibody binds with increased affinity to FcγRIIIa and binds with decreased affinity to FcγRIIa and FcγRIIb, compared to the same antibody that is not afucosylated.
95. The composition of claim 71 , wherein each of the antibodies in the composition is an IgG1 antibody, and wherein the antibodies bind with increased affinity to FcγRIIIa and bind with decreased affinity to FcγRIIa and FcγRIIb, compared to a composition of the same antibodies that are not afucosylated.
96. The composition of claim 72 , wherein each of the antibodies in the composition is an IgG1 antibody, and wherein the antibodies bind with increased affinity to FcγRIIIa and bind with decreased affinity to FcγRIIa and FcγRIIb, compared to a composition of the same antibodies that are not afucosylated.
97. The composition of claim 73 , wherein the antibodies bind with increased affinity to FcγRIIIa and bind with decreased affinity to FcγRIIa and FcγRIIb, compared to a composition of the same antibodies that are not afucosylated.
98. The isolated antibody of claim 28 , wherein the antibody is afucosylated, and wherein the antibody has a binding affinity (K D ) for human TIGIT of less than 5 nM.
99. The isolated antibody of claim 29 , wherein the antibody is afucosylated, and wherein the antibody has a binding affinity (K D ) for human TIGIT of less than 5 nM.
100. The isolated antibody of claim 30 , wherein the antibody is afucosylated, and wherein the antibody has a binding affinity (K D ) for human TIGIT of less than 5 nM.
101. A composition of isolated antibodies that bind to human TIGIT, wherein the antibodies are produced by a method comprising (a) culturing a host cell in the presence of a fucose analogue under conditions suitable for producing afucosylated antibodies, or (b) culturing a host cell engineered to produce afucosylated antibodies; wherein the host cell comprises a polynucleotide comprising a nucleotide sequence encoding the antibody of claim 28 .
102. A composition of isolated antibodies that bind to human TIGIT, wherein the antibodies are produced by a method comprising (a) culturing a host cell in the presence of a fucose analogue under conditions suitable for producing afucosylated antibodies, or (b) culturing a host cell engineered to produce afucosylated antibodies; wherein the host cell comprises a polynucleotide comprising a nucleotide sequence encoding the antibody of claim 29 .
103. A composition of isolated antibodies that bind to human TIGIT, wherein the antibodies are produced by a method comprising (a) culturing a host cell in the presence of a fucose analogue under conditions suitable for producing afucosylated antibodies, or (b) culturing a host cell engineered to produce afucosylated antibodies; wherein the host cell comprises a polynucleotide comprising a nucleotide sequence encoding the antibody of claim 30 .
104. The composition of claim 101 , wherein at least 90% of the antibodies in the composition are afucosylated.
105. The composition of claim 101 , wherein at least 95% of the antibodies in the composition are afucosylated.
106. The composition of claim 101 , wherein at least 97% of the antibodies in the composition are afucosylated.
107. The composition of claim 102 , wherein at least 90% of the antibodies in the composition are afucosylated.
108. The composition of claim 102 , wherein at least 95% of the antibodies in the composition are afucosylated.
109. The composition of claim 102 , wherein at least 97% of the antibodies in the composition are afucosylated.
110. The composition of claim 103 , wherein at least 90% of the antibodies in the composition are afucosylated.
111. The composition of claim 103 , wherein at least 95% of the antibodies in the composition are afucosylated.
112. The composition of claim 103 , wherein at least 97% of the antibodies in the composition are afucosylated.
113. The composition of claim 14 , wherein at least 95% of the antibodies in the composition are afucosylated.
114. The composition of claim 14 , wherein at least 97% of the antibodies in the composition are afucosylated.
115. The composition of claim 27 , wherein at least 95% of the antibodies in the composition are afucosylated.
116. The composition of claim 27 , wherein at least 97% of the antibodies in the composition are afucosylated.
117. The composition of claim 71 , wherein at least 95% of the antibodies in the composition are afucosylated.
118. The composition of claim 71 , wherein at least 97% of the antibodies in the composition are afucosylated.
119. The composition of claim 72 , wherein at least 95% of the antibodies in the composition are afucosylated.
120. The composition of claim 72 , wherein at least 97% of the antibodies in the composition are afucosylated.
121. The composition of claim 73 , wherein at least 95% of the antibodies in the composition are afucosylated.
122. The composition of claim 73 , wherein at least 97% of the antibodies in the composition are afucosylated.