Antibody molecules to PD-L1 and uses thereof
Antibody molecules that specifically bind to PD-L1 are disclosed. Combination therapies comprising the anti-PD-L1 antibody molecules are also disclosed. The anti-PD-L1 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious conditions and disorders.
1. An antibody molecule capable of binding to human Programmed Death-Ligand 1 (PD-L1), comprising:
(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence of SEQ ID NO: 11;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14; or
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence of SEQ ID NO: 11.
2. The antibody molecule of claim 1 , which comprises a VH comprising the amino acid sequence of SEQ ID NO: 18, 30, 38, 46, 50, 54, 62, 70, or 78, a VL comprising the amino acid sequence of SEQ ID NO: 22, 26, 34, 42, 58, 66, 74, 82, or 86, or both.
3. The antibody molecule of claim 1 , which comprises:
(a) a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 22;
(b) a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 26;
(c) a VH comprising the amino acid sequence of SEQ ID NO: 18 and a VL comprising the amino acid sequence of SEQ ID NO: 86;
(d) a VH comprising the amino acid sequence of SEQ ID NO: 30 and a VL comprising the amino acid sequence of SEQ ID NO: 34;
(e) a VH comprising the amino acid sequence of SEQ ID NO: 30 and a VL comprising the amino acid sequence of SEQ ID NO: 66;
(f) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 42;
(g) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 74;
(h) a VH comprising the amino acid sequence of SEQ ID NO: 46 and a VL comprising the amino acid sequence of SEQ ID NO: 42;
(i) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 42;
(j) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 22;
(k) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 86;
(l) a VH comprising the amino acid sequence of SEQ ID NO: 54 and a VL comprising the amino acid sequence of SEQ ID NO: 58;
(m) a VH comprising the amino acid sequence of SEQ ID NO: 54 and a VL comprising the amino acid sequence of SEQ ID NO: 86;
(n) a VH comprising the amino acid sequence of SEQ ID NO: 62 and a VL comprising the amino acid sequence of SEQ ID NO: 66;
(o) a VH comprising the amino acid sequence of SEQ ID NO: 62 and a VL comprising the amino acid sequence of SEQ ID NO: 86;
(p) a VH comprising the amino acid sequence of SEQ ID NO: 70 and a VL comprising the amino acid sequence of SEQ ID NO: 66; or
(q) a VH comprising the amino acid sequence of SEQ ID NO: 78 and a VL comprising the amino acid sequence of SEQ ID NO: 82.
4. The antibody molecule of claim 1 , which comprises:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 24;
(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 28;
(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;
(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 36;
(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 32 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 76;
(h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 24
(k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;
(l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 56 and a light chain comprising the amino acid sequence of SEQ ID NO: 60;
(m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 56 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;
(n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 88;
(p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 72 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 80 and a light chain comprising the amino acid sequence of SEQ ID NO: 84;
(r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 197 and a light chain comprising the amino acid sequence of SEQ ID NO: 36;
(s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;
(t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 96 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;
(u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 247 and a light chain comprising the amino acid sequence of SEQ ID NO: 84; or
(v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 260 and a light chain comprising the amino acid sequence of SEQ ID NO: 44.
5. The antibody molecule of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 30 and the VL comprises the amino acid sequence of SEQ ID NO: 66.
6. The antibody molecule of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 78 and the VL comprising the amino acid sequence of SEQ ID NO: 82.
7. The antibody molecule of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 96 and a light chain comprises the amino acid sequence of SEQ ID NO: 68.
8. The antibody molecule of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 80 and the light chain comprises the amino acid sequence of SEQ ID NO: 84.
9. A pharmaceutical composition comprising the antibody molecule of claim 1 and a pharmaceutically acceptable carrier, excipient or stabilizer.
10. A pharmaceutical composition comprising the antibody molecule of claim 5 and a pharmaceutically acceptable carrier, excipient or stabilizer.
11. A pharmaceutical composition comprising the antibody molecule of claim 6 and a pharmaceutically acceptable carrier, excipient or stabilizer.
12. A pharmaceutical composition comprising the antibody molecule of claim 7 and a pharmaceutically acceptable carrier, excipient or stabilizer.
13. A pharmaceutical composition comprising the antibody molecule of claim 8 and a pharmaceutically acceptable carrier, excipient or stabilizer.
14. The antibody molecule of claim 1 , which is a Fab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).
15. The antibody molecule of claim 1 , which comprises a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4 and/or a light chain constant region of kappa or lambda.
16. The antibody molecule of claim 15 , which comprises a kappa light chain constant region and:
(a) a human IgG4 heavy chain constant region comprising SEQ ID NO:188 or 190 or a human IgG4 heavy chain constant region comprising Proline at the position corresponding to amino acid 108 of SEQ ID NO:188;
(b) a human IgG1 heavy chain constant region comprising SEQ ID NO:192 or a human IgG1 heavy chain constant region comprising Alanine at the position corresponding to amino acid 180 of SEQ ID NO:191;
(c) a human IgG1 heavy chain constant region comprising SEQ ID NO:193 or a human IgG1 heavy chain constant region comprising Alanine at the positions corresponding to amino acid 148 and 212 of SEQ ID NO:191; or
(d) a human IgG1 heavy chain constant region comprising SEQ ID NO:194 or a human IgG1 heavy chain constant region comprising Alanine at the positions corresponding to amino acid 117 and 118 of SEQ ID NO:191.
17. The antibody molecule of claim 1 , which has one or more of the following properties:
(a) is capable of binding to human PD-L1 with a dissociation constant (K D ) of less than about 0.2 nM;
(b) binds an extracellular domain of PD-L1;
(c) is capable of reducing binding of PD-1 to PD-L1; or
(d) is capable of enhancing an antigen-specific T cell response.
18. The antibody molecule of claim 1 , wherein said antibody molecule is a humanized antibody molecule, a monospecific antibody molecule or a bispecific antibody molecule.
19. The antibody molecule of claim 18 , wherein said antibody molecule is a bispecific antibody molecule and has a first binding specificity for PD-L1 and a second binding specificity for TIM-3, LAG-3, CEACAM-1, CEACAM-5, PD-1 or PD-L2.
20. A nucleic acid molecule comprising a first nucleotide sequence that encodes a heavy chain variable region (VH), or a second nucleotide sequence that encodes a light chain variable region (VL), or both, of an antibody molecule capable of binding to human Programmed Death Ligand-1 (PD-L1), wherein the antibody molecule comprises:
(a) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14;
(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence of SEQ ID NO: 11;
(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14; or
(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence of SEQ ID NO: 11.
21. An expression vector comprising the nucleic acid molecule of claim 20 .
22. An isolated host cell comprising the nucleic acid molecule of claim 20 .
23. A method of producing an antibody molecule or fragment thereof, comprising culturing the host cell of claim 22 under conditions suitable for gene expression, wherein said host cell comprises said first nucleotide sequence that encodes a VH and said second nucleotide sequence that encodes a VL.
24. The nucleic acid molecule of claim 20 , wherein the first nucleotide sequence encodes a VH comprising the amino acid sequence of SEQ ID NO: 30 or comprises the nucleotide sequence of SEQ ID NO: 95; and/or wherein the second nucleotide sequence encodes a VL comprising the amino acid sequence of SEQ ID NO: 66 or comprises the nucleotide sequence of SEQ ID NO: 98.
25. The nucleic acid molecule of claim 20 , wherein the first nucleotide sequence encodes a VH comprising the amino acid sequence of SEQ ID NO: 78 or comprises the nucleotide sequence of SEQ ID NO: 100; and/or wherein the second nucleotide sequence encodes a VL comprising the amino acid sequence of SEQ ID NO: 82 or comprises the nucleotide sequence of SEQ ID NO: 102.
26. The nucleic acid molecule of claim 20 , wherein the first nucleotide sequence encodes a heavy chain comprising the amino acid sequence of SEQ ID NO: 80 or comprises a heavy chain nucleotide sequence of SEQ ID NO: 101; and/or wherein the second nucleotide sequence encodes a light chain comprising the amino acid sequence of SEQ ID NO: 84 or comprises a light chain nucleotide sequence of SEQ ID NO: 103.
27. The nucleic acid molecule of claim 20 , wherein the first nucleotide sequence encodes a heavy chain comprising the amino acid sequence of SEQ ID NO: 96 or comprises a heavy chain nucleotide sequence of SEQ ID NO: 97; and/or wherein the second nucleotide sequence encodes a light chain comprising the amino acid sequence of SEQ ID NO: 68 or comprises a light chain nucleotide sequence of SEQ ID NO: 99.