Anti-claudin antibodies and methods of use
View Patent ↗Provided herein are anti-CLDN antibodies and antibody drug conjugates (ADC), including derivatives thereof, and methods of using the same to treat proliferative disorders.
1. An anti-Claudin 6 (“anti-CLDN6”) antibody comprising:
(a) three CDRs of a light chain variable region set forth as SEQ ID NO: 21 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 23; or
(b) three CDRs of a light chain variable region set forth as SEQ ID NO: 25 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 27; or
(c) three CDRs of a light chain variable region set forth as SEQ ID NO: 29 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 31; or
(d) three CDRs of a light chain variable region set forth as SEQ ID NO: 33 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 35; or
(e) three CDRs of a light chain variable region set forth as SEQ ID NO: 37 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 39; or
(f) three CDRs of a light chain variable region set forth as SEQ ID NO: 41 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 43; or
(g) three CDRs of a light chain variable region set forth as SEQ ID NO: 45 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 47; or
(h) three CDRs of a light chain variable region set forth as SEQ ID NO: 49 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 51; or
(i) three CDRs of a light chain variable region set forth as SEQ ID NO: 53 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 55; or
(j) three CDRs of a light chain variable region set forth as SEQ ID NO: 57 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 59; or
(k) three CDRs of a light chain variable region set forth as SEQ ID NO: 61 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 63; or
(l) three CDRs of a light chain variable region set forth as SEQ ID NO: 65 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 67; or
(m) three CDRs of a light chain variable region set forth as SEQ ID NO: 69 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 71; or
(n) three CDRs of a light chain variable region set forth as SEQ ID NO: 73 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 87.
2. The anti-CLDN6 antibody of claim 1 comprising three CDRs of a light chain variable region set forth as SEQ ID NO: 73 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 87.
3. The anti-CLDN6 antibody of claim 1 , wherein the antibody binds specifically to CLDN6 and CLDN9.
4. The anti-CLDN6 antibody of claim 1 , wherein the antibody is an internalizing antibody.
5. The anti-CLDN6 antibody of claim 2 , wherein the CDR residues are numbered according to Kabat.
6. The anti-CLDN6 antibody of claim 2 , wherein the CDR residues are numbered according to Chothia.
7. The anti-CLDN6 antibody of claim 2 , wherein the CDR residues are numbered according to MacCallum.
8. The anti-CLDN6 antibody of claim 1 , comprising:
(a) a light chain variable region set forth as SEQ ID NO: 21 and a heavy chain variable region set forth as SEQ ID NO: 23; or
(b) a light chain variable region set forth as SEQ ID NO: 25 and a heavy chain variable region set forth as SEQ ID NO: 27; or
(c) a light chain variable region set forth as SEQ ID NO: 29 and a heavy chain variable region set forth as SEQ ID NO: 31; or
(d) a light chain variable region set forth as SEQ ID NO: 33 and a heavy chain variable region set forth as SEQ ID NO: 35; or
(e) a light chain variable region set forth as SEQ ID NO: 37 and a heavy chain variable region set forth as SEQ ID NO: 39; or
(f) a light chain variable region set forth as SEQ ID NO: 41 and a heavy chain variable region set forth as SEQ ID NO: 43; or
(g) a light chain variable region set forth as SEQ ID NO: 45 and a heavy chain variable region set forth as SEQ ID NO: 47; or
(h) a light chain variable region set forth as SEQ ID NO: 49 and a heavy chain variable region set forth as SEQ ID NO: 51; or
(i) a light chain variable region set forth as SEQ ID NO: 53 and a heavy chain variable region set forth as SEQ ID NO: 55; or
(j) a light chain variable region set forth as SEQ ID NO: 57 and a heavy chain variable region set forth as SEQ ID NO: 59; or
(k) a light chain variable region set forth as SEQ ID NO: 61 and a heavy chain variable region set forth as SEQ ID NO: 63; or
(l) a light chain variable region set forth as SEQ ID NO: 65 and a heavy chain variable region set forth as SEQ ID NO: 67; or
(m) a light chain variable region set forth as SEQ ID NO: 69 and a heavy chain variable region set forth as SEQ ID NO: 71; or
(n) a light chain variable region set forth as SEQ ID NO: 73 and heavy chain variable region set forth as SEQ ID NO: 87.
9. The anti-CLDN6 antibody of claim 8 , comprising a light chain variable region set forth as SEQ ID NO: 73 and heavy chain variable region set forth as SEQ ID NO: 87.
10. The anti-CLDN6 antibody of claim 9 , wherein the anti-CLDN6 antibody comprises two light chains and two heavy chains, and wherein the anti-CLDN6 antibody comprises two unpaired cysteine residues.
11. The anti-CLDN6 antibody of claim 10 , wherein each of the two light chains comprises an unpaired cysteine residue.
12. The anti-CLDN6 antibody of claim 11 , wherein each unpaired cysteine residue is at position C214.
13. The anti-CLDN6 antibody of claim 10 , wherein each of the two heavy chains comprises an unpaired cysteine residue.
14. The anti-CLDN6 antibody of claim 13 , wherein each of the two heavy chains is IgG1 and each unpaired cysteine residue is at position C220.
15. The anti-CLDN6 antibody of claim 1 comprising:
(a) a full length light chain set forth as SEQ ID NO: 114 and a full length heavy chain set forth as SEQ ID NO: 115; or
(b) a full length light chain set forth as SEQ ID NO: 116 and a full length heavy chain set forth as SEQ ID NO: 117; or
(c) a full length light chain set forth as SEQ ID NO: 116 and a full length heavy chain set forth as SEQ ID NO: 122; or
(d) a full length light chain set forth as SEQ ID NO: 118 and a full length heavy chain set forth as SEQ ID NO: 119; or
(e) a full length light chain set forth as SEQ ID NO: 120 and a full length heavy chain set forth as SEQ ID NO: 121; or
(f) a full length light chain set forth as SEQ ID NO: 120 and a full length heavy chain set forth as SEQ ID NO: 137.
16. The anti-CLDN6 antibody of claim 1 , wherein the antibody is selected from the group consisting of monoclonal antibody, chimeric antibody, CDR-grafted antibody, humanized antibody, primatized antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and scFv fragment; or an immunoreactive fragment thereof that binds CLDN6.
17. The anti-CLDN6 antibody of claim 16 , wherein the antibody is selected from the group consisting of chimeric antibody, CDR-grafted antibody, and humanized antibody.
18. The anti-CLDN6 antibody of claim 1 , wherein the anti-CLDN6 antibody is conjugated to a cytotoxic agent.
19. The anti-CLDN6 antibody of claim 18 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD), an auristatin, a maytansinoid, a calicheamicin or a radioisotope.
20. The anti-CLDN6 antibody of claim 19 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD).
21. The anti-CLDN6 antibody of claim 10 , wherein the anti-CLDN6 antibody is conjugated to a cytotoxic agent, and wherein the cytotoxic agent is conjugated to the two unpaired cysteine residues.
22. The anti-CLDN6 antibody of claim 21 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD), an auristatin, a maytansinoid, a calicheamicin or a radioisotope.
23. The anti-CLDN6 antibody of claim 22 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD).
24. An antibody drug conjugate comprising an anti-Claudin 6 (“anti-CLDN6”) antibody conjugated to a cytotoxic agent, wherein the anti-CLDN6 antibody comprises:
(a) three CDRs of a light chain variable region set forth as SEQ ID NO: 21 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 23; or
(b) three CDRs of a light chain variable region set forth as SEQ ID NO: 25 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 27; or
(c) three CDRs of a light chain variable region set forth as SEQ ID NO: 29 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 31; or
(d) three CDRs of a light chain variable region set forth as SEQ ID NO: 33 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 35; or
(e) three CDRs of a light chain variable region set forth as SEQ ID NO: 37 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 39; or
(f) three CDRs of a light chain variable region set forth as SEQ ID NO: 41 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 43; or
(g) three CDRs of a light chain variable region set forth as SEQ ID NO: 45 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 47; or
(h) three CDRs of a light chain variable region set forth as SEQ ID NO: 49 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 51; or
(i) three CDRs of a light chain variable region set forth as SEQ ID NO: 53 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 55; or
(j) three CDRs of a light chain variable region set forth as SEQ ID NO: 57 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 59; or
(k) three CDRs of a light chain variable region set forth as SEQ ID NO: 61 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 63; or
(l) three CDRs of a light chain variable region set forth as SEQ ID NO: 65 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 67; or
(m) three CDRs of a light chain variable region set forth as SEQ ID NO: 69 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 71; or
(n) three CDRs of a light chain variable region set forth as SEQ ID NO: 73 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 87.
25. The antibody drug conjugate of claim 24 wherein the antibody drug conjugate has the formula Ab-[L-D]n, wherein:
(a) Ab comprises the anti-CLDN6 antibody;
(b) L comprises an optional linker;
(c) D comprises a drug, which is the cytotoxic agent; and
(d) n is an integer from 1 to 8.
26. The antibody drug conjugate of claim 25 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD), an auristatin, a maytansinoid, a calicheamicin or a radioisotope.
27. The antibody drug conjugate of claim 26 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD).
28. The antibody drug conjugate of claim 27 , wherein Ab comprises a light chain variable region set forth as SEQ ID NO: 73 and a heavy chain variable region set forth as SEQ ID NO: 87 and wherein D is a pyrrolobenzodiazepine (PBD).
29. The antibody drug conjugate of claim 28 , wherein n is 2.
30. A pharmaceutical composition comprising the antibody drug conjugate of claim 24 and a pharmaceutically acceptable carrier.
31. A pharmaceutical composition comprising the antibody drug conjugate of claim 28 and a pharmaceutically acceptable carrier.
32. A pharmaceutical composition comprising the antibody drug conjugate of claim 29 and a pharmaceutically acceptable carrier.
33. The pharmaceutical composition of claim 30 comprising an average drug to antibody ratio (DAR) of 1, 2, 3, 4, 5, 6, 7 or 8 each ±0.4.
34. The pharmaceutical composition of claim 33 comprising an average drug to antibody ratio (DAR) of 2±0.4.
35. The pharmaceutical composition of claim 34 comprising less than 30% of non-predominant ADC species.
36. The anti-CLDN6 antibody of claim 2 , wherein the anti-CLDN6 antibody comprises two light chains and two heavy chains, and wherein the anti-CLDN6 antibody comprises two unpaired cysteine residues.
37. The anti-CLDN6 antibody of claim 36 , wherein the anti-CLDN6 antibody is an IgG1 antibody comprising a deletion or substitution of a cysteine residue at light chain position 214 or heavy chain position 220.
38. The anti-CLDN6 antibody of claim 37 comprising native cysteine residues at heavy chain positions 226 and 229.
39. The antibody drug conjugate of claim 24 , wherein the anti-CLDN6 antibody is an internalizing antibody.
40. The antibody drug conjugate of claim 24 , wherein anti-CLDN6 antibody comprises three CDRs of a light chain variable region set forth as SEQ ID NO: 73 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 87.
41. The antibody drug conjugate of claim 40 , wherein the CDR residues are numbered according to Kabat.
42. The antibody drug conjugate of claim 40 , wherein the CDR residues are numbered according to Chothia.
43. The antibody drug conjugate of claim 40 , wherein the CDR residues are numbered according to MacCallum.
44. The antibody drug conjugate of claim 24 , comprising:
(a) a light chain variable region set forth as SEQ ID NO: 21 and a heavy chain variable region set forth as SEQ ID NO: 23; or
(b) a light chain variable region set forth as SEQ ID NO: 25 and a heavy chain variable region set forth as SEQ ID NO: 27; or
(c) a light chain variable region set forth as SEQ ID NO: 29 and a heavy chain variable region set forth as SEQ ID NO: 31; or
(d) a light chain variable region set forth as SEQ ID NO: 33 and a heavy chain variable region set forth as SEQ ID NO: 35; or
(e) a light chain variable region set forth as SEQ ID NO: 37 and a heavy chain variable region set forth as SEQ ID NO: 39; or
(f) a light chain variable region set forth as SEQ ID NO: 41 and a heavy chain variable region set forth as SEQ ID NO: 43; or
(g) a light chain variable region set forth as SEQ ID NO: 45 and a heavy chain variable region set forth as SEQ ID NO: 47; or
(h) a light chain variable region set forth as SEQ ID NO: 49 and a heavy chain variable region set forth as SEQ ID NO: 51; or
(i) a light chain variable region set forth as SEQ ID NO: 53 and a heavy chain variable region set forth as SEQ ID NO: 55; or
(j) a light chain variable region set forth as SEQ ID NO: 57 and a heavy chain variable region set forth as SEQ ID NO: 59; or
(k) a light chain variable region set forth as SEQ ID NO: 61 and a heavy chain variable region set forth as SEQ ID NO: 63; or
(l) a light chain variable region set forth as SEQ ID NO: 65 and a heavy chain variable region set forth as SEQ ID NO: 67; or
(m) a light chain variable region set forth as SEQ ID NO: 69 and a heavy chain variable region set forth as SEQ ID NO: 71; or
(n) a light chain variable region set forth as SEQ ID NO: 73 and heavy chain variable region set forth as SEQ ID NO: 87.
45. The antibody drug conjugate of claim 44 , comprising a light chain variable region set forth as SEQ ID NO: 73 and heavy chain variable region set forth as SEQ ID NO: 87.
46. The antibody drug conjugate of claim 24 , wherein the anti-CLDN6 antibody comprises two light chains and two heavy chains, and wherein the anti-CLDN6 antibody comprises two unpaired cysteine residues.
47. The antibody drug conjugate of claim 46 , wherein each of the two light chains comprises an unpaired cysteine residue.
48. The antibody drug conjugate of claim 47 , wherein each unpaired cysteine residue is at position C214.
49. The antibody drug conjugate of claim 46 , wherein each of the two heavy chains comprises an unpaired cysteine residue.
50. The antibody drug conjugate of claim 49 , wherein each of the two heavy chains is IgG1 and each unpaired cysteine residue is at position C220.
51. The antibody drug conjugate of claim 46 , wherein the anti-CLDN6 antibody is an IgG1 antibody comprising a deletion or substitution of a cysteine residue at light chain position 214 or heavy chain position 220.
52. The antibody drug conjugate of claim 51 , comprising native cysteine residues at heavy chain positions 226 and 229.
53. The antibody drug conjugate of claim 45 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD).
54. The antibody drug conjugate of claim 53 , wherein the antibody drug conjugate has a drug loading of 2.
55. The antibody drug conjugate of claim 46 , wherein the anti-CLDN6 antibody comprises a light chain variable region set forth as SEQ ID NO: 73 and a heavy chain variable region set forth as SEQ ID NO: 87,
wherein the anti-CLDN6 antibody is an IgG1 antibody that comprises (i) a deletion or substitution of a cysteine residue at light chain position 214 or heavy chain position 220 and (ii) native cysteine residues at heavy chain positions 226 and 229,
and wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD).