Anti-FcRH5 antibodies and immunoconjugates and methods of use
The present invention is directed to compositions of matter useful for the treatment of hematopoietic tumor in mammals and to methods of using those compositions of matter for the same.
1. An isolated monoclonal anti-FcRH5 antibody comprising:
(a) a light chain variable domain comprising:
(i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26;
(ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and
(iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28; and
(b) a heavy chain variable domain comprising:
(i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35;
(ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; and
(iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37.
2. The antibody of claim 1 , wherein the antibody comprises a framework sequence, and wherein at least a portion of the framework sequence is a human consensus framework sequence.
3. The antibody of claim 1 , wherein the light chain variable domain comprises at least a portion of the human kappa subgroup I consensus framework sequence.
4. The antibody of claim 1 , wherein the light chain variable domain comprises one or more frameworks selected from the group consisting of FR1-LC comprising the amino acid sequence of SEQ ID NO:22; FR2-LC comprising the amino acid sequence of SEQ ID NO:23; FR3-LC comprising the amino acid sequence of SEQ ID NO:24; and FR4-LC sequence comprising the amino acid sequence of SEQ ID NO:25.
5. The antibody of claim 1 , wherein the heavy chain variable domain comprises at least a portion of a heavy chain human subgroup III consensus framework sequence.
6. The antibody of claim 1 , wherein the heavy chain variable domain comprises one or more frameworks selected from the group consisting of FR1-HC comprising the amino acid sequence of SEQ ID NO:31; FR2-HC comprising the amino acid sequence of SEQ ID NO:32; FR3-HC comprising the amino acid sequence of SEQ ID NO:33; and FR4-HC sequence comprising the amino acid sequence of SEQ ID NO:34.
7. The antibody of claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:21.
8. The antibody of claim 1 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:19.
9. The antibody of claim 7 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:19.
10. The antibody of claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:20.
11. The antibody of claim 1 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:18.
12. The antibody of claim 10 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:18.
13. The antibody of claim 9 , wherein the antibody comprises CL1 sequence depicted as SEQ ID NO:29.
14. The antibody of any one of claims 1 , 9 , and 13 , wherein the antibody comprises CH1 sequence depicted as SEQ ID NO:38 and/or Fc region sequence depicted as SEQ ID NO:39.
15. The antibody of claim 1 , wherein the antibody is monovalent and comprises an Fc region.
16. The antibody of claim 1 , wherein the antibody is bivalent.
17. The antibody of claim 1 , wherein the antibody is bispecific.
18. The antibody of claim 1 , wherein the antibody is an antibody fragment selected from the group consisting of a Fab, a Fab′-SH, an Fv, an scFv, and a (Fab′) 2 fragment.
19. The antibody of claim 1 , wherein the antibody is conjugated to a cytotoxic agent, and the antibody conjugated to the cytotoxic agent inhibits tumor cell growth.
20. The antibody of claim 1 , wherein the antibody comprises a single Fab region linked to an Fc region.
21. The antibody of claim 1 , wherein the antibody comprises a heavy chain constant domain and/or a light chain constant domain comprising one or more free cysteine amino acids at a position selected from the group consisting of position 205 of the light chain according to Kabat numbering convention; position 118 of the heavy chain according to EU numbering convention; and position 400 of the heavy chain according to EU numbering convention.
22. The antibody of claim 21 , wherein the antibody comprises a free cysteine amino acid at position 205 of the light chain.
23. The antibody of claim 21 , wherein the antibody comprises a free cysteine amino acid at position 118 of the heavy chain.
24. The antibody of claim 21 , wherein the antibody comprises a free cysteine amino acid at position 400 of the heavy chain.
25. The antibody of claim 21 , wherein the antibody comprises a free cysteine amino acid at position 205 of the light chain and position 118 of the heavy chain.
26. The antibody of claim 21 , wherein the one or more free cysteine amino acids have a thio reactivity value in the range of 0.6 to 1.0.
27. An immunoconjugate comprising an antibody of claim 1 covalently attached to a cytotoxic agent.
28. The immunoconjugate of claim 27 , wherein the cytotoxic agent is selected from the group consisting of a toxin, a chemotherapeutic agent, a drug moiety, an antibiotic, a radioactive isotope and a nucleolytic enzyme.
29. An immunoconjugate, wherein the immunoconjugate has the formula Ab-(L-D)p, wherein:
(a) Ab is the antibody of claim 1 ;
(b) L is a linker; and
(c) D is a drug moiety, wherein p is 1 to 8.
30. The immunoconjugate of claim 29 , wherein D is selected from the group consisting of a maytansinoid, an auristatin and dolostatin.
31. The immunoconjugate of claim 30 , wherein D is a drug of formula D E or D F
and wherein R 2 and R 6 are each methyl, R 3 and R 4 are each isopropyl, R 5 is H or methyl, R 7 is sec-butyl, each R 8 is independently selected from CH 3 , O—CH 3 , OH, and H; R 9 is H; R 10 is aryl; Z is —O— or —NH—; R 11 is H, C 1 -C 8 alkyl, or —(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 3 ; and R 18 is —C(R 8 ) 2 —C(R 8 ) 2 -aryl; and p ranges from 1 to 8.
32. The immunoconjugate of claim 29 , wherein D is MMAE or MMAF.
33. The immunoconjugate of claim 29 , the immunoconjugate having the Formula Ab-(L-MMAE)p, wherein L is a linker and p ranges from 2 to 5.
34. The immunoconjugate of claim 29 , the immunoconjugate having the Formula Ab-(L-MMAF)p, wherein L is a linker and p ranges from 2 to 5.
35. The immunoconjugate of claim 29 , wherein L comprises one or more linkers selected from the group consisting of 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4-(2-pyridylthio)pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate (SMCC), 4-(2-Pyridyldithio)butyric acid-N-hydroxysuccinimide ester (SPDB), and N-Succinimidyl (4-iodo-acetyl)aminobenzoate (SIAB).
36. The immunoconjugate of claim 29 , wherein L comprises one or more linkers selected from the group consisting of val-cit, MC, and PAB.
37. The immunoconjugate of claim 33 , wherein L is 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vc-PAB).
38. The immunoconjugate of claim 29 , wherein the heavy chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO:21 and the light chain variable domain of the antibody comprises the amino acid sequence of SEQ ID NO:19.
39. The immunoconjugate of claim 37 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:21 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:19.
40. An immunoconjugate comprising the antibody of claim 21 , covalently attached to a cytotoxic agent.
41. The immunoconjugate of claim 40 , wherein the cytotoxic agent is selected from the group consisting of a toxin, a chemotherapeutic agent, a drug moiety, an antibiotic, a radioactive isotope and a nucleolytic enzyme.
42. An immunoconjugate, wherein the immunoconjugate has the formula Ab-(L-D)p, wherein:
(a) Ab is the antibody of claim 21 ;
(b) L is a linker; and
(c) D is an auristatin or a maytansinoid drug moiety, wherein p is 1, 2, 3, or 4,
and wherein the antibody is attached through one or more free cysteine amino acids by L to D.
43. The immunoconjugate of claim 42 , wherein D is a maytansinoid drug moiety and the maytansinoid drug moiety is MMAE.
44. The immunoconjugate of claim 43 , wherein the immunoconjugate has the Formula Ab-(L-MMAE)p, wherein L is a linker and p ranges from 2 to 4.
45. The immunoconjugate of claim 44 , wherein L is MC-vc-PAB.
46. A pharmaceutical composition comprising the immunoconjugate of claim 29 and a pharmaceutically acceptable carrier.
47. A pharmaceutical composition comprising the immunoconjugate of claim 42 and a pharmaceutically acceptable carrier.
48. An immunoconjugate having the formula Ab-(L-D)p, wherein:
(a) Ab is an antibody, wherein the antibody is an isolated monoclonal anti-FcRH5 antibody comprising:
(i) a light chain variable domain comprising:
a. HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26;
b. HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and
c. HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28; and
(ii) a heavy chain variable domain comprising:
a. HVR-H1 comprising the amino acid sequence of SEQ ID NO: 35;
b. HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; and
c. HVR-H3 comprising the amino acid sequence of SEQ ID NO: 37;
(b) L is a linker, wherein the linker is MC-VC-PAB;
(c) D is a drug moiety, wherein the drug moiety is MMAE; and
(d) p is 1 to 8.
49. The immunoconjugate of claim 48 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:19, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:21.