Anti-FcRH5 antibodies and immunoconjugates and methods of use
Anti-FcRH5 antibodies and immunoconjugates thereof are provided. Methods of using anti-FcRH5 antibodies and immunoconjugates thereof are provided.
1. An isolated monoclonal anti-FcRH5 antibody comprising:
(a) a light chain variable domain comprising:
(i) HVR-L1 comprising the sequence KASQNVGSNVA (SEQ ID NO: 28);
(ii) HVR-L2 comprising the sequence SASYRYS (SEQ ID NO: 29); and
(iii) HVR-L3 comprising the sequence QQYKTWT (SEQ ID NO: 30); and
(b) a heavy chain variable domain comprising:
(i) HVR-H1 comprising the sequence GYTFTNYGMN (SEQ ID NO: 37) or GYTFTNYGIN (amino acid residues 26-35 of SEQ ID NO:22);
(ii) HVR-H2 comprising the sequence NTYTGEPTYTDDFKG (SEQ ID NO: 38); and
(iii) HVR-H3 comprising the sequence ARRSIPYYYAMDY (SEQ ID NO: 39).
2. The antibody of claim 1 , wherein HVR-H1 comprises the sequence GYTFTNYGIN (amino acid residues 26-35 of SEQ ID NO:22).
3. The antibody of claim 1 , wherein HVR-H1 comprising the sequence GYTFTNYGMN (SEQ ID NO: 37).
4. The antibody of claim 1 , wherein at least a portion of the framework sequence is a human consensus framework sequence.
5. 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.
6. The antibody of claim 1 , wherein the light chain variable domain comprises FR1-LC comprising the amino acid sequence of SEQ ID NO:24; FR2-LC comprising the amino acid sequence of SEQ ID NO:25; FR3-LC comprising the amino acid sequence of SEQ ID NO:26; and FR4-LC sequence comprising the amino acid sequence of SEQ ID NO:27.
7. 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.
8. 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:33; FR2-HC comprising the amino acid sequence of SEQ ID NO:34; FR3-HC comprising the amino acid sequence of SEQ ID NO:35; and FR4-HC sequence comprising the amino acid sequence of SEQ ID NO:36.
9. The antibody of claim 1 , wherein the heavy chain variable domain comprises FR1-HC comprising the amino acid sequence of SEQ ID NO:33; FR2-HC comprising the amino acid sequence of SEQ ID NO:34; FR3-HC comprising the amino acid sequence of SEQ ID NO:35; and FR4-HC sequence comprising the amino acid sequence of SEQ ID NO:36.
10. The antibody of claim 1 , wherein the heavy chain variable domain comprises FR1-HC comprising the amino acid sequence of amino acid residues 1-25 of SEQ ID NO:22; FR2-HC comprising the amino acid sequence of SEQ ID NO:34; FR3-HC comprising the amino acid sequence of amino acid residues 67-98 of SEQ ID NO:22; and FR4-HC sequence comprising the amino acid sequence of SEQ ID NO:36.
11. The antibody of claim 1 , wherein the heavy chain variable domain comprises FR1-HC comprising the amino acid sequence of amino acid residues 1-25 of SEQ ID NO:23; FR2-HC comprising the amino acid sequence of SEQ ID NO:34; FR3-HC comprising the amino acid sequence of amino acid residues 67-98 of SEQ ID NO:23; and FR4-HC sequence comprising the amino acid sequence of SEQ ID NO:36.
12. The antibody of claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:21.
13. The antibody of claim 12 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:32.
14. The antibody of claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:22.
15. The antibody of claim 14 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:32.
16. The antibody of claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:23.
17. The antibody of claim 16 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:32.
18. The antibody of claim 1 , wherein the antibody further comprises CL1 sequence depicted as SEQ ID NO:31.
19. The antibody of any one of claims 1 , 13 , 15 , and 17 , wherein the antibody comprises CH1 sequence depicted as SEQ ID NO:40 and/or Fc region sequence depicted as SEQ ID NO:41.
20. The antibody of claim 1 , wherein the antibody is monovalent and comprises an Fc region.
21. The antibody of claim 1 , wherein the antibody is bivalent.
22. The antibody of claim 1 , wherein the antibody is bispecific.
23. 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.
24. The antibody of claim 1 , wherein when conjugated to a cytotoxic agent inhibits tumor cell growth.
25. The antibody of claim 1 , wherein the antibody comprises a single Fab region linked to an Fc region.
26. 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.
27. The antibody of claim 26 , wherein the antibody comprises a free cysteine amino acid at position 205 of the light chain.
28. The antibody of claim 26 , wherein the antibody comprises a free cysteine amino acid at position 118 of the heavy chain.
29. The antibody of claim 26 , wherein the antibody comprises a free cysteine amino acid at position 400 of the heavy chain.
30. The antibody of claim 26 , wherein the antibody comprises a free cysteine amino acid at position 205 of the light chain and position 118 of the heavy chain.
31. The antibody of claim 26 , wherein the one or more free cysteine amino acids have a thio reactivity value in the range of 0.6 to 1.0.
32. An immunoconjugate comprising an antibody of claim 1 covalently attached to a cytotoxic agent.
33. The immunoconjugate of claim 32 , 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.
34. The immunoconjugate of claim 32 , wherein HVR-H1 of the antibody comprises the sequence GYTFTNYGIN (amino acid residues 26-35 of SEQ ID NO:22).
35. 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.
36. The immunoconjugate of claim 35 , wherein D is selected from the group consisting of a maytansinoid, an auristatin and dolostatin.
37. The immunoconjugate of claim 36 , 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 about 1 to 8.
38. The immunoconjugate of claim 37 , wherein the drug is MMAE or MMAF.
39. The immunoconjugate of claim 35 , the immunoconjugate having the Formula Ab-(L-MMAE)p, wherein L is a linker and p ranges from 2 to 5.
40. The immunoconjugate of claim 35 , the immunoconjugate having the Formula Ab-(L-MMAF)p, wherein L is a linker and p ranges from 2 to 5.
41. The immunoconjugate of claim 35 , 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).
42. The immunoconjugate of claim 35 , wherein L comprises one or more linkers selected from the group consisting of val-cit, MC, and PAB.
43. The immunoconjugate of claim 39 , wherein L is 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vc-PAB).
44. The immunoconjugate of claim 43 , wherein HVR-H1 of the antibody comprises the sequence GYTFTNYGIN (amino acid residues 26-35 of SEQ ID NO:22).
45. An immunoconjugate comprising the antibody of claim 26 , covalently attached to a cytotoxic agent.
46. The immunoconjugate of claim 45 , 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.
47. An immunoconjugate, wherein the immunoconjugate has the formula Ab-(L-D)p, wherein:
(a) Ab is the antibody of claim 26 ;
(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.
48. The immunoconjugate of claim 47 , wherein D is a maytansinoid drug moiety and the maytansinoid drug moiety is MMAE.
49. The immunoconjugate of claim 48 , wherein the immunoconjugate has the Formula Ab-(L-MMAE)p, wherein L is a linker and p ranges from 2 to 4.
50. The immunoconjugate of claim 49 , wherein L is MC-vc-PAB.
51. The immunoconjugate of claim 50 , wherein HVR-H1 of the antibody comprises the sequence GYTFTNYGIN (amino acid residues 26-35 of SEQ ID NO:22).
52. A pharmaceutical composition comprising the immunoconjugate of claim 35 and a pharmaceutically acceptable carrier.
53. A pharmaceutical composition comprising the immunoconjugate of claim 47 and a pharmaceutically acceptable carrier.