CD37-binding molecules and immunoconjugates thereof
Novel anti-cancer agents, including, but not limited to, antibodies and immunoconjugates, that bind to CD37 are provided. Methods of using the agents, antibodies, or immunoconjugates, such as methods of inhibiting tumor growth are further provided.
1. A monoclonal antibody or antigen binding fragment thereof that specifically binds to CD37, wherein said antibody or fragment thereof comprises the variable heavy chain CDR1, CDR2 and CDR3 and the variable light chain CDR1, CDR2, and CDR3 sequences of:
SEQ ID NOs: 13, 14, and 15 and SEQ ID NOs: 37, 40, and 39, respectively.
2. The antibody or antigen binding fragment thereof of claim 1 , wherein the antibody of fragment thereof comprises the variable heavy chain and variable light chain sequences of: SEQ ID NO:65 and SEQ ID NO:81, respectively.
3. An antibody or antigen-binding fragment thereof, wherein said antibody or fragment thereof is an antibody produced by a hybridoma of ATCC Deposit Designation PTA-10667 deposited with the ATCC on Feb. 18, 2010, or is an antigen binding fragment thereof.
4. An isolated cell producing the antibody or antigen binding fragment thereof of claim 1 .
5. A method of making an anti-CD37 antibody or antigen-binding fragment thereof comprising (a) culturing the cell of claim 4 ; and (b) isolating said antibody or antigen-binding fragment thereof from said cultured cell.
6. An immunoconjugate having the formula (A)-(L)-(C), wherein:
(A) is the antibody or antigen binding fragment of claim 1 ;
(L) is a linker; and
(C) is a cytotoxic agent; and
wherein said linker (L) links (A) to (C).
7. The immunoconjugate of claim 6 comprising 3-4 (C) per (A).
8. The immunoconjugate of claim 6 , wherein said linker is selected from the group consisting: N-succinimidyl 4- (2-pyridyldithio)pentanoate (SPP); N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) or N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB); N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC); N-sulfosuccinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (sulfoSMCC); N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB); and N-succinimidyl-[(N-maleimidopropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimide).
9. The immunoconjugate of claim 6 , wherein said cytotoxic agent is selected from the group consisting of a maytansinoid, maytansinoid analog, doxorubicin, a modified doxorubicin, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, auristatin, tomaymycin derivative, and leptomycin derivative, or a prodrug of the cytotoxic agent.
10. The immunoconjugate of claim 9 , wherein said cytotoxic agent is a maytansinoid.
11. The immunoconjugate of claim 10 , wherein said maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-l-oxopentyl)-maytansine (DM4).
12. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising at least two immunoconjugates of claim 6 , wherein the immunoconjugates have an average of about 3 to about 4 (C) per (A).
14. A diagnostic reagent comprising the antibody or antigen binding fragment thereof of claim 1 .
15. A kit comprising the antibody or antigen binding fragment thereof of claim 1 .
16. The antibody or antigen binding fragment thereof of claim 2 , wherein the antibody of fragment thereof comprises the full-length heavy chain and full-length light chain sequences of SEQ ID NO:98 and SEQ ID NO:114, respectively.
17. An immunoconjugate having the formula (A)-(L)-(C), wherein:
(A) is the antibody or antigen binding fragment of claim 2 ;
(L) is a linker; and
(C) is a cytotoxic agent; and
wherein said linker (L) links (A) to (C).
18. An immunoconjugate having the formula (A)-(L)-(C), wherein:
(A) is the antibody or antigen binding fragment of claim 16 ;
(L) is a linker; and
(C) is a cytotoxic agent; and
wherein said linker (L) links (A) to (C).
19. The immunoconjugate of claim 17 , wherein said maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).
20. The immunoconjugate of claim 18 , wherein said maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).
21. A pharmaceutical composition comprising at least two immunoconjugates of claim 19 , wherein the immunoconjugates have an average of about 3 to about 4 (C) per (A).
22. A pharmaceutical composition comprising at least two immunoconjugates of claim 20 , wherein the immunoconjugates have an average of about 3 to about 4 (C) per (A).