Monomethylvaline compounds capable of conjugation to ligands

1. An antibody-drug conjugate having the formula IIIa:

or a pharmaceutically acceptable salt thereof, wherein:

Ab is an antibody;

R 17 is selected from the group consisting of C 1 -C 10 alkylene-, -C 3 -C 8 carbocyclo-, -O-(C 1 -C 8 alkyl)-, -arylene-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo) -C 1 -C 10 alkylene-, -C 3 -C 8 hetercyclo-, -C 1 -C 10 alkylene -(C 3 -C 8 hetercyclo)-, -(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, -(CH 2 CH 2 O) r -, and -(CH 2 CH 2 O) r -CH 2 -;

r is an integer ranging from 1-10;

p ranges from 1 to about 20, and

D is a drug moiety of Formula D F :

wherein the wavy line of D F indicates the covalent attachment site to C(O) in formula IIIa, independently at each location:

R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;

R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

R 5 is selected from the group consisting of H and methyl;

or R 4 and R 5 jointly form a carbocyclic ring and have the formula -(CR a R b ) n - wherein R a and R b are independently selected from the group consisting of H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;

R 6 is selected from the group consisting of H and C 1 -C 8 alkyl;

R 7 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);

each R 8 is independently selected from the group consisting of H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and O-(C 1 -C 8 alkyl);

R 9 is selected from the group consisting of H and C 1 -C 8 alkyl;

R 10 is selected from aryl or C 3 -C 8 heterocycle;

Z is O, S, NH, or NR 12 , wherein R 12 is C 1 -C 8 alkyl;

R 11 is selected from H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, -(R 13 O) m -R 14 , or -(R 13 O) m -CH(R 15 ) 2 ;

m is an integer ranging from 1-1000;

R 13 is C 2 -C 8 alkyl;

R 14 is H or C 1 -C 8 alkyl;

each occurrence of R 15 is independently H, COOH, -(CH 2 ) n -N(R 16 ) 2 , -(CH 2 ) n -SO 3 H, or -(CH 2 ) n -SO 3 -C 1 -C 8 alkyl;

each occurrence of R 16 is independently H, C 1 -C 8 alkyl, or -(CH 2 ) n -COOH; and

n is an integer ranging from 0 to 6.

2. The antibody-drug conjugate compound of claim 1 , wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.

3. The antibody-drug conjugate compound of claim 2 wherein the p is 2 to 5.

4. The antibody-drug conjugate compound of claim 1 wherein the p is 2 to 8.

5. The antibody-drug conjugate compound of claim 1 wherein the p is 2 to 5.

6. The antibody-drug conjugate compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.

7. The antibody-drug conjugate compound of claim 6 wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

8. The antibody-drug conjugate compound of claim 1 wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

9. The antibody-drug conjugate compound of claim 1 wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

10. The antibody-drug conjugate compound of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

11. The antibody-drug conjugate compound of claim 1 , wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

12. The antibody-drug conjugate compound of claim 1 wherein D has the formula:

or a pharmaceutically acceptable salt thereof.

13. The antibody-drug conjugate compound of claim 1 , wherein the antibody is a monoclonal antibody.

14. The antibody-drug conjugate compound of claim 1 , wherein the antibody is a bispecific antibody.

15. The antibody-drug conjugate compound of claim 1 , wherein the antibody is a chimeric antibody.

16. The antibody-drug conjugate compound of claim 1 , wherein the antibody is humanized antibody.

17. The antibody-drug conjugate compound of claim 1 , wherein the antibody is an antibody fragment.

18. The antibody-drug conjugate compound of claim 17 , wherein the antibody fragment is a Fab fragment.

19. The antibody-drug conjugate compound of claim 1 , wherein a substantial amount of the drug moiety is not cleaved from the antibody until the antibody-drug conjugate compound enters a cell with a cell-surface receptor specific for the antibody of the antibody-drug conjugate, and the drug moiety is cleaved from the antibody when the antibody-drug conjugate does enter the cell.

20. The antibody-drug conjugate compound of claim 1 , wherein the bioavailability of the compound or an intracellular metabolite of the compound in a mammal is improved when compared to a drug compound comprising the drug moiety of the antibody-drug conjugate compound.

21. The antibody-drug conjugate compound of claim 1 wherein the bioavailability of the compound or an intracellular metabolite of the compound in a mammal is improved when compared to an analog of the compound not having the drug moiety.

22. The antibody-drug conjugate compound of claim 1 wherein the drug moiety is intracellularly cleaved in a mammal from the antibody of the compound, or an intracellular metabolite of the compound.

23. An antibody-drug conjugate compound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody.

24. A pharmaceutical composition comprising an effective amount of the antibody-drug conjugate compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, carrier or excipient.

25. The pharmaceutical composition of claim 24 further comprising a therapeutically effective amount of chemotherapeutic agent selected from a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder.

26. An article of manufacture comprising

an antibody drug conjugate compound of claim 1 ;

a container; and

a package insert or label indicating that the compound can be used to treat cancer.

27. The compound of claim 1 ,

wherein:

Ab is an antibody which binds to one or more tumor-associated antigens (1)-(35):

(1) BMPR1B (bone morphogenetic protein receptor-type IB, Genbank accession no. NM_001203);

(2) E16 (LAT1, SLC7A5, Genbank accession no. NM_003486);

(3) STEAP1 (six transmembrane epithelial antigen of prostate, Genbank accession no. NM_012449);

(4) 0772P (CA125, MUC16, Genbank accession no. AF361486);

(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin, Genbank accession no. NM_005823);

(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b, Genbank accession no. NM_006424);

(7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accession no. AB040878);

(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession no. AY358628);

(9) ETBR (Endothelin type B receptor, Genbank accession no. AY275463);

(10) MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession no. NM_017763);

(11) STEAP2 (HGNC — 8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein, Genbank accession no. AF455138);

(12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member 4, Genbank accession no. NM_017636);

(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor, Genbank accession no. NP_003203 or NM_003212);

(14) CD21 (CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792 Genbank accession no. M26004);

(15) CD79b (IGb (immunoglobulin-associated beta), B29, Genbank accession no. NM_000626);

(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C, Genbank accession no. NM_030764);

(17) HER2(Genbank accession no. M11730);

(18) NCA (Genbank accession no. M18728);

(19) MDP (Genbank accession no. BC017023);

(20) IL20Rα (Genbank accession no. AF184971);

(21) Brevican (Genbank accession no. AF229053);

(22) Ephb2R (Genbank accession no. NM_004442);

(23) ASLG659(Genbank accession no. AX092328);

(24) PSCA (Genbank accession no. AJ297436);

(25) GEDA (Genbank accession no. AY260763);

(26) BAFF-R (Genbank accession no. NP_443177.1);

(27) CD22 (Genbank accession no. NP-001762.1);

(28) CD79a (CD79A, CD79α, immunoglobulin-associated alpha, Genbank accession No. NP_001774.1);

(29) CXCR5 (Burkitt's lymphoma receptor 1, Genbank accession No. NP_001707.1);

(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+ T lymphocytes, Genbank accession No. NP_002111.1);

(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel 5, Genbank accession No. NP_002552.2);

(32) CD72 (B-cell differentiation antigen CD72, Lyb-2, Genbank accession No. NP_001773.1);

(33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family, Genbank accession No. NP_005573.1);

(34) FCRH1 (Fc receptor-like protein 1, Genbank accession No. NP_443170.1); and

(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated 2Genbank accession No. NP_112571.1).

28. The antibody-drug conjugate compound of claim 27 wherein the antibody specifically binds to a HER2 receptor.

29. The antibody-drug conjugate compound of claim 28 which specifically binds to the extracellular domain of the HER2 receptor and inhibits growth of tumor cells which overexpress HER2 receptor.

30. The antibody-drug conjugate compound of claim 16 wherein the humanized antibody is selected from huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8 (trastuzumab); or a humanized form of monoclonal antibody 4D5 (ATCC CRL 10463).

31. The antibody-drug conjugate compound of claim 30 wherein the antibody is huMAb4D5-8 (trastuzumab).

32. The article of manufacture of claim 30 wherein said package insert of label indicates that the compound can be used to treat cancer characterized by the overexpression of an ErbB2 receptor.

33. The article of manufacture of claim 30 wherein the cancer is breast cancer.

34. The article of manufacture of claim 30 wherein the cancer is characterized by the overexpression of an ErbB2 receptor at a 2+ level or above.

35. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (1) BMPR1B.

36. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (3) STEAP1.

37. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (4) 0772P.

38. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (5) MPF.

39. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (6) Napi3b.

40. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (7) Sema 5b.

41. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (8) PSCA hlg.

42. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (9) ETBR.

43. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (11) STEAP2.

44. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (13) CRIPTO.

45. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (15) CD79b.

46. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (17) HER2.

47. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (23) ASLG659.

48. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (27) CD22.

49. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (28) CD79a.

50. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (30) HLA-DOB.

51. The antibody-drug conjugate compound of claim 27 wherein the antibody binds to tumor-associated antigen (35) IRTA2.