Monomethylvaline compounds capable of conjugation to ligands

• US 7,964,566 B2
• Filed: 08/03/2007
• Issued: 06/21/2011
• Est. Priority Date: 11/06/2003
• Status: Active Grant

• Current Assignee: Seagen Inc.
• Original Assignee: Seattle Genetics Incorporated
• Inventors: Polakis, Paul, Doronina, Svetlana O., Senter, Peter D., Toki, Brian E., Spencer, Susan D., Ebens, Allen J., Sliwkowski, Mark X., Kline, Toni Beth
• Primary Examiner(s): Kosar; Andrew D
• Application Number:
  US11/833,959
• Publication Number:
  US 20080248053A1
• Time in Patent Office: 1,418 Days
• Field of Search: None
• US Class Current: 514/19.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10T 428/13 : Hollow or container type article [e.g., tube, vase, etc.]

Abstract

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

Claims

1. An antibody-drug conjugate compound comprising an antibody covalently attached to one or more drug moieties, the compound having Formula Ic:

Ab A_a-W_w-Y_y-D)_p  

 

Ic

or a pharmaceutically acceptable salt or solvate thereof, wherein;

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

(1) BMPR1B (bone morphogenetic protein receptor-type IB;

(2) E16 (LAT1, SLC7A5);

(3) STEAP1 (six transmembrane epithelial antigen of prostate);

(4) 0772P (CA125, MUC16);

(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin);

(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b);

(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);

(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene);

(9) ETBR (Endothelin type B receptor);

(10) MSG783 (RNF124, hypothetical protein FLJ20315);

(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);

(12) TrpM4 (BR22450, F1120041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member

     4);

(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor);

(14) CD21 (CR2 (Complement receptor

     2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792);

(15) CD79b (IGb (immunoglobulin-associated beta), B29);

(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C);

(17) HER2;

(18) NCA;

(19) MDP;

(20) IL20Rα

;

(21) Brevican;

(22) Ephb2R;

(23) ASLG659;

(24) PSCA;

(25) GEDA;

(26) BAFF-R;

(27) CD22;

(28) CD79a (CD79A, CD79α

, immunoglobulin-associated alpha);

(29) CXCR5 (Burkitt'"'"'s lymphoma receptor

     1);

(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen) that binds peptides and presents them to CD4+T lymphocytes);

(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel

     5);

(32) CD72 (B-cell differentiation antigen CD72, Lyb-2);

(33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family);

(34) FCRH1 (Fc receptor-like protein

     1); and

(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated

     2);

A is a Stretcher unit,

a is 0 or 1,

each W is independently an Amino Acid unit,

w is an integer ranging from 0 to 12,

Y is a Spacer unit, and

y is 0, 1 or 2,

p ranges from 1 to 20, and

D is a drug moiety of Formula D_E;

2. The antibody-drug conjugate compound of claim 1

wherein a, w, and y are each 0.

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

4. The antibody-drug conjugate compound of claim 3, wherein p is 1 to 4.

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

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

7. The antibody-drug conjugate compound of claim 3 having the formula:

8. The antibody-drug conjugate compound of claim 7 having the formula:

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

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

11. The antibody-drug conjugate compound of claim 10 having the formula:

12. The antibody-drug conjugate compound of claim 11 having the formula:

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

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

15. The antibody-drug conjugate compound of claim 1 wherein w is an integer ranging from 2 to 12.

16. The antibody-drug conjugate compound of claim 1 wherein w is 2.

17. The antibody-drug conjugate compound of claim 16 wherein W_w is -valine-citrulline-.

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

19. The antibody-drug conjugate compound of claim 1 wherein the antibody specifically binds to a HER2 receptor.

20. The antibody-drug conjugate compound of claim 19 which specifically binds to the extracellular domain of the HER2 receptor and inhibits growth of tumor cells which overexpress HER2 receptor.

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

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

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

24. The antibody-drug conjugate compound of claim 1 wherein the antibody is a humanized antibody.

25. The antibody-drug conjugate compound of claim 24 wherein the humanized antibody is selected from the group consisting of huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8 (trastuzumab).

26. The antibody-drug conjugate compound of claim 25 wherein the antibody is huMAb4D5-8 (trastuzumab).

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

28. The antibody-drug conjugate compound of claim 26 wherein the antibody fragment is a Fab fragment.

29. 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.

30. The antibody-drug conjugate compound of claim 1 wherein the bioavailability of the antibody-drug conjugate 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.

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

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

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

34. The antibody-drug conjugate compound of claim 33 wherein the antibody is huMAb4D5-8 (trastuzumab).

35. 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.

36. The pharmaceutical composition of claim 35 further comprising a therapeutically effective amount of chemotherapeutic agent selected from a tubulin-forming inhibitor, a topoisomerase inhibitor, and a DNA binder.

37. 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 characterized by the overexpression of an ErbB2 receptor.

38. The article of manufacture of claim 37 wherein said package insert or label indicates that the compound can be used to treat cancer characterized by the overexpression of an ErbB2 receptor.

39. The article of manufacture of claim 37 wherein the cancer is breast cancer.

40. The article of manufacture of claim 39 wherein the cancer is characterized by the overexpression of an ErbB2 receptor at a 2+ level or above.

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

42. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (3) STEAP1.

43. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (4) 0772P.

44. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (5) MPF.

45. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (6) Napi3b.

46. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (7) Sema 5b.

47. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (8) PSCA hlg.

48. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (9) ETBR.

49. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (11) STEAP2.

50. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (13) CRIPTO.

51. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (15) CD79b.

52. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (17) HER2.

53. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (23) ASLG659.

54. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (27) CD22.

55. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (28) CD79a.

56. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (30) HLA-DOB.

57. The antibody-drug conjugate compound of claim 1 wherein the antibody binds to tumor-associated antigen (35) IRTA2.

58. The antibody-drug conjugate compound of claim 1 wherein the antibody-drug conjugate compound having a formula selected from the group consisting of:

59. The antibody-drug conjugate compound of claim 58 wherein A is maleimidocaproyl and a is 1.

60. The antibody-drug conjugate compound of claim 58 wherein Y is PAB and y is 1.