Monomethylvaline compounds capable of conjugation to ligands

• US 7,964,567 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: Spencer, Susan D., Ebens, Allen J., Sliwkowski, Mark X., Kline, Toni Beth, Polakis, Paul, Doronina, Svetlana O., Senter, Peter D., Toki, Brian E.
• Primary Examiner(s): Kosar; Andrew D
• Application Number:
  US11/833,961
• Publication Number:
  US 20080248051A1
• 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. A method for treating cancer comprising administering to a patient in need thereof an effective amount of an antibody-drug conjugate compound having the formula IIa:

2. The method of claim 1 further comprising administering an effective amount of an additional anticancer agent.

3. The method of claim 1, wherein the antibody-drug conjugate compound is formulated with a pharmaceutically acceptable diluent, carrier or excipient.

4. The method of claim 1 wherein the amount of antibody-drug conjugate compound administered to the patient is in the range of about 0.1 to about 10 mg/kg of patient weight.

5. The method of claim 1 wherein the antibody-drug conjugate is administered at about three week intervals.

6. The method of claim 1 wherein said antibody-drug conjugate compound is administered parenterally or intravenously.

7. The method of claim 6 wherein said antibody-drug conjugate compound is formulated with a pharmaceutically acceptable parenteral vehicle.

8. The method of claim 1, wherein the antibody-drug conjugate compound is formulated in a unit dosage injectable form.

9. The method 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);

(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, FLJ20041, 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).

10. The method of claim 1 wherein the cancer is selected from the group consisting of breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, colorectal, thyroid, pancreatic, prostate and bladder cancer.

11. The method of claim 10 wherein the cancer is breast cancer and the breast cancer overexpresses ErbB2 at a 2+ level or more.

12. The method of claim 10 wherein the breast cancer overexpresses ErbB2 at a 3+ level.

13. The method of claim 1 wherein the antibody of the antibody-drug conjugate compound has a biological characteristic of a 4D5 monoclonal antibody.

14. The method of claim 1 wherein the antibody is a humanized form of monoclonal antibody 4D5 (ATCC CRL 10463).

15. The method of claim 14 wherein the antibody is selected from the group consisting of humanized antibodies huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8 (trastuzumab).

16. The method of claim 15 wherein the antibody is humanized antibody huMAb4D5-8 (trastuzumab).

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

18. The method of claim 17 wherein the antibody fragment is a Fab fragment.

19. The method of claim 1 wherein the cancer is characterized by the overexpresssion of an ErbB2 receptor.

20. The method of claim 1 wherein the cancer does not respond, or responds poorly, to treatment with an anti-ErbB2 antibody.

21. The method of claim 1 wherein the antibody binds to tumor-associated antigen (1) BMPR1B.

22. The method of claim 1 wherein the antibody binds to tumor-associated antigen (3) STEAP1.

23. The method of claim 1 wherein the antibody binds to tumor-associated antigen (4) 0772P.

24. The method of claim 1 wherein the antibody binds to tumor-associated antigen (5) MPF.

25. The method of claim 1 wherein the antibody binds to tumor-associated antigen (6) Napi3b.

26. The method of claim 1 wherein the antibody binds to tumor-associated antigen (7) Sema 5b.

27. The method of claim 1 wherein the antibody binds to tumor-associated antigen (8) PSCA hlg.

28. The method of claim 1 wherein the antibody binds to tumor-associated antigen (9) ETBR.

29. The method of claim 1 wherein the antibody binds to tumor-associated antigen (11) STEAP2.

30. The method of claim 1 wherein the antibody binds to tumor-associated antigen (13) CRIPTO.

31. The method of claim 1 wherein the antibody binds to tumor-associated antigen (15) CD79b.

32. The method of claim 1 wherein the antibody binds to tumor-associated antigen (17) HER2.

33. The method of claim 1 wherein the antibody binds to tumor-associated antigen (23) ASLG659.

34. The method of claim 1 wherein the antibody binds to tumor-associated antigen (27) CD22.

35. The method of claim 1 wherein the antibody binds to tumor-associated antigen (28) CD79a.

36. The method of claim 1 wherein the antibody binds to tumor-associated antigen (30) HLA-DOB.

37. The method of claim 1 wherein the antibody binds to tumor-associated antigen (35) IRTA2.

38. The method of claim 1, wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.

39. The method of claim 1, wherein the antibody-drug conjugate compound having the formula:

40. The method of claim 1, wherein the antibody is a monoclonal antibody.

41. The method of claim 1, wherein the antibody is a humanized antibody.

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