Methods of treatment using anti-ErbB antibody-maytansinoid conjugates

• US 7,575,748 B1
• Filed: 07/17/2006
• Issued: 08/18/2009
• Est. Priority Date: 03/16/2000
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Sliwkowski, Mark, Erickson, Sharon, Schwall, Ralph, Blattler, Walter
• Primary Examiner(s): Helms; Larry R.
• Assistant Examiner(s): Natarajan; Meera
• Application Number:
  US11/488,545
• Time in Patent Office: 1,128 Days
• Field of Search: None
• US Class Current: 424/178.1
• CPC Class Codes: A01K 2207/15 Humanized animals
• CPC Class Codes: A01K 2217/00 Genetically modified animals
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2217/052 inducing gain of function
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A01K 67/0278 Knock-in vertebrates, e.g. humanised vertebrates
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6871 the antibody targeting an enzyme
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/3015 Breast
• 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: C12N 15/8509 : for producing genetically modified animals, e.g. transgenic

Abstract

The application concerns methods of treatment using anti-ErbB receptor antibody-maytansinoid conjugates, and articles of manufacture suitable for use in such methods. In particular, the invention concerns ErbB receptor-directed cancer therapies, using anti-ErbB receptor antibody-maytansinoid conjugates.

Claims

1. A method for the treatment of a tumor in a mammal, comprising the steps of (i) identifying said tumor as being characterized by overexpression of an ErbB2 receptor and as being a tumor that does not respond, or responds poorly, to treatment with an anti-ErbB antibody, and (ii) intravenously administering to the mammal a therapeutically effective amount of a conjugate of a humanized antibody huMab 4D5-8 covalently linked via a thioether linking group with a maytansinoid DM1 having the structure

3. The method of claim 1 wherein the dose is between about 0.5 mg/kg and about 5 mg/kg.

4. The method of claim 1 wherein the dose is between about 1 mg/kg and about 3 mg/kg.

5. The method of claim 1 wherein the dose is about 4 mg/kg.

6. The method of claim 1 method wherein dose is 2 mg/kg.

7. The method of claim 1 wherein the dosing frequency is less than about 1 time per week.

14. The method of claim 1 wherein the thioether linking group is succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

15. The method of claim 1 wherein the conjugate comprises 1 to about 10 maytansinoid molecules per antibody molecule.

16. The method of claim 15 wherein the conjugate comprises from about 3 to about 5 maytansinoid molecules per antibody molecule.

17. The method of claim 1 further comprising the administration of a cytotoxic agent.

18. The method of claim 17 wherein the cytotoxic agent is selected from the group consisting of radioactive isotopes, chemotherapeutic agents, toxins, and fragments and/or variants thereof.

19. The method of claim 17 wherein the cytotoxic agent is a chemotherapeutic agent selected from the group consisting of alkylating agents, alkyl sulfonates, aziridines, ethylenimines, methylamelamines, nitrogen mustards, nitrosureas, antibiotics, anti-metabolites, folic acid analogues, purine analogs, pyrimidine analogs, androgens, anti-adrenals, folic acid replenishers, taxanes, platinum analogs, esperamicins, aromatase inhibiting 4(5)-imidazoles, anti-hormonal agents, anti-estrogens and anti-androgens.

20. The method of claim 17 wherein the chemotherapeutic agent is selected from the group consisting of thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide, trimethylolomelamine, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, 5-fluorouracil (5-FU), denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2, 2′

,2′

-trichlorotriethylamine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside (“

Ara-C”

), paclitaxel, doxetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, cisplatin, carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO), retinoic acid, capecitabine, tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifene (Fareston), flutamide, nilutamide, bicalutamide, leuprolide, goserelin and pharmaceutically acceptable salts, acids or derivatives thereof.

21. The method of claim 1 wherein the conjugate is administered at a dose of between about 0.1 mg/kg and about 20 mg/kg body weight.

22. The method of claim 21 wherein the conjugate is administered at a dose of between about 0.5 mg/kg and about 5 mg/kg body weight.

23. The method of claim 1 wherein the conjugate is administered at a dose of between about 0.01 mg/kg and about 0.3 mg/kg.

24. The method of claim 1 wherein the conjugate is administered at a dose of between about 0.1 mg/kg and about 0.3 mg/kg.

25. The method of claim 1 wherein the conjugate comprises about 3 to 4 maytansinoid molecules per antibody molecule.

2. A method for the treatment of a tumor in a human, comprising the steps of (i) identifying said tumor as being characterized by overexpression of an ErbB2 receptor and as being a tumor that does not respond, or responds poorly, to treatment with an anti-ErbB antibody, and (ii) intravenously administering to the human a therapeutically effective amount of a conjugate of a humanized antibody huMab 4D5-8 covalently linked via a thioether linking group with a maytansinoid DM1 having the structure

8. The method of claim 2 wherein the tumor is cancer.

9. The method of claim 8 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.

10. The method of claim 9 wherein the cancer is breast cancer.

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

12. The method of claim 11 wherein the breast cancer overexpresses ErbB2 at a 3+ level.

13. The method of claim 12 wherein the breast cancer is a metastatic breast cancer.

26. The method of claim 2 wherein the conjugate comprises about 3 to 4 maytansinoid molecules per antibody molecule.

27. The method of claim 2 wherein the thioether linking group is succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).