METHODS OF TREATMENT USING ANTI-ERBB ANTIBODY-MAYTANSINOID CONJUGATES

• US 20080226659A1
• Filed: 12/03/2007
• Published: 09/18/2008
• Est. Priority Date: 03/16/2000
• Status: Active Grant

• Current Assignee: ImmunoGen Incorporated
• Original Assignee: ImmunoGen Incorporated
• Inventors: Sliwkowski, Mark, Erickson, Sharon, Schwall, Ralph, Blattler, Walter
• Granted Patent: US 8,337,856 B2
• Time in Patent Office: Days
• US Class Current: 424/181.1
• 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 anri-ErbB receptor antibody-maytansinoid conjugates.

Claims

1. A composition of matter comprising an anti-ErbB2 antibody covalently linked to a maytansinoid by a covalent linker linked to a lysine residue of said anti-ErbB2 antibody, wherein said maytansinoid is selected from the group consisting of maytansine, maytansinol and a maytansinol ester, and wherein said anti-ErbB2 antibody lysine residue is selected from the group of anti-ErbB2 antibody lysine residues consisting of lysine 13 in the light chain, lysine 32 in the heavy chain, lysine 26 in both Fab fragments and lysine 38 in the Fc fragment.

2. The composition of matter of claim 1, wherein the maytansinoid is a C-3 ester of maytansinol.

3. The composition of matter of claim 1, wherein the maytansinoid is DM1 having the structure

4. The composition of matter of claim 1, wherein said covalent linker comprises a linking group selected from the group consisting of a disulfide group, a thioether group, an acid labile group, a photolabile group, a peptidase labile group, and an esterase labile group.

5. The composition of matter of claim 4, wherein said linking group is selected from the group consisting of a disulfide group and a thioether group.

6. The composition of matter of claim 4, wherein said linking group comprises a disulfide group.

7. The composition of matter of claim 1 wherein said conjugate comprises 1 to about 10 maytansinoid molecules per antibody molecule.

8. The composition of matter of claim 7, wherein the conjugate comprises from about 3 to about 5 maytansinoid molecules per antibody molecule.

9. The composition of matter of claim 1, wherein said covalent linker is a bispecific chemical linker.

10. The composition of matter of claim 1, wherein said covalent linker is selected from the group of linkers consisting of N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), N-succinimidyl-4-(2-pyridylthio)pentanoate (SPP), iminothiolane (IT), dimethyl adipimidate HCL), disuccinimidyl suberate, glutaraldehyde, bis (p-azidobenzoyl)hexanediamine, bis-(p-diazoniumbenzoyl)-ethylenediamine, toluene 2,6-diisocyanate, and 1,5-difluoro-2,4-dinitrobenzene.

11. The composition of matter of claim 9, wherein said covalent linker is selected from the group consisting of SPDP, SMCC, and SPP.

12. The composition of matter of claim 1, wherein the antibody is humanized.

13. The composition of matter of claim 12, wherein said anti-ErbB2 antibody is the humanized monoclonal antibody 4D5 (ATCC CRL 10463).

14. The composition of matter of claim 12, wherein said humanized anti-ErbB2 antibody is selected from the group of humanized antibodies consisting of huMAb4D5-1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8 (HERCEPTIN®

).

15. The composition of matter of claim 12, wherein said humanized anti-ErbB2 antibody is huMAb4D5-8 (HERCEPTIN®

).

16. The composition of matter of claim 1, wherein the anti-ErbB2 antibody is a growth inhibitory antibody effective to inhibit the growth of SK-BR-3 breast tumor cells in vitro.

17. The composition of matter of claim 1, wherein the antibody has a biological characteristic of a 4D5 monoclonal antibody (ATCC CRL 10463) such that the antibody shows a growth inhibitory effect on SK-BR-3 cells in a manner that is dependent on the ErbB2 expression level and/or blocks binding of monoclonal antibody 4D5 to ErbB2.

18. The composition of matter of claim 1, wherein the antibody binds essentially the same epitope as a 4D5 monoclonal antibody (ATCC CRL 10463).

19. The composition of matter of claim 1, wherein the antibody is an antigen binding fragment of said antibody.

20. The composition of matter of claim 19, wherein the antigen binding fragment is selected from the group consisting of a Fab, Fab′

, F(ab′

)₂, F_v fragment, diabody, linear antibody, and single-chain antibody molecule.