Antibody drug conjugates

Patent metadata

Field	Value
Publication number	US-10117953-B2
Application number	US-201615284444-A
Country	US
Kind code	B2
Filing date	Oct 3, 2016
Priority date	Mar 15, 2013
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

The present invention relates to anti-cKIT antibodies, antibody fragments, antibody drug conjugates, and their uses for the treatment of cancer.

First claim

What is claimed is:

1. An antibody drug conjugate of the formula
Ab—(L—(D) m ) n

or a pharmaceutically acceptable salt thereof; wherein
Ab is an antibody or antigen binding fragment thereof that comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 22, (b) a VH CDR2 of SEQ ID NO: 23, (c) a VH CDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 31, (e) a VL CDR2 of SEQ ID NO: 32, and (f) a VL CDR3 of SEQ ID NO: 33 and specifically binds to an epitope of human cKIT at domains 1-3 (SEQ ID NO:155);
L is a linker;
D is a drug moiety;
m is an integer from 1 to 8; and
n is an integer from 1 to 10.

2. The antibody drug conjugate of claim 1 , wherein said n is 3 or 4.

3. The antibody drug conjugate of claim 1 , wherein said linker is selected from the group consisting of a cleavable linker, a non-cleavable linker, a hydrophilic linker, a procharged linker and a dicarboxylic acid based linker.

4. The antibody drug conjugate of claim 3 , wherein the linker is derived from a cross-linking reagent selected from the group consisting of N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl(4-iodoacetyl)aminobenzoate (SIAB), maleimide PEG NHS, N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC), N-sulfosuccinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (sulfo-SMCC) or 2,5-dioxopyrrolidin-1-yl 17-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-1-oate (CX1-1).

5. The antibody drug conjugate of claim 4 , wherein said linker is derived from the cross-linking reagent N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC).

6. The antibody drug conjugate of claim 1 , wherein the drug moiety is a maytansinoid.

7. The antibody drug conjugate of claim 6 , wherein the maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).

8. An antibody drug conjugate of the formula

or a pharmaceutically acceptable salt thereof; wherein
Ab is an antibody or antigen binding fragment thereof that comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 22, (b) a VH CDR2 of SEQ ID NO: 23, (c) a VH CDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a VL CDR1 of SEQ ID NO: 31, (e) a VL CDR2 of SEQ ID NO: 32, and (f) a VL CDR3 of SEQ ID NO: 33 and specifically binds to human cKIT, and comprises at least n number of primary amines; and n is an integer from 1 to 10.

9. The antibody drug conjugate of claim 8 , wherein said n is 3 or 4.

10. The antibody drug conjugate of claim 1 or claim 8 , wherein said antibody is a humanized antibody.

11. The antibody drug conjugate of claim 1 or claim 8 , wherein said antibody is a monoclonal antibody.

12. A pharmaceutical composition comprising the antibody drug conjugate of claim 1 or claim 8 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 wherein said composition is prepared as a lyophilisate.

14. The pharmaceutical composition of claim 13 , wherein said lyophilisate comprises the antibody drug conjugate of claim 1 , sodium succinate, and polysorbate 20.

15. The antibody drug conjugate of claim 1 or 8 , wherein said antibody or antigen binding fragment thereof comprises a heavy chain variable region (vH) that comprises SEQ ID NO: 28, and a light chain variable region (vL) that comprises SEQ ID NO:37.

Assignees

• Novartis Ag

Inventors

• Abrams Tinya
• Cohen Steven Bruce
• Fanton Christie P
• Huber Thomas
• Miller Kathy
• Schleyer Siew Ho
• Tissot-Daguette Kathrin Ulrike
• Finner Catrin

Classifications

• G01N33/532

  Production of labelled immunochemicals · CPC title

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title

• G01N33/575

  for cancer · CPC title

• A61K47/6889

  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 title

• C07K2317/14

  Specific host cells or culture conditions, e.g. components, pH or temperature · CPC title