Antibody drug conjugates

Patent metadata

Field	Value
Publication number	US-9415118-B2
Application number	US-201414204023-A
Country	US
Kind code	B2
Filing date	Mar 11, 2014
Priority date	Mar 13, 2013
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

The present invention relates to anti-FGFR2 antibodies, antibody fragments, antibody drug conjugates, and their uses for the treatment of cancer.

First claim

We claim:

1. An antibody drug conjugate of the formula

or a pharmaceutically acceptable salt thereof; wherein
Ab is an antibody or antigen binding fragment thereof that specifically binds to human FGFR2; wherein the antibody comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 21, (b) a VH CDR2 of SEQ ID NO: 22, (c) a VH CDR3 of SEQ ID NO: 23; 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, (f) a VL CDR3 of SEQ ID NO: 33, wherein the CDR is defined in accordance with the Kabat definition; 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 antibody or antigen binding fragment thereof specifically binds to all isoforms of human FGFR2.

4. The antibody drug conjugate of claim 3 , wherein said antibody or antigen binding fragment specifically binds to an epitope of human FGFR2 comprising amino acids 174-189 and 198-216 of SEQ ID NO:257.

5. The antibody drug conjugate of claim 1 , wherein said antibody or antigen binding fragment thereof specifically binds to the human FGFR2 IIIb isoform.

6. The antibody drug conjugate of claim 5 , wherein said antibody or antigen binding fragment thereof specifically binds to an epitope of human FGFR2 comprising amino acids 346-354 of SEQ ID NO:257.

7. The antibody drug conjugate of claim 1 , wherein said antibody or antigen binding fragment has enhanced ADCC activity as compared to an antibody consisting of a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 19.

8. The antibody drug conjugate of claim 1 , wherein said antibody is a human antibody.

9. The antibody drug conjugate of claim 1 , wherein said antibody is a monoclonal antibody.

10. 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.

11. The antibody drug conjugate of claim 10 , 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).

12. The antibody drug conjugate of claim 11 , wherein said linker is N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC).

13. The antibody drug conjugate of claim 1 , wherein said drug moiety is selected from a group consisting of a V-ATPase inhibitor, a pro-apoptotic agent, a Bcl2 inhibitor, an MCL1 inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a maytansinoid, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1, a DPPIV inhibitor, proteasome inhibitors, inhibitors of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a kinesin inhibitor, an HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder and a DHFR inhibitor.

14. The antibody drug conjugate of claim 13 , wherein the cytotoxic agent is a maytansinoid.

15. The antibody drug conjugate of claim 14 , 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).

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

17. The pharmaceutical composition of claim 16 wherein said composition is prepared as a lyophilisate.

18. The pharmaceutical composition of claim 17 , wherein said lyophilisate comprises said antibody drug conjugate, -sodium succinate, and polysorbate 20.

19. An antibody or antigen binding fragment thereof that specifically bind to human FGFR2 and comprises a heavy chain variable region that comprises: (a) a VH CDR1 of SEQ ID NO: 21, (b) a VH CDR2 of SEQ ID NO: 22, (c) a VH CDR3 of SEQ ID NO: 23; 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, (f) a VL CDR3 of SEQ ID NO: 33, wherein the CDR is defined in accordance with the Kabat definition.

20. The antibody or antigen binding fragment of claim 19 , wherein said antibody is a human antibody.

21. The antibody or antigen binding fragment of claim 20 , wherein said antibody is a monoclonal antibody.

22. The antibody or antigen binding fragment of claim 19 , wherein said antibody or antigen binding fragment is a single chain antibody (scFv).

23. A diagnostic reagent comprising the antibody or antigen binding fragment thereof of claim 19 which is labeled.

24. The diagnostic reagent of claim 23 , wherein the label is selected from the group consisting of a radiolabel, a fluorophore, a chromophore, an imaging agent, and a metal ion.

Assignees

• Batt Julie Lynn
• Novartis Ag

Inventors

• Batt David Bryant
• Ettenberg Seth Alexander
• Haubst Nicole
• Hu Tiancen
• Jenkins David
• Toksoz Engin
• Petropoulos Konstantin
• Meyer Matthew John

Classifications

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/662

  Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon · CPC title