Antibody-drug conjugates for targeting CD56-positive tumors

Patent metadata

Field	Value
Publication number	US-10548987-B2
Application number	US-201615747620-A
Country	US
Kind code	B2
Filing date	Jul 29, 2016
Priority date	Jul 31, 2015
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

The identification and characterization of two fully human CD56-specific monoclonal antibodies targeting spatially separated epitopes proximal and distal to the plasma membrane is described. Also described are antibody-drug conjugates (ADCs) of the identified antibodies and their use for targeting CD56-expressing tumor cells.

First claim

The invention claimed is:

1. An antibody-drug conjugate (ADC), comprising a drug conjugated to a CD56-specific monoclonal antibody, or an antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a variable heavy (VH) domain and a variable light (VL) domain, and wherein:
the VH domain comprises the complementarity determining region (CDR) sequences of SEQ ID NO: 6 and the VL domain comprises the CDR sequences of SEQ ID NO: 8.

2. The ADC of claim 1 , wherein the CDR sequences are CDR sequences determined by IMGT or by Kabat.

3. The ADC of claim 2 , wherein:
the VH domain comprises amino acid residues 26-33, 51-59 and 97-111 of SEQ ID NO: 6 and the VL domain comprises amino acid residues 27-37, 55-57 and 94-103 of SEQ ID NO: 8.

4. The ADC of claim 2 , wherein:
the VH domain comprises amino acid residues 31-35, 50-66 and 99-110 of SEQ ID NO: 6 and the VL domain comprises amino acid residues 24-39, 55-61 and 94-102 of SEQ ID NO: 8.

5. The ADC of claim 1 , wherein the VH domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 6 and the VL domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 8.

6. The ADC of claim 5 , wherein the VH domain comprises the acid sequence of SEQ ID NO: 6 and the VL domain comprises the amino acid sequence of SEQ ID NO: 8.

7. The ADC of claim 1 , wherein the drug comprises a cytotoxic agent.

8. The ADC of claim 7 , wherein the cytotoxic agent comprises an interstrand crosslinking agent, an anti-mitotic agent or an anti-microtubule agent.

9. The ADC of claim 8 , wherein the interstrand crosslinking agent comprises a pyrrolobenzodiazepine (PBD).

10. The ADC of claim 1 , wherein the antigen-binding fragment is an Fab fragment, an Fab′ fragment, an F(ab)′ 2 fragment, a single chain variable fragment (scFv) or a disulfide stabilized variable fragment (dsFv).

11. The ADC of claim 1 , wherein the monoclonal antibody is an IgG.

12. The ADC of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is a fully human antibody.

13. The ADC of claim 1 , wherein the monoclonal antibody, or antigen-binding fragment thereof, is chimeric or synthetic.

14. A composition comprising the ADC of claim 1 and a pharmaceutically acceptable carrier.

15. A method of treating a subject having a CD56-positive cancer, comprising selecting a subject with a CD56-positive cancer and administering to the subject a therapeutically effective amount of the ADC of claim 1 , wherein the CD56-positive cancer is a neuroblastoma, multiple myeloma, ovarian cancer, acute myeloid leukemia, Wilms tumor or small cell lung cancer.

16. A method of inhibiting tumor growth or metastasis of a CD56-positive cancer in a subject, comprising selecting a subject with a CD56-positive cancer and administering to the subject a therapeutically effective amount of the ADC of claim 1 , wherein the CD56-positive cancer is a neuroblastoma, multiple myeloma, ovarian cancer, acute myeloid leukemia, Wilms tumor or small cell lung cancer.

Assignees

• Us Health
• Childrens Hospital Philadelphia
• Us Health

Inventors

• Dimitrov Dimiter S
• Feng Yang
• Maris John M
• Zhu Zhongyu
• Sussman Robyn Tovah

Classifications

• C07K2317/77

  Internalization into the cell · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title