Antigen-binding proteins targeting CD56 and uses thereof

Patent metadata

Field	Value
Publication number	US-10730941-B2
Application number	US-201815884608-A
Country	US
Kind code	B2
Filing date	Jan 31, 2018
Priority date	Jul 31, 2015
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

The presently disclosed subject matter provides for methods and compositions for treating cancer (e.g., multiple myeloma). It relates to anti-CD56 antibodies, chimeric antigen receptors (CARs) that specifically target human CD56, and immunoresponsive cells comprising such CARs. The presently disclosed CD56-specific CARs have enhanced immune-activating properties, including anti-tumor activity.

First claim

What is claimed is:

1. A chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain that binds to human CD56, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain comprises a heavy chain variable region and a light chain variable region, wherein:
(a) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3; and the light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;
(b) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;
(c) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11; and the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 15;
(d) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11; and the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16;
(e) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11; and the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 17; or
(f) the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11; and the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 13, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 18.

2. The CAR of claim 1 , wherein the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3; and the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6.

3. The CAR of claim 1 , wherein the heavy chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; and the light chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6.

4. The CAR of claim 1 , wherein:
(i) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:7; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:8;
(ii) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 19; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 20;
(iii) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 21; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 22;
(iv) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 23; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 24; or
(v) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 25; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 26.

5. The CAR of claim 1 , wherein the extracellular antigen-binding domain comprises a single-chain variable fragment (scFv), a Fab that is optionally crosslinked, or a F(ab) 2 .

6. The CAR of claim 1 , wherein the extracellular antigen-binding domain comprises a human scFv.

7. The CAR of claim 5 , wherein one or more of the scFV, Fab and F(ab) 2 are comprised in a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain.

8. The CAR of claim 1 , wherein the extracellular antigen-binding domain comprises a linker between the heavy chain variable region and the light chain variable region.

9. The CAR of claim 1 , the transmembrane domain comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, or a combination thereof.

10. The CAR of claim 9 , wherein the transmembrane domain comprises a CD28 polypeptide.

11. The CAR of claim 1 , wherein the intracellular domain comprises a CD3ζ polypeptide.

12. The CAR of claim 1 , wherein the intracellular domain further comprises at least one co-stimulatory signaling region.

13. The CAR of claim 12 , wherein the at least one co-stimulatory signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, or a combination thereof.

14. The CAR of claim 13 , wherein the at least one co-stimulatory signaling region comprises a CD28 polypeptide.

15. The CAR of claim 1 , wherein the transmembrane domain comprises a CD28 polypeptide, and the intracellular domain comprises a CD3ζ polypeptide and a co-stimulatory signaling domain comprising a CD28 polypeptide.

16. The CAR of claim 1 , wherein the CAR is recombinantly expressed or expressed from a vector.

17. An immunoresponsive cell comprising the CAR of claim 1 .

18. The immunoresponsive cell of claim 17 , wherein the CAR is constitutively expressed on the surface of the imm

Assignees

• Memorial Sloan Kettering Cancer Center
• Us Health

Inventors

• Sadelain Michel
• Benjamin Reuben
• Dimitrov Dimiter S
• Feng Yang

Classifications

• A61K40/4276

  Prostate specific membrane antigen [PSMA] · CPC title

• A61K40/4261

  Proteoglycans, e.g. glypican, brevican or CSPG4 · CPC title

• A61K40/4254

  Adhesion molecules, e.g. NRCAM, EpCAM or cadherins · CPC title

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/418

  Antigens related to induction of tolerance to non-self · CPC title