T cell receptor-like antibodies specific for a PRAME peptide

Patent metadata

Field	Value
Publication number	US-11384144-B2
Application number	US-201715817673-A
Country	US
Kind code	B2
Filing date	Nov 20, 2017
Priority date	May 22, 2015
Publication date	Jul 12, 2022
Grant date	Jul 12, 2022

Abstract

The presently disclosed subject matter provides antigen-binding proteins that specifically bind to Preferentially expressed antigen of melanoma (PRAME), including humanized, chimeric and fully human antibodies against PRAME, antibody fragments (e.g., scFv, Fab and F(ab)2), chimeric antigen receptors (CARs), fusion proteins, and conjugates thereof. The antigen-binding proteins and antibodies bind to a PRAME peptide/HLA class I molecule complex. Such antibodies, fragments, fusion proteins and conjugates thereof are useful for the treatment of PRAME associated diseases, including for example, breast cancer, ovarian cancer, melanoma, lung cancer, gastrointestinal cancer, brain tumor, head and neck cancer, renal cancer, myeloma, neuroblastoma, mantle cell lymphoma, chronic myelocytic leukemia, multiple myeloma, acute lymphoblastic leukemia (ALL), acute myeloid/myelogenous leukemia (AML), Non-Hodgkin lymphoma (NHL), and Chronic lymphocytic leukemia (CLL). The antibodies or antigen binding proteins may comprise one or more framework region amino acid substitutions designed to improve protein stability, antibody binding and/or expression levels.

First claim

What is claimed is:

1. A monoclonal antibody or an antigen-binding portion thereof, which binds to a PRAME peptide bound to a major histocompatibility complex (MHC) molecule, wherein the antibody or antigen-binding portion thereof each comprises: a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 7, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 8, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 9; and a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 10, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 11, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12.

2. The antibody or antigen-binding portion thereof of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 49; and/or the light chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 50.

3. The antibody or antigen-binding portion thereof of claim 2 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 49; or the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 50.

4. The antibody or antigen-binding portion thereof of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 49, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 50.

5. The antibody or antigen-binding portion thereof of claim 1 , wherein the antigen-binding portion is a Fab, a Fab′, a F(ab′) 2 , a variable fragment (Fv), or a single chain variable fragment (scFv).

6. An immunoconjugate comprising the antibody or antigen-binding portion thereof of claim 1 , linked to a therapeutic agent.

7. A bispecific molecule comprising the antibody or antigen-binding portion thereof of claim 1 , linked to a second functional moiety.

8. A composition comprising the antibody or antigen-binding portion thereof of claim 1 and a pharmaceutically acceptable carrier.

9. A composition comprising the immunoconjugate of claim 6 and a pharmaceutically acceptable carrier.

10. A composition comprising the bispecific molecule of claim 7 and a pharmaceutically acceptable carrier.

11. A monoclonal antibody or an antigen-binding portion thereof, which binds to a PRAME peptide bound to a major histocompatibility complex (MHC) molecule, wherein the antibody or antigen-binding portion thereof each comprises: (a) a heavy chain variable region comprising 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: 15; and (b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 16, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 18.

12. The antibody or antigen-binding portion thereof of claim 11 , wherein the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 51; and/or the light chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 52.

13. The antibody or antigen-binding portion thereof of claim 11 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 51, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 52.

14. The antibody or antigen-binding portion thereof of claim 11 , wherein the antigen-binding portion is a Fab, a Fab′, a F(ab′) 2 , a variable fragment (Fv), or a single chain variable fragment (scFv).

15. An immunoconjugate comprising the antibody or antigen-binding portion thereof of claim 11 , linked to a therapeutic agent.

16. A bispecific molecule comprising the antibody or antigen-binding portion thereof of claim 11 , linked to a second functional moiety.

17. A monoclonal antibody or an antigen-binding portion thereof, which binds to a PRAME peptide bound to a major histocompatibility complex (MHC) molecule, wherein the antibody or antigen-binding portion thereof each comprises: (a) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 19, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 20, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 21; and (b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24.

18. The antibody or antigen-binding portion thereof of claim 17 , wherein the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 53; and/or the light chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 54.

19. The antibody or antigen-binding portion thereof of claim 17 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 53, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 54.

20. The antibody or antigen-binding portion thereof of claim 17 , wherein the antigen-binding portion is a Fab, a Fab′, a F(ab′) 2 , a variable fragment (Fv), or a single chain variable fragment (scFv).

21. An immunoconjugate comprising the antibody or antigen-binding portion thereof of claim 17 , linked to a therapeutic agent.

22. A bispecific molecule comprising the antibody or antigen-binding portion thereof of claim 17 , linked to a second functional moiety.

23. A monoclonal antibody or an antigen-binding portion thereof, which binds to a PRAME peptide bound to a major histocompatibility complex (MHC) molecule, wherein the antibody or antigen-binding portion thereof each comprises: (a) a heavy chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; and (b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30.

24. The antibody or antigen-binding portion thereof of claim 23 , wherein the heavy chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 55; and/or the light chain variable region comprises an amino acid sequence that is at least 80% homologous to or identical to the amino acid sequence set forth in SEQ ID NO: 56.

25. The antibody

Assignees

• Memorial Sloan Kettering Cancer Center
• Eureka Therapeutics Inc

Inventors

• Scheinberg David A
• Dao Tao
• Liu Cheng
• Liu Hong
• Xu Yiyang
• Yan Su

Classifications

• G01N33/5759

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

• C07K16/2809 Primary

  against the T-cell receptor (TcR)-CD3 complex · CPC title

• A61K2039/5156

  expressing foreign proteins · CPC title

• A61K2039/5158

  Antigen-pulsed cells, e.g. T-cells · CPC title

• A61K39/0011

  Cancer antigens · CPC title