IP Library › Granted Patent US 11,384,144
Granted Patent B2
US 11,384,144 · App. 15/817,673 · Granted Jul 12, 2022

T cell receptor-like antibodies specific for a PRAME peptide

Inventors: David A. Scheinberg (New York, NY); Tao Dao (New York, NY); Cheng Liu (Emeryville, CA); Hong Liu (El Sobrante, CA); Yiyang Xu (Pleasanton, CA); Su Yan (State College, PA)
Assignees: MEMORIAL SLOAN-KETTERING CANCER CENTER; EUREKA THERAPEUTICS, INC.
C07K16/28A61K47/6849C07K16/2809C07K16/2833C07K16/30C07K16/3053G01N33/57492A61K39/0011A61K2039/505A61K2039/5156A61K2039/5158C07K14/00C07K2317/21C07K2317/31C07K2317/32C07K2317/34C07K2317/41C07K2317/56C07K2317/565C07K2317/622C07K2317/732C07K2319/03C07K2319/33C07K2319/74G01N2333/705
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Quick Facts
Patent No.
US 11,384,144
App. No.
15/817,673
Granted
Jul 12, 2022
Kind
B2
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.

Claims (46)

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 or antigen-binding portion thereof of claim 23 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 55, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 56.

26. The antibody or antigen-binding portion thereof of claim 23 , 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).

27. An immunoconjugate comprising the antibody or antigen-binding portion thereof of claim 23 , linked to a therapeutic agent.

28. A bispecific molecule comprising the antibody or antigen-binding portion thereof of claim 23 , linked to a second functional moiety.

29. 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: 31, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 33; and (b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36.

30. The antibody or antigen-binding portion thereof of claim 29 , 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: 57; 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: 58.

31. The antibody or antigen-binding portion thereof of claim 29 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 57, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 58.

32. The antibody or antigen-binding portion thereof of claim 29 , 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).

33. An immunoconjugate comprising the antibody or antigen-binding portion thereof of claim 29 , linked to a therapeutic agent.

34. A bispecific molecule comprising the antibody or antigen-binding portion thereof of claim 29 , linked to a second functional moiety.

35. 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: 37, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39; and (b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 42.

36. The antibody or antigen-binding portion thereof of claim 35 , 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: 59; and/or 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: 60.

37. The antibody or antigen-binding portion thereof of claim 35 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 59, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 60.

38. The antibody or antigen-binding portion thereof of claim 35 , 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).

39. An immunoconjugate comprising the antibody or antigen-binding portion thereof of claim 35 , linked to a therapeutic agent.

40. A bispecific molecule comprising the antibody or antigen-binding portion thereof of claim 35 , linked to a second functional moiety.

41. 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: 43, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 44, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; and (b) a light chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48.

42. The antibody or antigen-binding portion thereof of claim 41 , 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: 61; 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: 62.

43. The antibody or antigen-binding portion thereof of claim 41 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 61, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 62.

44. The antibody or antigen-binding portion thereof of claim 41 , 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).

45. An immunoconjugate comprising the antibody or antigen-binding portion thereof of claim 41 , linked to a therapeutic agent.

46. A bispecific molecule comprising the antibody or antigen-binding portion thereof of claim 41 , linked to a second functional moiety.

Assignments (2)
MERGER Recorded Mar 30, 2018
From: EUREKA THERAPEUTICS, INC
To: EUREKA THERAPEUTICS, INC.
Reel/Frame 045398/0048 →
CONFIRMATORY LICENSE Recorded Mar 14, 2018
From: SLOAN-KETTERING INST CAN RESEARCH
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 045583/0846 →
Continuity (3)
Continuation PCTUS2016033430 · May 20, 2016
Provisional Application 62165603 · May 22, 2015
Related Publication 20180148503A1 · May 31, 2018
Cited By (1)
US 12,570,760