Granted Patent B2

US 12,454,574 · App. 17/309,144 · Granted Oct 28, 2025

Inventors: Fuliang Chu (Houston, TX); Sattva S. Neelapu (Houston, TX); JingJing Cao (Houston, TX); Jingwei Liu (Houston, TX)

Assignee: BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM

C07K16/2803A61K40/11A61K40/31A61K40/421A61K40/4211A61K45/06A61P35/00C07K14/485C07K14/70503A61K38/00A61K2239/31A61K2239/38A61K2239/48

Abstract

Claims (153)

1. An isolated monoclonal antibody, wherein the antibody specifically binds to CD79b and comprises:

(I):

(a) a first VH CDR is identical to SEQ ID NO: 3;

(b) a second VH CDR is identical to SEQ ID NO: 4;

(c) a third VH CDR is identical to SEQ ID NO: 5;

(d) a first VL CDR is identical to SEQ ID NO: 8;

(e) a second VL CDR is identical to SEQ ID NO: 9; and

(f) a third VL CDR is identical to SEQ ID NO: 10;

(II):

(a) a first VH CDR is identical to SEQ ID NO: 13;

(b) a second VH CDR is identical to SEQ ID NO: 14;

(c) a third VH CDR is identical to SEQ ID NO: 15;

(d) a first VL CDR is identical to SEQ ID NO: 18;

(e) a second VL CDR is identical to SEQ ID NO: 19; and

(f) a third VL CDR is identical to SEQ ID NO: 20; or

(III):

(a) a first VH CDR is identical to SEQ ID NO: 23;

(b) a second VH CDR is identical to SEQ ID NO: 24;

(c) a third VH CDR is identical to SEQ ID NO: 25;

(d) a first VL CDR is identical to SEQ ID NO: 28;

(e) a second VL CDR is identical to SEQ ID NO: 29; and

(f) a third VL CDR is identical to SEQ ID NO: 30.

2. The antibody of claim 1 , wherein the antibody comprises:

(a) a first V H CDR is identical to SEQ ID NO: 3;

(b) a second V H CDR is identical to SEQ ID NO: 4;

(c) a third V H CDR is identical to SEQ ID NO: 5;

(d) a first V L CDR is identical to SEQ ID NO: 8;

(e) a second V L CDR is identical to SEQ ID NO: 9; and

(f) a third V L CDR is identical to SEQ ID NO: 10.

3. The antibody of claim 2 , wherein the antibody comprises a V H domain at least about 80% identical to the V H domain of SEQ ID NO: 2 and a V L domain at least about 80% identical to the V L domain of SEQ ID NO: 7, or wherein the antibody comprises a V H domain identical to the V H domain of SEQ ID NO: 2 and a V L domain identical to the V L domain of SEQ ID NO: 7.

4. The antibody of claim 1 , wherein the antibody comprises:

(a) a first V H CDR is identical to SEQ ID NO: 13;

(b) a second VH CDR is identical to SEQ ID NO: 14;

(c) a third VH CDR is identical to SEQ ID NO: 15;

(d) a first VL CDR is identical to SEQ ID NO: 18;

(e) a second VL CDR is identical to SEQ ID NO: 19; and

(f) a third VL CDR is identical to SEQ ID NO: 20.

5. The antibody of claim 4 , wherein the antibody comprises a V H domain at least about 80% identical to the V H domain of SEQ ID NO: 12 and a V L domain at least about 80% identical to the V L domain of SEQ ID NO: 17, or wherein the antibody comprises a V H domain identical to the V H domain of SEQ ID NO: 12 and a V L domain identical to the V L domain SEQ ID NO: 17.

6. The antibody of claim 1 , wherein the antibody comprises:

(a) a first V H CDR is identical to SEQ ID NO: 23;

(b) a second V H CDR is identical to SEQ ID NO: 24;

(c) a third V H CDR is identical to SEQ ID NO: 25;

(d) a first V L CDR is identical to SEQ ID NO: 28;

(e) a second V L CDR is identical to SEQ ID NO: 29; and

(f) a third V L CDR is identical to SEQ ID NO: 30.

7. The antibody of claim 6 , wherein the antibody comprises a V H domain at least about 80% identical to the V H domain of SEQ ID NO: 22 and a V L domain at least about 80% identical to the V L domain of SEQ ID NO: 27, or wherein the antibody comprises a V H domain identical to the V H domain of SEQ ID NO: 22 and a V L domain identical to the V L domain SEQ ID NO: 27.

8. The antibody of claim 1 , wherein

(a) the antibody is recombinant;

(b) the antibody is an IgG, IgM, IgA or an antigen binding fragment thereof;

(c) the antibody is a Fab′, a F(ab′)2, a F(ab′)3, a monovalent scFv, or a bivalent scFv;

(d) the antibody is a humanized antibody or de-immunized antibody; or

(e) the antibody is conjugated to an imaging agent, a chemotherapeutic agent, a toxin or a radionuclide.

9. A composition comprising an antibody of claim 1 in a pharmaceutically acceptable carrier.

10. A recombinant polypeptide comprising:

(a) an antibody V H domain comprising CDRs 1-3 of the V H domain of Clone 14 (SEQ ID NOs: 3, 4, and 5) and CDRs 1-3 of the V H domain of Clone 14 (SEQ ID NOS: 8, 9, and 10);

(b) an antibody V H domain comprising CDRs 1-3 of the V H domain of Clone 16a (SEQ ID NOs: 13, 14, and 15) and CDRs 1-3 of the V H domain of Clone 16a (SEQ ID NOs: 18, 19, and 20); or

(c) an antibody V H domain comprising CDRs 1-3 of the V H domain of Clone 45 (SEQ ID NOs: 23, 24, and 25) and CDRs 1-3 of the V H domain of Clone 45 (SEQ ID NOs: 28, 29, and 30).

11. A host cell comprising one or more polynucleotide molecule(s) encoding an antibody of claim 1 or a recombinant polypeptide of claim 10 .

12. A method for treating a subject having a cancer associated with B cells comprising administering an effective amount of an antibody of claim 1 to the subject.

13. The method of claim 12 , wherein the cancer is B cell malignancy.

14. An engineered CD79b-targeted chimeric antigen receptor (CAR) comprising CD3ζ, CD28, 4-1BB, and/or OX40 signaling domains, wherein the antigen-binding domain comprises an antibody of claim 1 or a fragment thereof.

15. The CAR of claim 14 , wherein the antigen-binding domain comprises:

(I):

(a) a first VH CDR is identical to SEQ ID NO: 3;

(b) a second VH CDR is identical to SEQ ID NO: 4;

(c) a third VH CDR is identical to SEQ ID NO: 5;

(d) a first VL CDR is identical to SEQ ID NO: 8;

(e) a second VL CDR is identical to SEQ ID NO: 9; and

(f) a third VL CDR is identical to SEQ ID NO: 10;

(II):

(a) a first VH CDR is identical to SEQ ID NO: 13;

(b) a second VH CDR is identical to SEQ ID NO: 14;

(c) a third VH CDR is identical to SEQ ID NO: 15;

(d) a first VL CDR is identical to SEQ ID NO: 18;

(e) a second VL CDR is identical to SEQ ID NO: 19; and

(f) a third VL CDR is identical to SEQ ID NO: 20; or

(III):

(a) a first VH CDR is identical to SEQ ID NO: 23;

(b) a second VH CDR is identical to SEQ ID NO: 24;

(c) a third VH CDR is identical to SEQ ID NO: 25;

(d) a first VL CDR is identical to SEQ ID NO: 28;

(e) a second VL CDR is identical to SEQ ID NO: 29; and

(f) a third V L CDR is identical to SEQ ID NO: 30.

16. The CAR of claim 14 , wherein the antigen-binding domain comprises an scFV having at least 90% identity to the amino acid sequence of SEQ ID NOs: 31, 32, or 33 or wherein the antigen-binding domain comprises an scFV having an amino acid sequence of SEQ ID NOs: 31, 32, or 33.

17. The CAR of claim 14 , wherein the antigen-binding domain comprises a V H domain linked to a V L domain by a linker.

18. The CAR of claim 17 , wherein the linker is Linker 1 (SEQ ID NOs: 44 or 45), Linker 2 (SEQ ID NOs: 46 or 47), Linker 3 (SEQ ID NOs: 48 or 49), or Linker 4 (SEQ ID NOs: 50 or 51) or wherein the CAR comprises V L -Linker1-V H , V L -Linker2-V H , V L -Linker3-V H , V L -Linker4-V H , V H -Linker1-V L , V H -Linker2-V L , V H -Linker3-V L , or V H -Linker4-V L .

19. The CAR of claim 14 , wherein the CAR comprises a hinge, wherein the hinge is CD8 Hinge 1 (SEQ ID NOs: 52 or 53), CD8 Hinge 2 (SEQ ID NOs: 54 or 55), CD8 Hinge 3 (SEQ ID NOs: 56 or 57), CD28 Hinge (SEQ ID NOs: 58 or 59), IgG4 Hinge (SEQ ID NOs: 60 or 61), IgG4 CH2 (SEQ ID NOs: 62 or 63), IgG4 CH2CH3 (SEQ ID NOs: 64 or 65), or IgG4 CH1CH2CH3 (SEQ ID NOs: 66 or 67).

20. The CAR of claim 14 , wherein the CAR comprises a transmembrane domain, wherein the transmembrane domain is CD8 TM1 (SEQ ID NOs: 68 or 69), CD8 TM2 (SEQ ID NOs: 70 or 71), or CD28 TM (SEQ ID NOs: 72 or 73).

21. The CAR of claim 14 , wherein the CAR comprises a sequence having at least 90% identity to the amino acid sequence of SEQ ID NOs: 34, 35, 36, 37, 38, 39, 86, 87, or 88 or wherein the CAR comprises a sequence having an amino acid sequence of SEQ ID NOs: 34, 35, 36, 37, 38, 39, 86, 87, or 88.

22. The CAR of claim 14 , wherein the CAR further comprises a second antigen binding domain.

23. The CAR of claim 22 , wherein the second antigen binding domain is a CD19, CD20, or CD22 antigen binding domain.

24. An engineered CD79b CAR or TCR having an antigen binding domain comprising:

(I):

(a) a first VH CDR is identical to SEQ ID NO: 3;

(b) a second VH CDR is identical to SEQ ID NO: 4;

(c) a third VH CDR is identical to SEQ ID NO: 5;

(d) a first VL CDR is identical to SEQ ID NO: 8;

(e) a second VL CDR is identical to SEQ ID NO: 9; and

(f) a third V L CDR is identical to SEQ ID NO: 10;

(II):

(a) a first VH CDR is identical to SEQ ID NO: 13;

(b) a second VH CDR is identical to SEQ ID NO: 14;

(c) a third VH CDR is identical to SEQ ID NO: 15;

(d) a first VL CDR is identical to SEQ ID NO: 18;

(e) a second VL CDR is identical to SEQ ID NO: 19; and

(f) a third VL CDR is identical to SEQ ID NO: 20; or

(III):

(a) a first VH CDR is identical to SEQ ID NO: 23;

(b) a second VH CDR is identical to SEQ ID NO: 24;

(c) a third VH CDR is identical to SEQ ID NO: 25;

(d) a first VL CDR is identical to SEQ ID NO: 28;

(e) a second VL CDR is identical to SEQ ID NO: 29; and

(f) a third V L CDR is identical to SEQ ID NO: 30.

25. The CAR of claim 24 , wherein the antigen-binding domain comprises:

(a) a first VH CDR is identical to SEQ ID NO: 3;

(b) a second VH CDR is identical to SEQ ID NO: 4;

(c) a third VH CDR is identical to SEQ ID NO: 5;

(d) a first VL CDR is identical to SEQ ID NO: 8;

(e) a second V L CDR is identical to SEQ ID NO: 9; and

(f) a third V L CDR is identical to SEQ ID NO: 10.

26. The CAR or TCR of claim 25 , wherein the antigen-binding domain comprises a V H domain at least about 80% identical to the V H domain of SEQ ID NO: 2 and a V L domain at least about 80% identical to the V L domain of SEQ ID NO: 7, or wherein the antigen-binding domain comprises a V H domain identical to the V H domain of SEQ ID NO: 2 and a V L domain identical to the V L domain of SEQ ID NO: 7.

27. The CAR or TCR of claim 24 , wherein the antibody comprises:

(a) a first VH CDR is identical to SEQ ID NO: 13;

(b) a second VH CDR is identical to SEQ ID NO: 14;

(c) a third VH CDR is identical to SEQ ID NO: 15;

(d) a first VL CDR is identical to SEQ ID NO: 18;

(e) a second VL CDR is identical to SEQ ID NO: 19; and

(f) a third VL CDR is identical to SEQ ID NO: 20.

28. The CAR or TCR of claim 27 , wherein the antigen-binding domain comprises a V H domain at least about 80% identical to the V H domain of SEQ ID NO: 12 and a V L domain at least about 80% identical to the V L domain of SEQ ID NO: 17, or wherein the antigen-binding domain comprises a V H domain identical to the V H domain of SEQ ID NO: 12 and a V L domain identical to the V L domain SEQ ID NO: 17.

29. The CAR or TCR of claim 24 , wherein the antigen-binding domain comprises:

(a) a first V H CDR is identical to SEQ ID NO: 23;

(b) a second V H CDR is identical to SEQ ID NO: 24;

(c) a third V H CDR is identical to SEQ ID NO: 25;

(d) a first V L CDR is identical to SEQ ID NO: 28;

(e) a second V L CDR is identical to SEQ ID NO: 29; and

(f) a third V L CDR is identical to SEQ ID NO: 30.

30. The CAR or TCR of claim 29 , wherein the antigen-binding domain comprises a V H domain at least about 80% identical to the V H domain of SEQ ID NO: 22 and a V L domain at least about 80% identical to the V L domain of SEQ ID NO: 27, or wherein the antigen-binding domain comprises a V H domain identical to the V H domain of SEQ ID NO: 22 and a V L domain identical to the V L domain SEQ ID NO: 27.

31. The CAR or TCR of claim 24 , wherein the antigen-binding domain comprises an scFV having at least 90% identity to the amino acid sequence of SEQ ID NOs: 31, 32, or 33, or wherein the antigen-binding domain comprises an scFV having an amino acid sequence of SEQ ID NOs: 31, 32, or 33.

32. The CAR or TCR of claim 24 , wherein the antigen-binding domain comprises a V H domain linked to a V L domain by a linker.

33. The CAR or TCR of claim 32 , wherein the linker is Linker 1 (SEQ ID NOs: 44 or 45), Linker 2 (SEQ ID NOs: 46 or 47), Linker 3 (SEQ ID NOs: 48 or 49), or Linker 4 (SEQ ID NOs: 50 or 51), or wherein the CAR comprises V L -Linker1-V H , V L -Linker2-V H , V L -Linker3-V H , V L -Linker4-V H , V H -Linker1-V L , V H -Linker2-V L , V H -Linker3-V L , or V H -Linker4-V L .

34. The CAR or TCR of claim 24 , wherein the CAR or TCR comprises a hinge, wherein the hinge is CD8 Hinge 1 (SEQ ID NOs: 52 or 53), CD8 Hinge 2 (SEQ ID NOs: 54 or 55), CD8 Hinge 3 (SEQ ID NOs: 56 or 57), CD28 Hinge (SEQ ID NOs: 58 or 59), IgG4 Hinge (SEQ ID NOs: 60 or 61), IgG4 CH2 (SEQ ID NOs: 62 or 63), IgG4 CH2CH3 (SEQ ID NOs: 64 or 65), or IgG4 CH1CH2CH3 (SEQ ID NOs: 66 or 67).

35. The CAR or TCR of claim 24 , wherein the CAR comprises a transmembrane domain, wherein the transmembrane domain is CD8 TM1 (SEQ ID NOs: 68 or 69), CD8 TM2 (SEQ ID NOs: 70 or 71), or CD28 TM (SEQ ID NOs: 72 or 73).

36. The CAR or TCR of claim 24 , wherein the CAR comprises a sequence having at least 90% identity to the amino acid sequence of SEQ ID NOs: 34, 35, 36, 37, 38, 39, 86, 87, or 88,or wherein the CAR comprises a sequence having an amino acid sequence of SEQ ID NOs: 34, 35, 36, 37, 38, 39, 86, 87, or 88.

37. An expression vector encoding the CAR or TCR of claim 14 .

38. A host cell engineered to express a CD79b CAR or a CD79b TCR of claim 24 , wherein the host cell is an immune cell.

39. A pharmaceutical composition comprising the host cell of claim 38 and a pharmaceutical carrier.

40. A method for treating cancer associated with B cells in a subject comprising administering an effective amount of the host cell of claim 38 to the subject.

41. The method of claim 40 , wherein the cancer is a B cell malignancy.

42. The method of claim 41 , wherein the B cell malignancy is B cell acute lymphoblastic leukemia (ALL), diffuse, large B cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, Burkitt lymphoma, or chronic lymphocytic leukemia.

43. The method of claim 40 , wherein the subject has been previously administered a CD19 CAR therapy.

44. The method of claim 43 , wherein the subject is resistant to CD19 CAR therapy.

45. The method of claim 44 , wherein the subject has CD19 antigen loss.

46. The method of claim 45 , wherein the subject has relapsed with a CD19-negative tumor.

Assignments (1)

Continuity (2)

References Cited (33)