CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell

Patent metadata

Field	Value
Publication number	US-12344657-B2
Application number	US-202117464528-A
Country	US
Kind code	B2
Filing date	Sep 1, 2021
Priority date	Apr 8, 2015
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with one or more B-cell inhibitors, e.g., inhibitors of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. The disclosure additionally features novel antigen binding domains and CAR molecules directed to CD20 and CD22, and uses, e.g., as monotherapies or in combination therapies. The invention also provides kits and compositions described herein.

First claim

What is claimed is:

1. A method of treating a young adult or pediatric subject having a cancer comprising administering to the subject an effective amount of a population of cells that comprises a CAR molecule comprising a CD19 binding domain and a CD22 binding domain, wherein:
(i) the CD19 binding domain comprises a scFv comprising the LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3 of FMC63; and
(ii) the CD22 binding domain comprises a scFv comprising the LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3 of m971,
wherein the population of cells that comprises a CAR molecule is administered at a dose of 10 4 cells/kg to 2×10 7 cells/kg.

2. The method of claim 1 , wherein the subject is between about 1 and 18 years of age; between about 16 and 30 years of age; or between about 1 and 30 years of age.

3. The method of claim 1 , wherein the population of cells that comprises a CAR molecule is administered at a dose of 1×10 5 cells/kg, 1×10 6 cells/kg, 3×10 6 cells/kg, or 1×10 7 cells/kg.

4. The method of claim 1 , wherein the subject has minimal residual disease.

5. The method of claim 1 , wherein prior to the administration of the population of cells that comprises a CAR molecule, the subject has received a cyclophosphamide and fludarabine lymphodepletion regimen.

6. The method of claim 5 , wherein the lymphodepletion regimen comprises 25 mg/m 2 fludarabine daily for three days and a single dose of 900 mg/m 2 cyclophosphamide.

7. The method of claim 1 , wherein prior to administration of the population of cells that comprises a CAR molecule the subject has received a stem cell transplantation.

8. The method of claim 1 , wherein the subject has a relapsed cancer.

9. The method of claim 1 , wherein the cancer is a hematologic cancer, an acute leukemia, an acute lymphoblastic leukemia (ALL); a B cell leukemia; a B-cell acute lymphoblastic leukemia (BALL), a B cell lymphoma; T-cell acute lymphoblastic leukemia (TALL), small lymphocytic lymphoma (SLL), chronic leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma, or myeloma.

10. The method of claim 1 , wherein the cancer expresses one or both of CD19 and CD22.

11. The method of claim 1 , wherein the CAR molecule is a bispecific CAR molecule.

12. The method of claim 1 , wherein the CAR comprises one, two, three, or all of:
(a) a transmembrane domain comprising a transmembrane domain of a protein selected from the group consisting of the alpha, beta, or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154, wherein optionally the CD19 and/or CD22 binding domain is connected to the transmembrane domain by a hinge region, wherein, optionally, the hinge region comprises SEQ ID NO:14, or a sequence with 95-99% identity thereof;
(b) a costimulatory domain that is a functional signaling domain obtained from a protein selected from the group consisting of OX40, CD2, CD27, CD28, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137), wherein optionally the costimulatory domain comprises a sequence of SEQ ID NO: 16 or SEQ ID NO:51;
(c) an intracellular signaling domain that comprises a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta or comprises the sequence of SEQ ID NO: 16 and/or the sequence of SEQ ID NO:17 or SEQ ID NO: 43; and
(d) leader sequence, wherein, optionally, the leader sequence comprises SEQ ID NO: 13.

13. The method of claim 12 , wherein the CAR molecule comprises a 4-1BB costimulatory domain.

14. The method of claim 1 , wherein the population of cells comprises T cells or NK cells.

15. The method of claim 1 , further comprising administering one or both of: (i) an agent that increases the efficacy of a cell expressing a CAR molecule, or (ii) an agent that ameliorates one or more side effects associated with administration of a cell expressing a CAR molecule.

16. The method of claim 1 , wherein the subject is, or is identified as being, a non-responder, a partial responder, or a relapser to a CD19 inhibitor.

17. A method of treating a subject having a cancer comprising administering to the subject an effective amount of a population of cells that comprises a CAR molecule comprising a CD19 binding domain and a CD22 binding domain, wherein:
(i) the CD19 binding domain comprises a scFv comprising the LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3 of FMC63; and
(ii) the CD22 binding domain comprises a scFv comprising the LC CDR1, LC CDR2, LC CDR3, HC CDR1, HC CDR2, and HC CDR3 of m971; and
wherein the population of cells that comprises a CAR molecule is administered at a dose of 10 4 cells/kg to 2×10 7 cells/kg.

18. The method of claim 17 , wherein the population of cells that comprises a CAR molecule is administered at a dose of 1×10 5 cells/kg, 1×10 6 cells/kg, 3×10 6 cells/kg, or 1×10 7 cells/kg.

19. The method of claim 17 , wherein the subject has minimal residual disease.

20. The method of claim 17 , wherein prior to the administration of the population of cells that comprises a CAR molecule, the subject has received a cyclophosphamide and fludarabine lymphodepletion regimen.

21. The method of claim 20 , wherein the lymphodepletion regimen comprises 25 mg/m 2 fludarabine daily for three days and a single dose of 900 mg/m 2 cyclophosphamide.

22. The method of claim 17 , wherein prior to administration of the population of cells that comprises a CAR molecule the subject has received a stem cell transplantation.

23. The method of claim 17 , wherein the subject has a relapsed cancer.

24. The method of claim 8 , wherein the relapsed cancer is a relapsed ALL cancer, a relapsed CLL cancer, a relapsed SLL cancer, or a relapsed CD19+ lymphoma.

25. The method of claim 23 , wherein the relapsed cancer is a relapsed ALL cancer, a relapsed CLL cancer, a relapsed SLL cancer, or a relapsed CD19+ lymphoma.

26. The method of claim 16 , wherein the CD19 inhibitor is a CD19 CAR therapy.

27. The method of claim 1 , wherein the subject has relapsed, or is identified as having relapsed, to a CD19 inhibitor based on one or more of:
reappearance of blasts in the blood, bone marrow, or any extramedullary site, after a complete response.

Assignees

• Novartis Ag
• Univ Pennsylvania

Inventors

• Bitter Hans
• Bordeaux Jennifer Mary
• Brannetti Barbara
• Brogdon Jennifer
• Dakappagari Naveen Kumar
• Gill Saar
• Highfill Steven
• Huang Lu
• June Carl H
• Kim Ju Young
• Lei Ming
• Li Na
• Loew Andreas
• Orlando Elena
• Ruella Marco
• Tran Thai
• Zhang Jimin
• Zhou Li

Classifications

• A61K40/4221

  CD20 · CPC title

• A61K40/4217

  Receptors for interleukins [IL] · CPC title

• A61K40/4212

  CD22, BL-CAM, siglec-2 or sialic acid binding Ig-related lectin 2 · CPC title

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/36

  Immune checkpoint inhibitors · CPC title