Method of treating cancer by administering immune effector cells expressing a chimeric antigen receptor comprising a CD20 binding domain

Patent metadata

Field	Value
Publication number	US-11872249-B2
Application number	US-202117246351-A
Country	US
Kind code	B2
Filing date	Apr 30, 2021
Priority date	Oct 7, 2016
Publication date	Jan 16, 2024
Grant date	Jan 16, 2024

Abstract

The invention provides compositions and methods for treating diseases associated with expression of CD20 or CD22. The invention also relates to chimeric antigen receptor (CAR) specific to CD20 or CD22, vectors encoding the same, and recombinant T or natural killer (NK) cells comprising the CD20 CAR or CD22 CAR. The invention also includes methods of administering a genetically modified T cell or NK cell expressing a CAR that comprises a CD20 or CD22 binding domain.

First claim

We claim:

1. A method of treating a cancer, wherein said method comprises administering to the mammal an effective amount of a plurality of immune effector cells expressing an isolated chimeric antigen receptor (CAR), wherein the plurality of immune effector cells comprise T cells, NK cells, or both T cells and NK cells, wherein the CAR comprises a CD20 binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein the CD20 binding domain comprises a light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), light chain complementarity determining region 3 (LCDR3), heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3), wherein the LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3 comprise:
(i) SEQ ID NOs: 147, 148, 149, 136, 137, and 138, respectively;
(ii) SEQ ID NOs: 150, 151, 152, 139, 140, and 141, respectively;
(iii) SEQ ID NOs: 153, 154, 155, 142, 143, and 144, respectively;
(iv) SEQ ID NOs: 929, 930, 931, 926, 927, and 928, respectively;
(v) SEQ ID NOs: 228, 229, 230, 217, 218, and 219, respectively;
(vi) SEQ ID NOs: 231, 232, 233, 220, 221, and 222, respectively;
(vii) SEQ ID NOs: 234, 235, 236, 223, 224, and 225, respectively; or
(viii) SEQ ID NOs: 944, 945, 988, 941, 942, and 943, respectively.

2. The method of claim 1 , wherein the cancer is acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (BALL), small lymphocytic lymphoma (SLL), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, hairy cell leukemia, small cell-lymphoma, large cell-follicular lymphoma, a malignant lymphoproliferative condition, MALT lymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia, or myelodysplastic syndrome, myeloproliferative neoplasm, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, preleukemia, or a combination thereof.

3. The method of claim 2 , wherein the cancer is a leukemia or a lymphoma.

4. The method of claim 2 , wherein the cancer is a B-cell malignancy.

5. The method of claim 1 , further comprising administering to the subject a B-cell inhibitor chosen from one or more of an inhibitor of CD19, CD22, CD10, CD34, CD123, FLT-3, ROR-1, CD79b, CD79a, or CD179b.

6. The method of claim 5 , wherein the B-cell inhibitor is a small molecule inhibitor of CD10 or FLT-3.

7. The method of claim 5 , wherein the B-cell inhibitor comprises a cell expressing a CAR that binds a B-cell antigen.

8. The method of claim 5 , wherein the B-cell inhibitor is administered prior to, concurrently with, or after the plurality of immune effector cells expressing a CAR.

9. The method of claim 1 , wherein the plurality of immune effector cells expressing a CAR is administered in combination with an agent that ameliorates one or more side effects associated with administration of the plurality of immune effector cells expressing a CAR molecule, or an agent that treats a cancer associated with CD20.

10. The method of claim 7 , wherein the B-cell antigen is CD19, CD22, CD10, CD34, CD123, FLT-3, ROR-1, CD79b, CD79a, or CD179b.

11. The method of claim 1 , wherein the CD20 binding domain comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein:
(i) the VL comprises the amino acid sequence of SEQ ID NO: 156, 129, 439, 237, 264, 291, 318, or 443, or an amino acid sequence with 95% identity thereto;
(ii) the VH comprises the amino acid sequence of SEQ ID NO: 145, 118, 437, 226, 253, 280, 307, or 441, or an amino acid sequence with at least 95% identity thereto; or
(iii) the VL and VH comprise:
(a) SEQ ID NOs: 156 and 145, respectively;
(b) SEQ ID NOs: 129 and 118, respectively;
(c) SEQ ID NOs: 439 and 437, respectively;
(d) SEQ ID NOs: 237 and 226, respectively;
(e) SEQ ID NOs: 264 and 253, respectively;
(f) SEQ ID NOs: 291 and 280, respectively;
(g) SEQ ID NOs: 318 and 307, respectively; or
(h) SEQ ID NOs: 443 and 441, respectively.

12. The method of claim 1 , wherein the CD20 binding domain is an scFv.

13. The method of claim 1 , wherein the CD20 binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 159, SEQ ID NO: 240, SEQ ID NO: 132, SEQ ID NO: 267, SEQ ID NO: 294, SEQ ID NO: 321, and an amino acid sequence with at least 95% identity thereto.

14. The method of claim 1 , wherein the transmembrane domain comprises 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, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD123, CD134, CD137 and CD154.

15. The method of claim 14 , wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 801 or an amino acid sequence with at least 95% identity thereto.

16. The method of claim 1 , wherein the CD20 binding domain is connected to the transmembrane domain by a hinge region, wherein the hinge region comprises the amino acid sequence of SEQ ID NO: 799 or SEQ ID NO: 814, or an amino acid sequence with at least 95% identity thereto.

17. The method of claim 1 , wherein the intracellular signaling domain comprises a costimulatory domain, wherein the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of OX40, CD2, CD27, CD28, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), and 4-1BB (CD137).

18. The method of claim 1 , wherein the intracellular signaling domain comprises a costimulatory domain, wherein the costimulatory domain comprises the amino acid sequence of SEQ ID NO: 803, or an amino acid sequence with at least 95% identity thereto.

19. The method of claim 1 , wherein the intracellular signaling domain comprises a primary signaling domain, wherein the primary signaling domain comprises a functional signaling domain of CD3 zeta.

20. The method of claim 1 , wherein the intracellular domain comprises a primary signaling domain, wherein the primary signaling domain comprises the amino acid sequence of SEQ ID NO: 805 or SEQ ID NO: 807, or an amino acid sequence with at least 95% identity thereto.

21. The method of claim 1 , wherein the intracellular signaling domain comprises a functional signaling domain comprising a functional signaling domain of 4-1BB and/or a functional signaling domain of CD3 zeta.

22. The method of claim 1 , wherein:
(i) the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 803 and/or the amino acid sequence of SEQ ID NO: 805;
(ii) the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 803 and/or the amino acid sequence of SEQ ID NO: 807;
(iii) the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 803, or an amino acid sequence with at least 95% identity thereto, and/or the amino acid sequence of SEQ ID NO: 805 or SEQ ID NO: 807, or an amino acid sequence with at least 95% identity thereto; or
(iv) the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 803 and the amino acid sequence of SEQ ID NO: 805 or SEQ ID NO:

Assignees

• Novartis Ag
• Univ Pennsylvania

Inventors

• Brannetti Barbara
• Brogdon Jennifer
• Engels Boris
• Granda Brian Walter
• Huang Lu
• Lei Ming
• Li Na
• Zhang Jimin
• Guimaraes Carla Patricia Pinto
• Gill Saar
• Ruella Marco
• Young Regina M

Classifications

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/4212

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

• A61K40/4221

  CD20 · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title