Granted Patent B2

US 12,594,321 · App. 18/529,915 · Granted Apr 7, 2026

Inventors: Barbara Brannetti (Cambridge, MA); Jennifer Brogdon (Sudbury, MA); Boris Engels (Arlington, MA); Brian Walter Granda (Salisbury, MA); Ming Lei (Acton, MA); Jimin Zhang (Chestnut Hill, MA)

Assignees: Novartis AG; The Trustees of the University of Pennsylvania

A61K38/1774A61K40/11A61K40/31A61K40/4211A61K40/4212A61K40/4221A61P35/00C07K16/2803C07K16/2887C07K16/2896C12N5/0636C12N15/85A61K2039/505A61K2239/31A61K2239/38A61K2239/48C07K2317/24C07K2317/31C07K2317/622C07K2319/03C07K2319/33

Abstract

Claims (36)

1 . A bispecific chimeric antigen receptor (CAR) molecule comprising:

(a) first antigen binding domain that binds to CD20 comprising a heavy chain variable domain (VH) comprising an amino acid sequence of SEQ ID NO: 512, a linker comprising an amino acid sequence of SEQ ID NO: 541, and a light chain variable domain (VL) comprising an amino acid sequence of SEQ ID NO: 514;

(b) a (Gly 4 -Ser) 5 linker;

(c) a second antigen binding domain that binds to CD19 comprising an amino acid sequence of SEQ ID NO: 771;

(d) a CD8 hinge comprising an amino acid sequence of SEQ ID NO: 799;

(e) a CD8 transmembrane domain comprising an amino acid sequence of SEQ ID NO: 801;

(f) a 4-1BB costimulatory domain comprising an amino acid sequence of SEQ ID NO: 803; and

(g) a CD3z intracellular signaling domain comprising an amino acid sequence of SEQ ID NO: 807.

2 . The bispecific CAR molecule of claim 1 , wherein the CAR molecule comprises two scFvs.

3 . A nucleic acid molecule encoding the bispecific CAR molecule of claim 1 .

4 . A vector comprising the nucleic acid molecule of claim 3 .

5 . The vector of claim 4 , wherein the vector:

(a) is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, adenoviral vector, and a retrovirus vector; and/or

(b) is an in vitro transcribed vector.

6 . The vector of claim 4 , wherein the vector comprises a single promoter.

7 . The vector of claim 6 , wherein the single promoter is an EF-1a promoter.

8 . The vector of claim 7 , wherein the EF-1a promoter comprises the nucleic acid sequence of SEQ ID NO: 833.

9 . A cell comprising the nucleic acid molecule of claim 3 .

10 . The cell of claim 9 , wherein the cell is:

(a) a human T cell or NK cell, optionally wherein the T cell is a CD8+ T cell; and/or

(b) an autologous T cell or NK cell or an allogeneic T cell or NK cell.

11 . A method of making a cell, comprising transducing a T cell or an NK cell with the nucleic acid molecule of claim 3 .

12 . A method of generating a population of RNA-engineered cells comprising introducing an in vitro transcribed RNA or synthetic RNA into a cell, wherein the RNA comprises the nucleic acid molecule of claim 3 .

13 . A population of immune effector cells, comprising a bispecific chimeric antigen receptor (CAR) molecule comprising:

(a) first antigen binding domain that binds to CD20 comprising a heavy chain variable domain (VH) comprising an amino acid sequence of SEQ ID NO: 512, a linker comprising an amino acid sequence of SEQ ID NO: 541, and a light chain variable domain (VL) comprising an amino acid sequence of SEQ ID NO: 514;

(b) a (Gly 4 -Ser) 5 linker;

(c) a second antigen binding domain that binds to CD19 comprising an amino acid sequence of SEQ ID NO: 771;

(d) a CD8 hinge comprising an amino acid sequence of SEQ ID NO: 799;

(e) a CD8 transmembrane domain comprising an amino acid sequence of SEQ ID NO: 801;

(f) a 4-1BB costimulatory domain comprising an amino acid sequence of SEQ ID NO: 803; and

(g) a CD3z intracellular signaling domain comprising an amino acid sequence of SEQ ID NO: 807.

14 . The population of immune effector cells of claim 13 , wherein the population comprises autologous T cells.

15 . A method of treating cancer, wherein said method comprises administering to the mammal an effective amount of a population of T cells or NK cells comprising a nucleic acid molecule of claim 3 .

16 . The method of claim 15 , wherein the mammal has a cancer, and 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.

17 . The method of claim 15 , wherein the cell is administered in combination with: (i) an agent that increases the efficacy of the cell, (ii) an agent that ameliorates one or more side effects associated with administration of the cell, or (iii) an agent that treats a cancer.

18 . A method of treating diffuse large B cell lymphoma (DLBCL) in a subject in need thereof, the method comprising administering the population of immune effector cells of claim 13 to the subject, wherein the population of immune effector cells comprises T cells or NK cells.

Assignments (10)

Continuity (5)

References Cited (400)