Enhancing activity of CAR T cells by co-introducing a bispecific antibody
The present invention provides compositions and methods for treating cancer in a human. The invention includes administering a T cell, genetically modified to express a chimeric antigen receptor (CAR), a bispecific antibody, or a combination thereof to a subject. The CAR and bispecific antibody of the invention can comprise a human antibody, a humanized antibody, or antigen-binding fragments thereof.
1. An isolated cell comprising:
a first nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises one or more antigen binding domains of a first bispecific antibody, a transmembrane domain, and a CD3 zeta signaling domain, further wherein each antigen binding domain is selected from the group consisting of a human antibody, a humanized antibody, and an antigen binding fragment thereof; and
a second nucleic acid sequence encoding a second bispecific antibody, wherein the second bispecific antibody does not comprise and is not linked to a transmembrane domain.
2. The isolated cell of claim 1 , wherein the first nucleic acid sequence comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22.
3. The isolated cell of claim 1 , wherein at least one antigen binding domain of the CAR is an antigen binding fragment.
4. The isolated cell of claim 3 , wherein the antigen binding fragment is a Fab or a scFv.
5. The isolated cell of claim 1 , wherein at least one antigen binding domain of the CAR binds to a tumor antigen.
6. The isolated cell of claim 5 , wherein the tumor antigen is associated with a hematologic malignancy.
7. The isolated cell of claim 5 , wherein the tumor antigen is associated with a solid tumor.
8. The isolated cell of claim 5 , wherein the tumor antigen is selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33, IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1, and MAGE A3.
9. The isolated cell of claim 1 , wherein the CAR further comprises a costimulatory signaling region comprising the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, CD83, and any combination thereof.
10. The isolated cell of claim 1 , wherein the cell is a T cell.
11. The isolated cell of claim 1 , wherein the cell exhibits an anti-tumor immunity when the antigen binding domain of the CAR binds to its corresponding antigen.
12. The isolated cell of claim 1 , wherein the nucleic acid sequence encoding the one or more antigen binding domains of the first bispecific antibody encodes a bispecific antibody.
13. The isolated cell of claim 12 , wherein the first bispecific antibody differs from the second bispecific antibody encoded by the second nucleic acid sequence.
14. The isolated cell of claim 1 , wherein the nucleic acid sequence encoding the one or more antigen binding domains of the first bispecific antibody comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19.
15. The isolated cell of claim 1 , wherein the second nucleic acid sequence encoding the second bispecific antibody comprises the nucleic acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19.
16. The isolated cell of claim 1 , wherein the second bispecific antibody encoded by the second nucleic acid sequence comprises a human antibody, or an antigen binding fragment thereof.
17. The isolated cell of claim 1 , wherein the second bispecific antibody encoded by the second nucleic acid sequence comprises a humanized antibody, or an antigen binding fragment thereof.
18. The isolated cell of claim 1 , wherein the second bispecific antibody encoded by the second nucleic acid sequence comprises an antigen binding domain that binds a T cell antigen.
19. An isolated cell comprising:
a first nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a tumor antigen binding domain, a transmembrane domain, and a CD3 zeta signaling domain, wherein the tumor antigen binding domain is selected from the group consisting of a human antibody, a humanized antibody, and an antigen binding fragment thereof; and
a second nucleic acid sequence encoding a bispecific antibody comprising an antigen binding domain that binds a T cell antigen, wherein the bispecific antibody does not comprise and is not linked to a transmembrane domain.