Methods and compositions for modulating CAR-T activity
AssigneeSana Biotechnology, Inc.
InventorsSonja Schrepfer, Lindong Weng, Terry James Fry
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Abstract
Disclosed herein are engineered cells and/or hypoimmunogenic cells including engineered and/or hypoimmunogenic stem cells, engineered and/or hypoimmunogenic cells differentiated therefrom, engineered and/or hypoimmunogenic CAR-T cells (primary or differentiated from engineered and/or hypoimmunogenic stem cells) and related methods of their use and generation. Provided herein are engineered and/or hypoimmunogenic cells exhibiting reduced expression of MHC class I and/or MHC class II human leukocyte antigens and T-cell receptors. In some embodiments, such cells also exogenously express one or more tolerogenic factors such as CD47 and one or more chimeric antigen receptors (CAR)s.
Claims31
An engineered T cell comprising (a) reduced expression of B2M, CIITA, and/or T cell receptor (TCR)-alpha relative to a control T cell, (b) expression of CD47 encoded by a first exogenous polynucleotide so that the engineered T cells comprise increased CD47 expression relative to the control T cell, and (c) expression of a BCMA-specific chimeric antigen receptor (CAR) encoded by a second exogenous polynucleotide,
- wherein the engineered T cell is derived from a primary T cell,
- wherein the CAR comprises an antigen binding domain comprising:
- (i) a light chain variable region comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO:
- 120, the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO:
- 121, and the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO:
- 122, and
- (ii) a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 amino acid, wherein the heavy chain CDR1 comprises the amino acid sequence set forth in SEQ ID NO:
- 124, the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO:
- 125, and the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO:
- 126,
- wherein the first exogenous polynucleotide is inserted into a locus of at least one allele of the engineered T cell, and
- wherein the second exogenous polynucleotide is inserted into a locus of at least one allele of the engineered T cell.
A pharmaceutical composition comprising an engineered T cell and a pharmaceutically acceptable carrier, wherein the engineered T cell comprises (a) reduced expression of B2M, CIITA, and/or T cell receptor (TCR)-alpha relative to a control T cell, (b) expression of CD47 encoded by a first exogenous polynucleotide so that the engineered T cells comprise increased CD47 expression relative to the control T cell, and (c) expression of a BCMA-specific chimeric antigen receptor (CAR) encoded by a second exogenous polynucleotide,
- wherein the engineered T cell is derived from a primary T cell,
- wherein the CAR comprises an antigen binding domain comprising:
- (i) a light chain variable region comprising a light chain CDR1, a light chain CDR2, and a light chain CDR3 of the light chain variable region sequence set forth in SEQ ID NO:
- 119, and
- (ii) a heavy chain variable region comprising a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 amino acid of the heavy chain variable region sequence set forth in SEQ ID NO:
- 123,
- wherein the first exogenous polynucleotide is inserted into a locus of at least one allele of the engineered T cell, and
- wherein the second exogenous polynucleotide is inserted into a locus of at least one allele of the engineered T cell.
Dependencies are inferred from the claim text.