Engineered ipsc and immune effector cells for heterogenous tumor control
AssigneeFate Therapeutics, Inc.
InventorsBahram VALAMEHR, Martin HOSKING, Tom Tong LEE, John Charles GOULDING
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Abstract
Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. The iPSC-derived effector cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the use thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.
Claims71
A cell or a population thereof, wherein the cell comprises a polynucleotide encoding a CAR targeting a B7H3 tumor antigen, wherein the CAR comprises a binding domain comprising:
- (i) an amino acid sequence that is of at least about 99%, 98%, 96%, 95%, 90%, 85%, or 80% identity to SEQ ID NO:
- 36, 37, 38, 39, 40, or 41;
- (ii) an amino acid sequence represented by a variant of SEQ ID NO:
- 36, and wherein the variant has one or more mutations at positions comprising 1, 40, 46, 79, 87, 88, 89, 97, 98, and 117 of SEQ ID NO:
- 36;
- (iii) an amino acid sequence represented by a variant of SEQ ID NO:
- 36, wherein the variant has one or more substitutions comprising Q1E, T40A, E46V, G79L, K87R, P88A, D89E, V97A, S98R, and Q117L according to SEQ ID NO:
- 36;
- or
- (iv) an amino acid sequence represented by any of SEQ ID NOs:
- 36, 37, 38, 39, 40, and 41;
- and
- wherein the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, an induced pluripotent cell (iPSC), or a derivative cell differentiated therefrom.
A composition comprising a cell or a population thereof, wherein the cell comprises one or more polynucleotides encoding a chimeric antigen receptor (CAR), an engager, and optionally a CFR (chimeric fusion receptor), wherein the CFR is optionally for engager coupling, and wherein the cell is an eukaryotic cell, an animal cell, a human cell, an immune cell, an induced pluripotent cell (iPSC), or a derivative cell differentiated therefrom.
A method of manufacturing a derivative effector cell comprising a first polynucleotide encoding a chimeric antigen receptor (CAR) and one or more additional polynucleotides encoding one or both of an engager and a CFR, wherein the engager has a different tumor targeting specificity from the CAR, wherein the method comprises:
- differentiating a genetically engineered iPSC, wherein the iPSC comprises the first and the one or more additional polynucleotides and optionally one or more genomic edits comprising:
- (i) CD38 knockout;
- (ii) HLA-I deficiency and/or HLA-II deficiency;
- (iii) introduction of HLA-G or non-cleavable HLA-G, or knockout of one or both of CD58 and CD54;
- (iv) an exogenous CD16 or a variant thereof;
- (v) a chimeric fusion receptor (CFR);
- (vi) an inactivation CAR;
- (vii) a signaling complex comprising a partial or full peptide of a cell surface expressed exogenous cytokine and/or a receptor thereof;
- (viii) at least one of the genotypes listed in Table 1;
- (ix) disruption of at least one of B2M, CIITA, TAP1, TAP2, Tapasin, NLRC5, RFXANK, RFX5, RFXAP, TCR, NKG2A, NKG2D, CD25, CD69, CD44, CD56, CIS, CBL-B, SOCS2, PD1, CTLA4, LAG3, TIM3, and TIGIT;
- or
- (x) introduction of at least one of HLA-E, 4-1BBL, CD3, CD4, CD8, CD16, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, antigen-specific TCR, Fc receptor, an antibody or functional variant or fragment thereof, a checkpoint inhibitor, and surface triggering receptor for coupling with an agonist, in comparison to its counterpart primary cell.
A chimeric antigen receptor (CAR) comprising a binding domain that comprises:
- (i) an amino acid sequence that is of at least about 99%, 98%, 96%, 95%, 90%, 85%, or 80% identity to SEQ ID NO:
- 36, 37, 38, 39, 40, or 41;
- (ii) an amino acid sequence represented by a variant of SEQ ID NO:
- 36, and wherein the variant has one or more mutations at positions comprising 1, 40, 46, 79, 87, 88, 89, 97, 98, and 117 of SEQ ID NO:
- 36;
- (iii) an amino acid sequence represented by a variant of SEQ ID NO:
- 36, wherein the variant has one or more substitutions comprising Q1E, T40A, E46V, G79L, K87R, P88A, D89E, V97A, S98R, and Q117L according to SEQ ID NO:36;
- or
- (iv) an amino acid sequence represented by any of SEQ ID NOs:
- 36, 37, 38, 39, 40, and 41.
Dependencies are inferred from the claim text.