Artificial cell death polypeptide for chimeric antigen receptor and uses thereof
Inventors
Naso, Michael • Carton, Jill • Wheeler, John • Borges, Luis • Wallet, Mark • Morse, Barry • Quinn, Hillary • Campion, Liam • Gurung, Buddha • Jessup, Heidi • BRASEL, KENNETH • Thompson, Lucas
Assignees
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Publication Number
US-12269888-B2
Publication Date
2025-04-08
Expiration Date
Abstract
Provided are polynucleotides encoding inactivated cell surface receptors. Also provided are genetically engineered induced pluripotent stem cells (iPSCs) and derivative cells thereof expressing a chimeric antigen receptor (CAR) and methods of using the same. Also provided are compositions, polypeptides, vectors, and methods of manufacturing.
Core Innovation
The invention relates to genetically engineered induced pluripotent stem cell (iPSC)-derived immune effector cells, including iPSCs, natural killer (NK) cells, and T cells, comprising a chimeric antigen receptor (CAR) having the amino acid sequence of SEQ ID NO: 61. The engineered cells further comprise a truncated epithelial growth factor (tEGFR) variant having the amino acid sequence of SEQ ID NO: 71, an autoprotease peptide having the amino acid sequence of SEQ ID NO: 73, and interleukin 15 (IL-15) having the amino acid sequence of SEQ ID NO: 72.
The engineered cells optionally comprise a human leukocyte antigen E (HLA-E) having the amino acid sequence of SEQ ID NO: 66. The tEGFR variant, autoprotease peptide, and IL-15 are used together with the CAR to provide an artificial cell-death “inactivated cell surface receptor,” and the optional HLA-E is associated with resistance to NK activity as described in the provided content.
The exogenous polynucleotides are integrated at loci of the AAVS1, CIITA, and B2M genes. Integration at these loci is stated to thereby delete or reduce expression of CIITA and B2M, which results in MHC class II deficiency and MHC class I deficiency as described in the provided content.
Claims Coverage
The independent claim defines engineered iPSCs, NK cells, or T cells with a CAR plus an engineered artificial cell-death module and IL-15, optionally with HLA-E, and integration of exogenous polynucleotides at AAVS1, CIITA, and B2M loci to delete or reduce CIITA and B2M expression. Two inventive features are identified.
CAR, tEGFR variant, autoprotease peptide and IL-15 in engineered iPSC/NK/T cells
An induced pluripotent stem cell (iPSC), a natural killer (NK) cell or a T cell comprising a first exogenous polynucleotide encoding a chimeric antigen receptor (CAR) having the amino acid sequence of SEQ ID NO: 61; a second exogenous polynucleotide encoding a truncated epithelial growth factor (tEGFR) variant having the amino acid sequence of SEQ ID NO: 71, an autoprotease peptide having the amino acid sequence of SEQ ID NO: 73, and interleukin 15 (IL-15) having the amino acid sequence of SEQ ID NO: 72; and optionally, a third exogenous polynucleotide encoding a human leukocyte antigen E (HLA-E) having the amino acid sequence of SEQ ID NO: 66.
Integration at AAVS1, CIITA and B2M to delete or reduce CIITA and B2M
The first, second and third exogenous polynucleotides are integrated at loci of AAVS1, CIITA and B2M genes, to thereby delete or reduce expression of CIITA and B2M.
The claim coverage is anchored by engineered iPSC/NK/T cells expressing a specified CAR together with a tEGFR variant, an autoprotease peptide, and IL-15, optionally including HLA-E, and by targeted integration at AAVS1, CIITA, and B2M loci to delete or reduce CIITA and B2M expression.
Stated Advantages
The integration at AAVS1, CIITA and B2M loci is used to thereby delete or reduce expression of CIITA and B2M.
The engineered cell includes tEGFR-based and IL-15-related elements as part of a cancer therapeutic configuration described in the document.
Integration at AAVS1, CIITA and B2M loci thereby deletes or reduces expression of CIITA and B2M.
Documented Applications
Therapeutic methods for treating cancer using the engineered iPSC/NK/T cells and related compositions described in the document.
Engineered iPSC-derived immune effector cells for allogeneic CAR therapy, including CAR targeting CD19, are described in the provided content.
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