Artificial cell death polypeptide for chimeric antigen receptor and uses thereof
Inventors
Naso, Michael • Carton, Jill • Wheeler, John • Borges, Luis
Assignees
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Publication Number
US-11661459-B2
Publication Date
2023-05-30
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 a CAR-based allogeneic cell therapy platform that uses genetically engineered induced pluripotent stem cells (iPSCs) and/or derivative immune effector cells. The engineered cells express a chimeric antigen receptor (CAR) that targets tumor antigens, and they co-express an artificial cell death polypeptide that provides a safety control mechanism.
In the engineered artificial cell death polypeptide, an inactivated cell surface receptor is formed from a truncated epithelial growth factor receptor (tEGFR) variant. The tEGFR variant and interleukin 15 (IL-15) are operably linked by an autoprotease peptide comprising a defined amino acid sequence.
The platform defines specific sequence-identity targets for the tEGFR variant, IL-15, and the autoprotease peptide. It also describes additional immune-evasion edits, including B2M and CIITA disruption with optional HLA-E/HLA-G, HLA construct-encoding isolated nucleic acids and vectors, and pharmaceutical compositions comprising the described constructs for cancer treatment.
The described analyses include engineered iPSC-derived NK cells and related workflows, non-classical HLA expression (HLA-E/HLA-G) and IL-15 mediated persistence, and in vitro and in vivo anti-tumor efficacy and elimination/persistence analyses.
Claims Coverage
The independent claim coverage centers on a polynucleotide encoding an inactivated cell surface receptor formed by a tEGFR variant and IL-15, with operable linkage provided by a defined autoprotease peptide. Additional claim content covers vector and host-cell contexts, and HLA construct-related features including defined linkers and homology arms.
Inactivated cell surface receptor with tEGFR variant and IL-15 linked by autoprotease peptide
A polynucleotide encoding an inactivated cell surface receptor that comprises a truncated epithelial growth factor receptor (tEGFR) variant comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 71 and an interleukin 15 (IL-15) comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO. 72, wherein the tEGFR variant and the IL-15 are operably linked by an autoprotease peptide comprising the amino acid sequence of SEQ ID NO: 73.
Vector with promoter, terminator, polyadenylation signal, and homology sequences
A vector further comprises a promoter, a terminator and/or polyadenylation signal, and left/right homology sequences with at least 90% identity to SEQ ID NO: 84 and 85.
iPSC or derivative cell comprising the polynucleotide
An induced pluripotent stem cell (iPSC) or a derivative cell thereof comprising the polynucleotide of claim 1.
HLA construct-encoding isolated nucleic acids and vectors
HLA construct-encoding isolated nucleic acids and vectors, including signal peptide to mature B2M and/or mature HLA-E fusions, HLA-E/HLA-G related non-classical HLA expression constructs linked using defined 4×GGGGS and 3×GGGGS linkers, and optional engineered integration features including homology arms for targeted integration.
The inventive concept is a polynucleotide encoding an inactivated cell surface receptor that combines a tEGFR variant and IL-15 in a defined linkage architecture using an autoprotease peptide. Coverage is further narrowed by SEQ ID NO–based sequences, vector and iPSC host contexts, and HLA construct features including defined linkers and homology arms.
Stated Advantages
Provides safety control via antibody-triggered ablation described as ADCC/ADCP/ADC action.
Supports functional outcomes including cytotoxicity, IL-15 release, and persistence as described in figure-based and example-level conceptual coverage.
Documented Applications
Use in a CAR-based allogeneic cell therapy platform employing genetically engineered iPSCs/derivative immune effector cells that co-express a CAR targeting tumor antigens and an artificial cell death polypeptide.
Therapeutic use for cancer treatment.
Use of antibody-triggered ablation behavior in the context of monoclonal antibody-specific epitopes, including cetuximab/tEGFR, CD79b/polatuzumab, CD20/rituximab, and trastuzumab/Her2/ErbB.
Engineered iPSC-derived NK cells and related workflows, including in vitro and in vivo anti-tumor efficacy and elimination/persistence analyses.
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