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Abstract

The present disclosure relates to bicistronic polypeptide constructs for use in allogeneic gene therapy, for example, CAR-T cell therapy. The bicistronic constructs comprise first polynucleotide encoding a therapeutic molecule (e.g., a CAR-T or an antibody) and a second polynucleotide encoding an Immune Surveillance Masking Molecule (ISMM). The ISMM comprises a human leukocyte antigen-E genetically fused to a non-functional version, e.g., a fragment, of the protein knock-out by the insertion of the bicistronic construct, e.g., beta-2 microglobulin or B2M. Also provided are vectors comprising the bicistronic constructs, cells (e.g., CAR-T cells), and methods of use. Also provided are kits and articles of manufacture. The present disclosure also provides four novel insertion sites that can be used to insert an expression construct in the B2M gene.

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First Claim