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bioRxiv · 10.1101/2024.05.05.592600

Universal protection of allogeneic cell therapies from natural killer cells via CD300a agonism

Zhang, S.-Q.·Thomas, F.·Fang, J.·Austgen, K.·Cowan, C.·Welstead, G. G.
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Abstract

Immunogenicity limits the persistence of off-the-shelf, allogeneic cell therapies and transplants. While ablation of human leukocyte antigen (HLA) removes most T cell and humoral alloreactivity, no solution has enabled universal protection against the resulting natural killer (NK) cell response. Here, we engineered Trans Antigen Signaling Receptors (TASR) as a new class of NK inhibitory ligands and discovered CD300a, a previously inaccessible receptor, as a functional target. CD300a TASR outperformed leading alternative strategies in focused screens, including CD47 and HLA-E, and was solely capable of universally protecting allogeneic T cells against a large human cohort (45/45 donors), spanning diverse demographics and NK cell phenotypes. A model allogeneic T cell therapy co-expressing an anti-CD19 Chimeric Antigen Receptor (CAR) and CD300a TASR, produced using multiplexed non-viral integration, exhibited enhanced B cell killing potency under allogeneic immune pressure. CD300 TASR represents a universal solution to NK alloreactivity, broadening the population that could be effectively treated by next-generation allogeneic cell therapies. CategoryImmunobiology and Immunotherapy Key PointsO_LIAn engineered CD300a agonist ligand (CD300a TASR) universally protects HLA-deficient allogeneic T cells from NK-mediated rejection. C_LIO_LICD300a TASR is more protective in CMV seropositive hosts than HLA-E ligand and enhances CAR-T efficacy under allogeneic immune pressure. C_LI

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Zhang, S.-Q., Thomas, F., Fang, J., Austgen, K., Cowan, C., Welstead, G. G.. 2024-05-07. Universal protection of allogeneic cell therapies from natural killer cells via CD300a agonism. https://doi.org/10.1101/2024.05.05.592600

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