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HER2Me CAR T cells are an experimental second-generation chimeric antigen receptor (CAR) T-cell therapy designed to target the Human Epidermal Growth Factor Receptor 2 (HER2). These cells are engineered with a medium-affinity single-chain variable fragment (scFv) derived from the 4D5-5 antibody variant, which possesses attenuated binding affinity compared to standard high-affinity trastuzumab-based CARs. The CAR construct incorporates CD28 and CD3ζ signaling domains. Developed as a research comparator to evaluate the therapeutic index of affinity-tuned receptors, HER2Me CAR T cells were intended to discriminate between HER2-amplified tumor cells and normal tissues expressing physiological levels of HER2. However, preclinical studies demonstrated that despite the reduced affinity, the potent signaling of the CAR format still led to significant activation and cytotoxicity against cells with normal HER2 expression, suggesting a potential risk for on-target off-tumor toxicity.
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