肿瘤细胞治疗研究
英文原题：Structural dissection of CD38 antigen engagement by CAR binders and rational affinity tuning.
嵌合抗原受体（CAR）T 细胞疗法利用合成受体引导 T 细胞靶向并裂解癌细胞。
嵌合抗原受体（CAR）T细胞疗法利用合成受体引导T细胞识别并裂解癌细胞。CD38是一种参与免疫调节的多功能胞外酶，也是血液系统恶性肿瘤的治疗靶点。本研究对两种靶向CD38的结合分子RP02和028进行了结构与功能表征，揭示二者具有不同的表位结合方式及酶抑制机制。晶体结构显示，RP02通过VH介导的相互作用结合CD38的N端结构域；028则跨越N端和C端结构域并诱导变构抑制。丙氨酸扫描确定了调节亲和力的关键残基。功能实验表明，028可强效抑制CD38环化酶活性，而RP02影响极小；这与028通过环6介导的二聚化遮挡催化口袋相吻合。此外，采用亲和力减弱型028 R103G构建的CAR-T细胞减少了同类相残，同时保留了对CD38阳性肿瘤的细胞毒性。本研究阐明了基于结构指导优化CD38靶向疗法的策略，可在亲和力、抑制作用与细胞选择性之间进行平衡。
Chimeric antigen receptor (CAR) T cell therapy uses synthetic receptors to direct T cells to target and lyse cancer cells. CD38 is a multifunctional ectoenzyme involved in immunomodulation and a therapeutic target in hematological malignancies. Here, we report structural and functional characterization of two CD38-targeting binders, RP02 and 028, revealing distinct mechanisms of epitope engagement and enzymatic inhibition. Crystal structures demonstrate that RP02 binds the N-lobe of CD38 via VH-mediated interactions, while 028 spans both N- and C-lobes, inducing allosteric inhibition. Alanine scanning identified critical residues for affinity tuning. Functional assays showed 028 potently inhibits CD38's cyclase activity, whereas RP02 has minimal effect, correlating with 028's occlusion of the catalytic pocket via 6 loop-mediated dimerization. Further, CAR-T cells engineered with affinity-attenuated 028 R103G exhibited reduced fratricide while retaining cytotoxicity against CD38 + tumors. Our work delineates structure-guided strategies to optimize CD38-targeted therapeutics by balancing affinity, inhibition, and cellular selectivity.
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