肿瘤细胞治疗研究
英文原题：Safe immunosuppression-resistant pan-cancer immunotherapeutics by velcro-like density-dependent targeting of tumor-associated carbohydrate antigens.
双特异性抗体和CAR-T 细胞是临床使用中最有效的癌症免疫治疗药物之一，但大多数癌症仍然难以靶向。
双特异性抗体和CAR-T 细胞是临床应用中效力最强的一类癌症免疫治疗手段，但大多数癌症仍难以有效靶向。为最大限度增强杀伤作用所需的高亲和力抗体，会识别正常组织中的低水平抗原表达，带来“靶向肿瘤但同时攻击肿瘤外组织”的毒性风险。因此，需要寻找肿瘤特异的细胞表面蛋白抗原，但这类抗原十分罕见。肿瘤相关糖类抗原（TACA）是已知最丰富、分布最广的癌症抗原，却难以用抗体靶向。本研究介绍了一类糖链依赖性T细胞募集剂（GlyTR）泛癌免疫治疗药物，利用类似魔术贴的高多价凝集素结合，杀伤TACA高表达而非低表达的细胞。GlyTR1和GlyTR2分别结合具有免疫抑制作用的β1,6GlcNAc分支N-聚糖，或多种TACA（Tn、唾液酸化Tn、LacDiNAc和GD2）；它们能够克服肿瘤微环境中的免疫抑制机制，触发依赖靶点密度的T细胞介导泛癌杀伤，同时在表达类似人类水平TACA的小鼠中未见毒性。依赖抗原密度的凝集素与TACA结合，为开发高效且安全的泛癌免疫治疗提供了新思路。
Bispecific antibodies and chimeric antigen receptor T cells are some of the most potent cancer immunotherapeutics in clinical use, yet most cancers remain poorly targetable. High-affinity antibodies required to maximize killing detect low antigen expression in normal tissue, risking "on-target, off-cancer" toxicity. This compels identification of cancer-restricted cell-surface protein antigens, which are rare. Tumor-associated carbohydrate antigens (TACAs) are the most abundant and widespread cancer antigens known but are poorly targetable by antibodies. Here, we describe glycan-dependent T cell recruiter (GlyTR) pan-cancer immunotherapeutics that utilize high-avidity "velcro-like" lectin binding to kill cells with high but not low TACA expression. GlyTR1 and GlyTR2 bind immunosuppressive β1,6GlcNAc-branched N-glycans or multiple TACAs (Tn, sialyl-Tn, LacDiNAc, and GD2), respectively, overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.
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