Precision glycocalyx editing as a strategy for cancer immunotherapy
Precision glycocalyx editing as a strategy for cancer immunotherapy
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DOI：
10.1073/pnas.1608069113
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发表时间：
2016-08
期刊：
影响因子：
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通讯作者：
Han Xiao;Elliot C. Woods;Petar Vukojicic;C. Bertozzi
中科院分区：
文献类型：
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作者：
Han Xiao;Elliot C. Woods;Petar Vukojicic;C. Bertozzi
成功的肿瘤能够逃避免疫系统，否则免疫系统能够杀死转化的细胞。防止这种逃避的疗法已经成为不可治愈癌症的革命性治疗方法。逃避的一种机制是在细胞表面的糖涂层或糖萼内呈现糖，称为唾液酸。在这里，我们设计了双抗体分子，称为“抗体-酶结合物”，它选择性地从肿瘤细胞中去除唾液酸。抗体将酶引导到癌细胞，酶切割糖，然后抗体引导免疫细胞杀死去唾液酸化的癌细胞。与单独的抗体相比，缀合物增加了肿瘤细胞杀伤。用抗体-酶缀合物编辑癌细胞糖萼代表了癌症免疫治疗的一种有前途的方法。细胞表面唾液酸苷构成免疫调节的中心轴，其被肿瘤利用以逃避先天性和适应性免疫破坏。因此，靶向肿瘤相关唾液酸糖苷的治疗策略可能会增强抗肿瘤免疫力。在这里，我们报告了抗体-唾液酸酶缀合物的开发，其通过肿瘤细胞糖萼的选择性去唾液酸化来增强肿瘤细胞对抗体依赖性细胞介导的细胞毒性（ADCC）的易感性。我们通过C-末端醛标签将重组唾液酸酶与人表皮生长因子受体2（HER 2）特异性抗体曲妥珠单抗化学融合。抗体-唾液酸酶缀合物以HER 2依赖性方式使肿瘤细胞去唾液酸化，减少自然杀伤（NK）细胞抑制性唾液酸结合Ig样凝集素（Siglec）受体的结合，并增强与NK激活受体自然杀伤组2D（NKG 2D）的结合。唾液酸酶与曲妥珠单抗偶联增强了对表达中等水平HER 2的肿瘤细胞的ADCC，这表明了对HER 2水平较低或固有曲妥珠单抗耐药的癌症患者的治疗策略。因此，用抗体-酶缀合物进行精确的糖萼编辑是癌症免疫治疗的有希望的途径。
Significance Successful tumors are able to evade the immune system, which is otherwise capable of killing transformed cells. Therapies that prevent this evasion have become revolutionary treatments for incurable cancers. One mechanism of evasion is the presentation of sugars, called sialic acids, within the cell surface’s sugar coating, or glycocalyx. Here, we designed biotherapeutic molecules, termed “antibody–enzyme conjugates,” that selectively remove sialic acids from tumor cells. The antibody directs the enzyme to the cancer cells, the enzyme cleaves the sugars, and then the antibody directs immune cells to kill the desialylated cancer cells. The conjugate increased tumor cell killing compared with the antibody alone. Editing the cancer cell glycocalyx with an antibody–enzyme conjugate represents a promising approach to cancer immune therapy. Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody–sialidase conjugates that enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag. The antibody–sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by natural killer (NK) cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and enhanced binding to the NK-activating receptor natural killer group 2D (NKG2D). Sialidase conjugation to trastuzumab enhanced ADCC against tumor cells expressing moderate levels of HER2, suggesting a therapeutic strategy for cancer patients with lower HER2 levels or inherent trastuzumab resistance. Precision glycocalyx editing with antibody–enzyme conjugates is therefore a promising avenue for cancer immune therapy.