Xiao Han, Woods Elliot C, Vukojicic Petar, Bertozzi Carolyn R
Department of Chemistry, Stanford University, Stanford, CA 94305-4404; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-4404.
Department of Chemistry, Stanford University, Stanford, CA 94305-4404; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-4404
Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):10304-9. doi: 10.1073/pnas.1608069113. Epub 2016 Aug 22.
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.
细胞表面唾液酸苷构成免疫调节的核心轴，肿瘤利用这一轴来逃避先天性和适应性免疫破坏。因此，靶向肿瘤相关唾液酸苷的治疗策略可能会增强抗肿瘤免疫力。在此，我们报告了抗体-唾液酸酶偶联物的研发，该偶联物通过对肿瘤细胞糖萼进行选择性去唾液酸化作用，增强肿瘤细胞对抗体依赖性细胞介导的细胞毒性（ADCC）的敏感性。我们通过C末端醛标签将重组唾液酸酶化学融合至人表皮生长因子受体2（HER2）特异性抗体曲妥珠单抗上。该抗体-唾液酸酶偶联物以HER2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免疫球蛋白样凝集素（Siglec）受体的结合，并增强与NK激活受体自然杀伤细胞组2D（NKG2D）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HER2的肿瘤细胞的ADCC作用，这为HER2水平较低或存在曲妥珠单抗固有耐药性的癌症患者提供了一种治疗策略。因此，用抗体-酶偶联物进行精准糖萼编辑是癌症免疫治疗的一个有前景的途径。
