A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies
A Novel Therapeutic Strategy to Rescue the Immune Effector Function of Proteolytically Inactivated Cancer Therapeutic Antibodies
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DOI：
10.1158/1535-7163.mct-14-0715
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发表时间：
2015-03-01
影响因子：
5.7
通讯作者：
An, Zhiqiang
中科院分区：
文献类型：
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作者：
Fan, Xuejun;Brezski, Randall J.;An, Zhiqiang
对抗癌抗体免疫疗法的原发性和获得性抗性提出了重大的临床挑战。在这里，我们证明了癌症靶向抗体的蛋白水解失活是癌症免疫逃避的一个不受重视的贡献者，这一发现为治疗干预提供了新的机会。由于Fc区的结构紊乱，IgG 1铰链中的单个肽键裂解会损害癌细胞杀伤。铰链切割的曲妥珠单抗在体外逐渐积累在表达HER 2的癌细胞系的表面上，并且当细胞被工程化以表达有效的细菌IgG降解蛋白酶（IdeS）时大大加速。与癌症相关的基质金属蛋白酶（MMP）类似，IdeS暴露铰链新表位，我们已经开发了抗体mAb 2095 -2来特异性靶向该表位。在体外研究中，mAb 2095 -2恢复了细胞结合的单裂解曲妥珠单抗（scIgG-T）丧失的抗体依赖性细胞介导的细胞毒性功能。在体内，mAb 2095 -2挽救了异种移植肿瘤模型中scIgG-T的受损的Fc依赖性肿瘤抑制活性，并恢复了免疫效应细胞向肿瘤微环境中的募集。更重要的是，mAb 2095 -2的Fc工程化蛋白酶抗性版本在具有分泌IdeS的人癌细胞的小鼠肿瘤模型中挽救了曲妥珠单抗的抗肿瘤功效，而曲妥珠单抗单独在相同模型中显示出显著降低的抗肿瘤活性。同样，Fc工程化蛋白酶抗性形式的曲妥珠单抗也极大地改善了异种移植肿瘤模型中的抗肿瘤功效。总之，这些发现指出了一种新的癌症治疗策略，以通过针对铰链新表位的Fc工程化mAb来挽救抗体效应子功能的蛋白水解损伤，并克服抗体免疫的癌症逃避。(C)2014年AACR。
Primary and acquired resistance to anticancer antibody immunotherapies presents significant clinical challenges. Here, we demonstrate that proteolytic inactivation of cancer-targeting antibodies is an unappreciated contributor to cancer immune evasion, and the finding presents novel opportunities for therapeutic intervention. A single peptide bond cleavage in the IgG1 hinge impairs cancer cell killing due to structural derangement of the Fc region. Hinge-cleaved trastuzumab gradually accumulated on the surfaces of HER2-expressing cancer cell lines in vitro, and was greatly accelerated when the cells were engineered to express the potent bacterial IgG-degrading proteinase (IdeS). Similar to cancer-related matrix metalloproteinases (MMP), IdeS exposes a hinge neoepitope that we have developed an antibody, mAb2095-2, to specifically target the epitope. In in vitro studies, mAb2095-2 restored the lost antibody-dependent cell-mediated cytotoxicity functionality of cell-bound single-cleaved trastuzumab (scIgG-T). In vivo, mAb2095-2 rescued the impaired Fc-dependent tumor-suppressive activity of scIgG-T in a xenograft tumor model and restored the recruitment of immune effector cells into the tumor microenvironment. More importantly, an Fc-engineered proteinase-resistant version of mAb2095-2 rescued trastuzumab antitumor efficacy in a mouse tumor model with human cancer cells secreting IdeS, whereas trastuzumab alone showed significantly reduced antitumor activity in the same model. Consistently, an Fc-engineered proteinase-resistant version of trastuzumab also greatly improved antitumor efficacy in the xenograft tumor model. Taken together, these findings point to a novel cancer therapeutic strategy to rescue proteolytic damage of antibody effector function by an Fc-engineered mAb against the hinge neoepitope and to overcome cancer evasion of antibody immunity. (C) 2014 AACR.