Combating HER2-overexpressing breast cancer through induction of calreticulin exposure by Tras-Permut CrossMab
Combating HER2-overexpressing breast cancer through induction of calreticulin exposure by Tras-Permut CrossMab
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通过 Tras-Permut CrossMab 诱导钙网蛋白暴露来对抗 HER2 过度表达的乳腺癌。
DOI：
10.4161/2162402x.2014.994391
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发表时间：
2015-03-01
期刊：
影响因子：
7.2
通讯作者：
Yang, Junlan
中科院分区：
文献类型：
--
作者：
Zhang, Fan;Zhang, Jie;Yang, Junlan
尽管曲妥珠单抗在乳腺癌治疗中取得了成功，但获得性耐药是乳腺癌治疗的主要障碍之一。迫切需要开发针对曲妥珠单抗耐药性的新型 HER2 抗体。在这里，我们首先合理设计了亲和力改善的曲妥珠单抗和帕妥珠单抗变体，并探讨了结合亲和力的改善与其抗肿瘤活性之间的相关性。在表征具有有效抗肿瘤活性的帕妥珠单抗变体 L56TY 后，由曲妥珠单抗和结合亲和力改进的帕妥珠单抗变体 L56TY 生成双特异性免疫球蛋白 G 样 CrossMab (Tras-Permut CrossMab)。虽然曲妥珠单抗的抗肿瘤功效并没有通过提高其结合亲和力而增强，但结合亲和力的提高可以显着增加帕妥珠单抗的抗增殖和抗体依赖性细胞毒性（ADCC）活性。进一步的研究表明，Tras-Permut CrossMab 在抑制曲妥珠单抗耐药性乳腺癌的进展方面表现出异常高的效率。值得注意的是，我们发现 Tras-Permut CrossMab 诱导的钙网蛋白 (CRT) 暴露对于诱导针对肿瘤复发的肿瘤特异性 T 细胞免疫至关重要。这些数据表明，Tras-Permut CrossMab 同时阻断 HER2 蛋白可以触发 CRT 暴露，随后诱导有效的肿瘤特异性 T 细胞免疫，这表明它可能是对抗曲妥珠单抗耐药性的一种有前途的治疗策略。
Although trastuzumab has succeeded in breast cancer treatment, acquired resistance is one of the prime obstacles for breast cancer therapies. There is an urgent need to develop novel HER2 antibodies against trastuzumab resistance. Here, we first rational designed avidity-imporved trastuzumab and pertuzumab variants, and explored the correlation between the binding avidity improvement and their antitumor activities. After characterization of a pertuzumab variant L56TY with potent antitumor activities, a bispecific immunoglobulin G-like CrossMab (Tras-Permut CrossMab) was generated from trastuzumab and binding avidity-improved pertuzumab variant L56TY. Although, the antitumor efficacy of trastuzumab was not enhanced by improving its binding avidity, binding avidity improvement could significantly increase the anti-proliferative and antibody-dependent cellular cytotoxicity (ADCC) activities of pertuzumab. Further studies showed that Tras-Permut CrossMab exhibited exceptional high efficiency to inhibit the progression of trastuzumab-resistant breast cancer. Notably, we found that calreticulin (CRT) exposure induced by Tras-Permut CrossMab was essential for induction of tumor-specific T cell immunity against tumor recurrence. These data indicated that simultaneous blockade of HER2 protein by Tras-Permut CrossMab could trigger CRT exposure and subsequently induce potent tumor-specific T cell immunity, suggesting it could be a promising therapeutic strategy against trastuzumab resistance.