Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab
Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab
复制标题
DOI：
10.1073/pnas.1617941114
复制
发表时间：
2017-05-23
影响因子：
11.1
通讯作者：
Almo, Steven C.
中科院分区：
文献类型：
--
作者：
Ramagopal, Udupi A.;Liu, Weifeng;Almo, Steven C.
用生物制剂合理调节免疫应答代表了实现新治疗策略的最有前途和最活跃的领域之一。特别是，使用靶向检查点抑制剂如CTLA-4和PD-1的功能阻断单克隆抗体已被证明对人体免疫系统的系统性激活高度有效，以治疗多种癌症。Ipilimumab是一种靶向CTLA-4的全人抗体，于2011年获得FDA批准用于治疗转移性黑色素瘤。Ipilimumab是第一种用于阻断CTLA-4的免疫抑制剂，并显著有益于转移性黑色素瘤患者的总生存期。了解这些单克隆抗体识别的化学和物理决定因素，可以直接了解途径阻断的机制，细胞表面抗原-抗体复合物的组织，以及进一步设计亲和力和选择性的机会。在这里，我们报告了由伊匹单抗与其人CTLA-4靶标形成的复合物的3.0埃分辨率X射线晶体结构。该结构揭示了伊匹单抗接触CTLA-4的前β-折叠并与CTLA-4：7识别表面相交，表明伊匹单抗和B7配体之间的直接空间重叠是伊匹单抗功能的主要机制贡献者。通过针对CTLA-4突变体文库的全面的基于细胞的结合测定和通过直接生物化学方法证实了晶体学上观察到的结合界面。该结构还突出了负责伊匹单抗相对于同源和功能相关的CD 28对CTLA-4表现出的选择性的决定因素。
Rational modulation of the immune response with biologics represents one of the most promising and active areas for the realization of new therapeutic strategies. In particular, the use of function blocking monoclonal antibodies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for the systemic activation of the human immune system to treat a wide range of cancers. Ipilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of metastatic melanoma in 2011. Ipilimumab is the first-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of patients with metastatic melanoma. Understanding the chemical and physical determinants recognized by these mAbs provides direct insight into the mechanisms of pathway blockade, the organization of the antigen-antibody complexes at the cell surface, and opportunities to further engineer affinity and selectivity. Here, we report the 3.0 angstrom resolution X-ray crystal structure of the complex formed by ipilimumab with its human CTLA-4 target. This structure reveals that ipilimumab contacts the front beta-sheet of CTLA-4 and intersects with the CTLA-4:.7 recognition surface, indicating that direct steric overlap between ipilimumab and the B7 ligands is a major mechanistic contributor to ipilimumab function. The crystallographically observed binding interface was confirmed by a comprehensive cell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches. This structure also highlights determinants responsible for the selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally related CD28.