瑞士提契诺大学Luca Piccoli研究组近日取得一项新成果。他们发现单个T细胞表位导致多发性硬化患者对那他珠单抗的中和抗药物抗体反应。这一研究成果发表在2019年9月出版的国际学术期刊《自然—医学》上。

据悉，Natalizumab（NZM，中文名：那他珠）是整合素α4的人源化单克隆IgG4抗体，用于治疗复发缓解型多发性硬化症（MS）患者，但在约6％的病例中，持续中和抗药物抗体（ADA）的产生导致治疗停止。

为了解ADA反应的基础和ADA介导的中和机制，研究人员对两名患者的B细胞和T细胞反应进行了深入分析。通过表征一大类NZM特异性单克隆抗体，研究人员发现，在两名患者中，该反应是多克隆的并且靶向NZM独特型的不同表位。中和活性是通过体细胞突变获得的，并与缓慢解离率相关，这一发现得到了结构数据的支持。有趣的是，在两名患者中，通过CD4 阳性T细胞应答的分析与基于质谱的肽技术相结合，研究人员揭示了跨越NZM轻链的FR2-CDR2区域的单一免疫显性T细胞表位。此外，CDR细胞的CDR2修饰形式未被T细胞识别，同时保持与整合素α4的结合。总的来说，这些综合分析确定了导致ADA介导的治疗抗性的T细胞与B细胞合作的基础，并描述了设计自身免疫疾病和癌症治疗的新型去免疫抗体的方法。

附：英文原文

Title: A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients

Author: Antonino Cassotta, Vincent Mikol, Thomas Bertrand, Stphanie Pouzieux, Josiane Le Parc, Paul Ferrari, Jacques Dumas, Michael Auer, Florian Deisenhammer, Matteo Gastaldi, Diego Franciotta, Chiara Silacci-Fregni, Blanca Fernandez Rodriguez, Isabella Giacchetto-Sasselli, Mathilde Foglierini, David Jarrossay, Roger Geiger, Federica Sallusto, Antonio Lanzavecchia, Luca Piccoli

Issue&Volume: Volume 25 Issue 9

Abstract: Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4+ T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.

DOI: 10.1038/s41591-019-0568-2

Source:https://www.nature.com/articles/s41591-019-0568-2