小柯机器人

英国南安普敦大学医学院Mark S. Cragg研究团队取得一项新突破。他们发现同型转换将抗CD40拮抗剂转换为激动剂，从而激发有效的抗肿瘤活性。相关论文在线发表在2020年5月21日出版的《癌细胞》杂志上。

研究人员发现用于治疗自身免疫性疾病的临床相关拮抗剂，可以通过同型转换hIgG2转化为具有显著抗肿瘤活性的强效FcγR非依赖性激动剂。与以前报道的抗CD40 单克隆抗体（mAb）强激动的相比，一种拮抗剂可以更有效地转化为超级激动剂。这种转化取决于hIgG2铰链独特的二硫键结合特性。该研究揭示了hIgG2通过同型转换将拮抗剂转化为激动剂以治疗癌症的转化能力。

研究人员表示，抗CD40 mAb包含激动剂和拮抗剂，分别在癌症和自身免疫中具有治疗潜力。先前研究表明抗CD40 mAb通过表位和同型相互作用以发挥最佳的激动剂作用。 但是，针对Fc的改造对拮抗剂的影响尚待探索。

附：英文原文

Title: Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity

Author: Xiaojie Yu, H.T. Claude Chan, Hayden Fisher, Christine A. Penfold, Jinny Kim, Tatyana Inzhelevskaya, C. Ian Mockridge, Ruth R. French, Patrick J. Duriez, Leon R. Douglas, Vikki English, J. Sjef Verbeek, Ann L. White, Ivo Tews, Martin J. Glennie, Mark S. Cragg

Issue&Volume: 2020-05-21

Abstract: Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcγR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer.

DOI: 10.1016/j.ccell.2020.04.013

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30212-9

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx