Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK.
Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK.
Cancer Cell. 2020 Jun 8;37(6):850-866.e7. doi: 10.1016/j.ccell.2020.04.013. Epub 2020 May 21.
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.
抗 CD40 单克隆抗体（mAbs）包括激动剂和拮抗剂，它们分别在癌症和自身免疫性疾病中显示出有前景的治疗活性。我们之前曾表明，表位和同种型相互作用可提供最佳的激动性抗 CD40 mAbs。然而，Fc 工程对拮抗剂的影响在很大程度上仍未得到探索。在这里，我们表明，用于治疗自身免疫性疾病的临床相关拮抗剂可以通过同种型转换为 hIgG2 转化为有效的 FcγR 非依赖性激动剂，并具有显著的抗肿瘤活性。一种拮抗剂被转化为一种超激动剂，其效力大于先前报道的高度激动性抗 CD40 mAbs。这种转化依赖于 hIgG2 铰链的独特二硫键结合特性。这项研究强调了 hIgG2 同种型将拮抗剂转化为激动剂以治疗癌症的转化能力。
