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Instruments / Technical Area	Publication Details	Published	Actions
B21-High Throughput SAXS	Isotype switching converts anti-CD40 antagonism to agonism to elicit potent antitumor activity 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 Cancer Cell DOI: 10.1016/j.ccell.2020.04.013 Diamond Proposal Number(s): [21035] Open Access Show Abstract ▼ 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.	May 2020

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