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

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. [Display omitted] •Antagonistic anti-CD40 mAbs can be converted into agonists by isotype switching to hIgG2•Transformation is based upon the hIgG2 hinge•Transforms an antagonist to an agonist four times more potent than existing anti-CD40 mAbs•This converted antagonist exhibits antitumor synergy with cell therapy and vaccination Yu et al. show that isotype switching can convert clinically relevant anti-CD40 antagonistic antibodies to potent FcγR-independent agonists. The converted antibodies can elicit strong antitumor responses in mouse models.