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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I23-Long wavelength MX	Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility Christian M. Orr , Hayden Fisher , Xiaojie Yu , Claude H.-T. Chan , Yunyun Gao , Patrick J. Duriez , Steven G. Booth , Isabel Elliott , Tatyana Inzhelevskaya , Ian Mockridge , Christine A. Penfold , Armin Wagner , Martin J. Glennie , Ann L. White , Jonathan W. Essex , Arwen R. Pearson , Mark S. Cragg , Ivo Tews Science Immunology 7 DOI: 10.1126/sciimmunol.abm3723 Diamond Proposal Number(s): [22563] Open Access Show Abstract ▼ Abstract: Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural “switch” affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.	Jul 2022
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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