2. Academic Validation
  3. Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity

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

  • Cancer Cell. 2020 Jun 8;37(6):850-866.e7. doi: 10.1016/j.ccell.2020.04.013.
Xiaojie Yu 1,  H T Claude Chan 2,  Hayden Fisher 3,  Christine A Penfold 2,  Jinny Kim 2,  Tatyana Inzhelevskaya 2,  C Ian Mockridge 2,  Ruth R French 2,  Patrick J Duriez 4,  Leon R Douglas 4,  Vikki English 5,  J Sjef Verbeek 6,  Ann L White 2,  Ivo Tews 7,  Martin J Glennie 2,  Mark S Cragg 8
Affiliations

Affiliations

  • 1 Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK. Electronic address: x.yu@soton.ac.uk.
  • 2 Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK.
  • 3 Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK; Biological Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
  • 4 CRUK Protein Core Facility, University of Southampton Faculty of Medicine, Southampton, UK.
  • 5 Pre-clinical Unit, University of Southampton Faculty of Medicine, Southampton, UK.
  • 6 Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
  • 7 Institute for Life Sciences, University of Southampton, Southampton, UK; Biological Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
  • 8 Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK; Institute for Life Sciences, University of Southampton, Southampton, UK. Electronic address: msc@soton.ac.uk.
PMID: 32442402 DOI: 10.1016/j.ccell.2020.04.013
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.

Keywords

CD40; Fc engineering; TNF receptor; agonists; antagonists; antibody; hIgG2; immunostimulatory; immunotherapy; structure function.

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