Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies

Ann L White ¹, H T Claude Chan ², Ruth R French ², Jane Willoughby ², C Ian Mockridge ², Ali Roghanian ², Christine A Penfold ², Steven G Booth ², Ali Dodhy ², Marta E Polak ³, Elizabeth A Potter ², Michael R Ardern-Jones ³, J Sjef Verbeek ⁴, Peter W M Johnson ², Aymen Al-Shamkhani ², Mark S Cragg ², Stephen A Beers ², Martin J Glennie ²

Affiliations

¹ Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK. Electronic address: a.l.white@soton.ac.uk.
² Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK.
³ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK.
⁴ Department of Human Genetics, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.

PMID: 25500122
60 References
61 citations

Abstract

Monoclonal antibody (mAb) drugs that stimulate antitumor immunity are transforming cancer treatment but require optimization for maximum clinical impact. Here, we show that, unlike other immunoglobulin isotypes, human IgG2 (h2) imparts FcγR-independent agonistic activity to immune-stimulatory mAbs such as anti-CD40, -4-1BB, and -CD28. Activity is provided by a subfraction of h2, h2B, that is structurally constrained due its unique arrangement of hinge region disulfide bonds. Agonistic activity can be transferred from h2 to h1 by swapping their hinge and CH1 domains, and substitution of key hinge and CH1 cysteines generates homogenous h2 variants with distinct agonistic properties. This provides the exciting opportunity to engineer clinical reagents with defined therapeutic activity regardless of FcγR expression levels in the local microenvironment.

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Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties. Valentina Ceglia, Sandra Zurawski, +6 authors, Gerard Zurawski. less J Immunol, 2021 Sep 24; 207(8). PMID: 34551965 Free PMC article.
Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies. Khiyam Hussain, Mark S Cragg, Stephen A Beers. Cancers (Basel), 2021 Oct 14; 13(19). PMID: 34638388 Free PMC article. Review.
Agonist antibody discovery: Experimental, computational, and rational engineering approaches. John S Schardt, Harkamal S Jhajj, +3 authors, Peter M Tessier. less Drug Discov Today, 2021 Sep 28; 27(1). PMID: 34571277 Free PMC article. Review.
Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments. Julia Moreno-Vicente, Jane E Willoughby, +11 authors, Stephen A Beers. less J Immunother Cancer, 2022 Jan 13; 10(1). PMID: 35017153 Free PMC article.
Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering. Franziska Heckel, Anna H Turaj, +12 authors, Sean H Lim. less Commun Biol, 2022 Mar 16; 5(1). PMID: 35288635 Free PMC article.

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