Journal Article
. 2014 Dec; 27(1):138-48.
doi: 10.1016/j.ccell.2014.11.001.

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
  • 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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Pharmacol Ther, 2020 Oct 23; 219. PMID: 33091428    Free PMC article.
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Isotype selection for antibody-based cancer therapy.
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Clin Exp Immunol, 2020 Nov 07; 203(3). PMID: 33155272    Free PMC article.
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Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily.
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Front Cell Dev Biol, 2021 Mar 02; 8. PMID: 33644033    Free PMC article.
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Coming together at the hinges: Therapeutic prospects of IgG3.
Thach H Chu, Edward F Patz, Margaret E Ackerman.
MAbs, 2021 Feb 20; 13(1). PMID: 33602056    Free PMC article.
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Agonistic CD40 Antibodies in Cancer Treatment.
Dijana Djureinovic, Meina Wang, Harriet M Kluger.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33804039    Free PMC article.
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OX40 as a novel target for the reversal of immune escape in colorectal cancer.
Lin-Hai Yan, Xiao-Liang Liu, +3 authors, Wei-Zhong Tang.
Am J Transl Res, 2021 Apr 13; 13(3). PMID: 33841630    Free PMC article.
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Rigid monoclonal antibodies improve detection of SARS-CoV-2 nucleocapsid protein.
Curtis D Hodge, Daniel J Rosenberg, +4 authors, Michal Hammel.
MAbs, 2021 Apr 13; 13(1). PMID: 33843452    Free PMC article.
TNF receptor agonists induce distinct receptor clusters to mediate differential agonistic activity.
Xiaojie Yu, Sonya James, +14 authors, Mark S Cragg.
Commun Biol, 2021 Jun 25; 4(1). PMID: 34162985    Free PMC article.
Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties.
Valentina Ceglia, Sandra Zurawski, +6 authors, Gerard Zurawski.
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.
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Agonist antibody discovery: Experimental, computational, and rational engineering approaches.
John S Schardt, Harkamal S Jhajj, +3 authors, Peter M Tessier.
Drug Discov Today, 2021 Sep 28; 27(1). PMID: 34571277    Free PMC article.
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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.
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.
Commun Biol, 2022 Mar 16; 5(1). PMID: 35288635    Free PMC article.