White, Ann L., Chan, H.T. Claude, French, Ruth R., Willoughby, Jane E., Mockridge, C. Ian, Roghanian, Ali, Penfold, Christine A., Booth, Steven G., Dodhy, Ali, Polak, Marta E., Potter, Elizabeth A., Ardern-Jones, Michael R., Verbeek, J. Sjef, Johnson, Peter W.M., Al-Shamkhani, Aymen, Cragg, Mark S., Beers, Stephen A. and Glennie, Martin J. (2015) Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies. Cancer Cell, 27 (1), 138-148. (doi:10.1016/j.ccell.2014.11.001). (PMID:25500122)
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 Fc?R-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 Fc?R expression levels in the local microenvironment.
More information
Identifiers
Catalogue record
Export record
Altmetrics
Contributors
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.