The role of activatory and inhibitory FcgR in antibody immunotherapy


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Mark Cragg, Emily Williams, Claude Chan, Alison Tutt, Jinny Kim, Kerry Cox, Ann White, Betty Lau, Annika Bruger, Stephen Beers, Sjef Verbeek, Ruth French, Martin Glennie

1Southampton University School of Medicine, UK, 2Leiden University Medical Center, Netherlands

Abstract

Work to date (both in humans and mouse models) indicates R-expressing effector cells (such as macrophages, neutrophilsgthat Fc and NK cells) are essential for effective antibody immunotherapy. Critically, R can be divided into two types: activating and inhibitory with thegFc relative level of signalling coming from these opposing receptors determining the immune/therapeutic outcome. To explore the role of the activatory R KO and gammagR in immunotherapy, we used a wide array of FcgFc chain KO mice and a selection of different mouse models. Using these models we have shown that immunostimulatory mAb such as anti-CD40 (unlike direct targeting mAb such as anti-Idiotype or anti-CD20 mAb) do not require the R for effective function in vivo. This knowledge allowsgactivatory Fc Rgfor these mAb to be engineered with Fc regions that do not engage Fc thereby reducing potentially unnecessary side-effects resulting from effector cell activation.

To investigate the potential of augmenting existing RIIb) wegantibody therapeutics by blocking the inhibitory receptor (Fc RIIb mAb that are entirely specific and doggenerated a new panel of Fc RIIb mAb fall intogR. These anti-Fcgnot cross-react with other Fc two distinct categories; those which cause tyrosine phosphorylation and subsequent activation of the receptor (stimulatory) and those which block RIIb mAbgreceptor phosphorylation (inhibitory).