Abstract
Isotype plays a crucial role in therapeutic monoclonal antibody (mAb) function, mediated in large part through differences in Fcγ receptor (FcγR) interaction. Monoclonal Abs such as rituximab and alemtuzumab, which bind target cells directly, are designed for efficient recruitment of immune effector cells through their activatory FcγR engagement to mediate maximal target cell killing. In this setting, binding to inhibitory FcγRIIB is thought to inhibit function, making mAbs with high activatory/inhibitory (A/I) FcγR binding ratios, such as mouse IgG2a and human IgG1, the first choice for this role. In contrast, exciting new data show that agonistic mAbs directed against the tumour necrosis factor receptor superfamily member CD40 require interaction with FcγRIIB for in vivo function. Such ligation activates antigen-presenting cells, promotes myeloid and CTL responses and potentially stimulates effective anti-cancer immunity. It appears that the role of FcγRIIB is to mediate mAb hyper-crosslinking to allow CD40 downstream intracellular signalling. Previous work has shown that mAbs directed against other TNFR family members, Fas and death receptor 5 and probably death receptor 4, also require FcγRIIB hyper-crosslinking to promote target cell apoptosis, suggesting a common mechanism of action. In mouse models, IgG1 is optimal for these agents as it binds to FcγRIIB with tenfold higher affinity than IgG2a and hence has a relatively low A:I FcγR binding ratio. In contrast, human IgG isotypes have a universally low affinity for FcγRIIB, but in the case of human IgG1, engineering the Fc to increase its affinity for FcγRIIB can potentially overcome this problem. Thus, modifying the A/I binding ratio of human IgG Fc can be used to optimise different types of therapeutic activity by enhancing cytotoxic or hyper-crosslinking function.
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This work was funded by Cancer Research UK
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Animal experiments were cleared through local ethical committee and performed under Home Office licences PPL30/2450 and 30/2451 and 30/2964
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This paper is a Focussed Research Review based on a presentation given at the Tenth Annual Meeting of the Association for Cancer Immunotherapy (CIMT), held in Mainz, Germany, 23rd–25th May 2012. It is part of a CII series of Focussed Research Reviews and meeting report.
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White, A.L., Chan, H.T.C., French, R.R. et al. FcγRΙΙB controls the potency of agonistic anti-TNFR mAbs. Cancer Immunol Immunother 62, 941–948 (2013). https://doi.org/10.1007/s00262-013-1398-6
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DOI: https://doi.org/10.1007/s00262-013-1398-6