FcgammaRIotaIotaB controls the potency of agonistic anti-TNFR mAbs.

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White AL, Chan HT, French RR, Beers SA, Cragg MS, Johnson PW, Glennie MJ

FcgammaRIotaIotaB controls the potency of agonistic anti-TNFR mAbs.

Cancer Immunol Immunother. 2013 May;62(5):941-8. doi: 10.1007/s00262-013-1398-6. Epub 2013 Mar 31.

PubMed ID

23543215 [ View in PubMed

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Abstract

Isotype plays a crucial role in therapeutic monoclonal antibody (mAb) function, mediated in large part through differences in Fcgamma receptor (FcgammaR) 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 FcgammaR engagement to mediate maximal target cell killing. In this setting, binding to inhibitory FcgammaRIIB is thought to inhibit function, making mAbs with high activatory/inhibitory (A/I) FcgammaR 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 FcgammaRIIB 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 FcgammaRIIB 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 FcgammaRIIB 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 FcgammaRIIB with tenfold higher affinity than IgG2a and hence has a relatively low A:I FcgammaR binding ratio. In contrast, human IgG isotypes have a universally low affinity for FcgammaRIIB, but in the case of human IgG1, engineering the Fc to increase its affinity for FcgammaRIIB 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Alemtuzumab	High affinity immunoglobulin gamma Fc receptor I	Protein	Humans	Unknown	Binder	Details
Alemtuzumab	Low affinity immunoglobulin gamma Fc region receptor II-b	Protein	Humans	Unknown	Binder	Details
Alemtuzumab	Low affinity immunoglobulin gamma Fc region receptor II-c	Protein	Humans	Unknown	Binder	Details