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Cancer Immunology, Immunotherapy

, Volume 62, Issue 5, pp 941–948 | Cite as

FcγRΙΙB controls the potency of agonistic anti-TNFR mAbs

  • Ann L. White
  • H. T. Claude Chan
  • Ruth R. French
  • Stephen A. Beers
  • Mark S. Cragg
  • Peter W. M. Johnson
  • Martin J. Glennie
Focussed Research Review

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.

Keywords

Anti-CD40 Isotype Immunomodulatory Cancer therapy CIMT 2012 

Notes

Acknowledgments

This work was funded by Cancer Research UK

Conflict of interest

The authors declare that they have no conflict of interest

Ethical statement

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ann L. White
    • 1
  • H. T. Claude Chan
    • 1
  • Ruth R. French
    • 1
  • Stephen A. Beers
    • 1
  • Mark S. Cragg
    • 1
  • Peter W. M. Johnson
    • 1
  • Martin J. Glennie
    • 1
  1. 1.Antibody and Vaccine Group, MP88, Cancer Sciences Unit, Faculty of MedicineSouthampton University HospitalSouthamptonUK

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