Fcγ receptor dependency of agonistic CD40 antibody in lymphoma therapy can be overcome through antibody multimerization

Ann L White, Lang Dou, H T Claude Chan, Vikki L Field, C Ian Mockridge, Kane Moss, Emily L Williams, Steven G Booth, Ruth R French, Elizabeth A Potter, Cherié Butts, Aymen Al-Shamkhani, Mark S Cragg, J Sjef Verbeek, Peter W M Johnson, Martin J Glennie, Stephen A Beers

Research output: Contribution to journalArticle (Academic Journal)peer-review

33 Citations (Scopus)

Abstract

Immunomodulatory mAbs, led by the anti-CTLA4 mAb ipilimumab, are an exciting new class of drugs capable of promoting anticancer immunity and providing durable control of some tumors. Close analysis of a number of agents has revealed a critical yet variable role for Fcγ receptors in their efficacy. In this article, we reveal that agonistic anti-CD40 mAbs have an absolute requirement for cross-linking by inhibitory FcγRIIB when used systemically to treat established BCL1 syngeneic lymphoma, and therapy is lost when using a mouse IgG2a mAb not cross-linked by FcγRIIB. Furthermore, in FcγRIIB-deficient mice the lymphoma itself can provide FcγRIIB to cross-link anti-CD40 on neighboring cells, and only when this is blocked does therapy fail. The dependence on FcγRIIB for immunostimulatory activity was not absolute, however, because when anti-CD40 mAbs were administered systemically with the TLR3 agonist polyinosinic:polycytidylic acid or were given subcutaneously, activatory FcγR could also provide cross-linking. Using this mechanistic insight, we designed multimeric forms of anti-CD40 mAb with intrinsic FcγR-independent activity that were highly effective in the treatment of lymphoma-bearing mice. In conclusion, FcγR-independent anti-CD40 activation is a viable strategy in vivo. These findings have important translational implications, as humans, unlike mice, do not have IgG that binds strongly to FcγRIIB; therefore FcγR-independent derivatives represent an attractive therapeutic option.

Original languageEnglish
Pages (from-to)1828-35
Number of pages8
JournalJournal of Immunology
Volume193
Issue number4
DOIs
Publication statusPublished - 15 Aug 2014

Keywords

  • Animals
  • Antibodies, Monoclonal
  • Antigens, CD40
  • B-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation
  • Cells, Cultured
  • Immunoglobulin G
  • Immunotherapy
  • Lymphoma
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C
  • Protein Multimerization
  • Receptors, IgG
  • Surface Plasmon Resonance
  • Toll-Like Receptor 3

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