White, Ann, Dou, Lang, Chan, Hak, Field, Vikki, Mockridge, Christopher, Booth, Steven, Williams, Emily, French, Ruth, Al-Shamkhani, Aymen, Cragg, Mark, Johnson, Peter, Glennie, Martin, Beers, Stephen, Potter, Elizabeth, Butts, Cherie, Verbeek, J.S. and Moss, Kane (2014) Fcy receptor dependency of agonistic CD40 antibody in lymphoma therapy can be overcome through antibody multimerization. Journal of Immunology, 193 (4), 1828-1835. (doi:10.4049/jimmunol.1303204). (PMID:25024386)
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 Fc? receptors in their efficacy. In this article, we reveal that agonistic anti-CD40 mAbs have an absolute requirement for cross-linking by inhibitory Fc?RIIB when used systemically to treat established BCL1 syngeneic lymphoma, and therapy is lost when using a mouse IgG2a mAb not cross-linked by Fc?RIIB. Furthermore, in Fc?RIIB-deficient mice the lymphoma itself can provide Fc?RIIB to cross-link anti-CD40 on neighboring cells, and only when this is blocked does therapy fail. The dependence on Fc?RIIB 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 Fc?R could also provide cross-linking. Using this mechanistic insight, we designed multimeric forms of anti-CD40 mAb with intrinsic Fc?R-independent activity that were highly effective in the treatment of lymphoma-bearing mice. In conclusion, Fc?R-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 Fc?RIIB; therefore Fc?R-independent derivatives represent an attractive therapeutic option
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