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Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.

Bulliard, Yannick and Jolicoeur, Rose and Windman, Maurice and Rue, Sarah M and Ettenberg, Seth and Knee, Deborah A and Wilson, Nicholas S and Dranoff, Glenn and Brogdon, Jennifer L (2013) Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. The Journal of Experimental Medicine, 210 (9). pp. 1685-1693. ISSN 1540-9538

Abstract

Fc γ receptor (FcγR) coengagement can facilitate antibody-mediated receptor activation in target cells. In particular, agonistic antibodies that target tumor necrosis factor receptor (TNFR) family members have shown dependence on expression of the inhibitory FcγR, FcγRIIB. It remains unclear if engagement of FcγRIIB also extends to the activities of antibodies targeting immunoregulatory TNFRs expressed by T cells. We have explored the requirement for activating and inhibitory FcγRs for the antitumor effects of antibodies targeting the TNFR glucocorticoid-induced TNFR-related protein (GITR; TNFRSF18; CD357) expressed on activated and regulatory T cells (T reg cells). We found that although FcγRIIB was dispensable for the in vivo efficacy of anti-GITR antibodies, in contrast, activating FcγRs were essential. Surprisingly, the dependence on activating FcγRs extended to an antibody targeting the non-TNFR receptor CTLA-4 (CD152) that acts as a negative regulator of T cell immunity. We define a common mechanism that correlated with tumor efficacy, whereby antibodies that coengaged activating FcγRs expressed by tumor-associated leukocytes facilitated the selective elimination of intratumoral T cell populations, particularly T reg cells. These findings may have broad implications for antibody engineering efforts aimed at enhancing the therapeutic activity of immunomodulatory antibodies.

Item Type: Article
Additional Information: This manuscript was submitted to OAK for approval by the postdoc. Yannick has since left the company so I don't have access to edit the OAK submission.
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/11356

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