Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Publication date: 11 June 2018
Source:Cancer Cell, Volume 33, Issue 6
Author(s): Jeremy D. Waight, Dhan Chand, Sylvia Dietrich, Randi Gombos, Thomas Horn, Ana M. Gonzalez, Mariana Manrique, Lukasz Swiech, Benjamin Morin, Christine Brittsan, Antoine Tanne, Belinda Akpeng, Ben A. Croker, Jennifer S. Buell, Robert Stein, David A. Savitsky, Nicholas S. Wilson
The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.

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Teaser

Waight et al. report an FcγR-dependent, but independent of Treg depletion, mechanism of action of anti-CTLA-4 antibodies and show that Fc-FcγR co-engagement by anti-CTLA-4 antibodies improves T cell signaling and function. This mechanism also applies to anti-TIGIT and anti-CD45RB antibodies.


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