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

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...

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Bibliographic Details
Published in:	Cancer cell 2018-06, Vol.33 (6), p.1033-1047.e5
Main Authors:	Waight, Jeremy D., Chand, Dhan, Dietrich, Sylvia, Gombos, Randi, Horn, Thomas, Gonzalez, Ana M., Manrique, Mariana, Swiech, Lukasz, Morin, Benjamin, Brittsan, Christine, Tanne, Antoine, Akpeng, Belinda, Croker, Ben A., Buell, Jennifer S., Stein, Robert, Savitsky, David A., Wilson, Nicholas S.
Format:	Article
Language:	eng
Subjects:	Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - metabolism Antibodies, Monoclonal - therapeutic use Antigen-Presenting Cells - immunology Antigen-Presenting Cells - metabolism Antigens, Differentiation, T-Lymphocyte - immunology Antigens, Differentiation, T-Lymphocyte - metabolism cancer immunotherapy CD45RB CTLA-4 CTLA-4 Antigen - immunology CTLA-4 Antigen - metabolism effector T cells Fc engineering Fcγ receptor Humans immune synapse Mice, Inbred BALB C Mice, Inbred C57BL Neoplasms - drug therapy Neoplasms - immunology Neoplasms - metabolism Protein Binding Receptors, Antigen, T-Cell - immunology Receptors, Antigen, T-Cell - metabolism Receptors, IgG - immunology Receptors, IgG - metabolism Receptors, Immunologic - immunology Receptors, Immunologic - metabolism regulatory T cells Signal Transduction - drug effects Signal Transduction - immunology T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism TCR signaling TIGIT
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Summary:	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. [Display omitted] •CTLA-4 and TIGIT mAbs required human FcγRIIIA on APCs for optimal T cell responses•FcγRIV contributed to CTLA-4 mAb activity in mice, independent of Treg cells•Fc-FcγR co-engagement by anti-CTLA-4 mAbs modulated both TCR and CD28 signaling•Fc-FcγR co-engagement enhanced Treg cell expansion by an mAb targeting CD45RB 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.
ISSN:	1535-6108 1878-3686