Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote antitumor immunity
(1) Avraham Y (2) Barth N (3) Yair Bar-On T (4) Toval B (5) Habshush Menachem A (6) Blanga J (7) Herzog E (8) Rotem H (9) Shapir Itai Y (10) Feferman T (11) Biton M (12) Dahan R
Avraham and Barth et al. focused on optimizing the therapeutic potential of agonistic anti-GITR mAbs. Fc-engineered versions of human anti-GITR mAbs were evaluated in humanized FcγR mice. The Fc variant GA-aFuc (enhanced binding to hFcγRIIa and hFcγRIIIa, but not to inhibitory hFcγRIIb) outperformed other IgG scaffolds in tumor models via multiple FcγR-mediated pathways, and was less reliant on GITR agonism. These included selective Treg depletion in the TIME and increased CD4+ T cell and dendritic cell engagement and activation, resulting in cytotoxic Foxp3-CD4+ T cell activation and enhanced CD8+ T cell activity.
Contributed by Katherine Turner
(1) Avraham Y (2) Barth N (3) Yair Bar-On T (4) Toval B (5) Habshush Menachem A (6) Blanga J (7) Herzog E (8) Rotem H (9) Shapir Itai Y (10) Feferman T (11) Biton M (12) Dahan R
Avraham and Barth et al. focused on optimizing the therapeutic potential of agonistic anti-GITR mAbs. Fc-engineered versions of human anti-GITR mAbs were evaluated in humanized FcγR mice. The Fc variant GA-aFuc (enhanced binding to hFcγRIIa and hFcγRIIIa, but not to inhibitory hFcγRIIb) outperformed other IgG scaffolds in tumor models via multiple FcγR-mediated pathways, and was less reliant on GITR agonism. These included selective Treg depletion in the TIME and increased CD4+ T cell and dendritic cell engagement and activation, resulting in cytotoxic Foxp3-CD4+ T cell activation and enhanced CD8+ T cell activity.
Contributed by Katherine Turner
ABSTRACT: Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells. The antitumor activity of anti-GITR mAbs depends on the engagement of the fragment crystallizable (Fc) domain to their receptors (FcγRs); however, this has not been comprehensively investigated in human anti-GITR mAbs. Here, we used Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized mice. We identified an Fc-optimized human IgG scaffold that enhances antitumor efficacy through multiple FcγR-mediated mechanisms, including regulatory T cell depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to antitumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human anti-GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.
Author Info:
(1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Depa
rtment of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (8) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (9) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (10) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (11) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (12) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. rony.dahan@weizmann.ac.il.
