EOS-448 is an anti-TIGIT human immunoglobulin G1, or IgG1, antibody that we are developing to inhibit the immunosuppressive activity of TIGIT. TIGIT is a cell surface receptor expressed on multiple immune cells, including CD8+ T cells, natural killer, or NK, cells and T regulatory cells, or Tregs, a cell population that inhibits the immune response and, in the context of cancer, promotes tumor growth by inhibiting the activation and proliferation of effector T cells and NK cells. TIGIT has also been shown to be a mediator of resistance to existing CPIs, including anti-PD-1. We have designed EOS-448 to have high affinity for TIGIT and also to actively engage FcγR. We have shown in preclinical studies using a mouse anti-TIGIT antibody that engagement of FcγR was an important mediator of antitumor activity in vivo. Engagement of FcγR by EOS-448 results in activation of a number of immune cells, including NK cells, macrophages and other effector cells, promoting inflammation and their cell killing function. Through engagement of FcγR and activation of ADCC, EOS-448 is designed to deplete Tregs, which are known to express high levels of TIGIT, within the tumor microenvironment. In our preclinical studies, we also showed that EOS-448 had superior binding to TIGIT and functional potency compared to a number of clinical-stage anti-TIGIT antibody equivalents.
EOS-448 blocks the TIGIT receptor, enhancing anti-tumor activity, and the death of tumor cells further augments the immune response.
1) EOS-448 binds to TIGIT, leaving the CD226 receptor free to bind to CD155 and CD112 without competition. This blocks activation of TIGIT’s immunosuppressive function and activates anti-tumor immune cells.
2) Tumor destruction can lead to cross presentation of antigens by Antigen Presenting Cells (APCs) to T cells and augmentation of the immune response.
EOS-448 depletes immunosuppressive Treg cells, and EOS-448 stimulates cytokines to activate more immune cells.
3) Regulatory T cells (Tregs) inhibit the anti-tumor function of cytotoxic T cells. EOS-448 binds to TIGIT which is highly expressed on the surface of Tregs and stimulates NK cells and macrophages via FcγR engagement. This releases cytotoxic T cells inhibition and enhances tumor cell killing.
4) NK and macrophage activation stimulates the release inflammatory cytokines that signal and activate other immune cells to further augment the anti-tumor response.