Next Generation Immune Checkpoint Inhibitor for Cancer Therapy

Immune checkpoint inhibitors (ICIs) for cancer therapy have revolutionized the treatment of several cancers. These ICIs are made from monoclonal antibodies that antagonize inhibitory signals via cytotoxic T-lymphocyte- associated antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) that block the tumoricidal activity of T cells. Although these ICIs have improved the overall survival of cancer patients such as cutaneous melanoma patients, only one third of patients has remained progression-free 5 years after initiating ICI therapy. This low efficacy is largely due to (1) the presence of immune suppressive regulatory T cells (Treg) within tumor microenvironment (TME) (2) the lack of efficacy of tumor penetration and retention. To improve the current ICI, this project RenTenTion aims to develop a next generation ICIs with smaller molecule so called single domain antibody (sdAb), give rise to enhanced tumor penetration. Targeting against a new immune checkpoint molecule 41-BB that highly expressed by intratumoral Treg, this next generation sdAb based ICI will inhibit tumor promoting immune cells Treg, while stimulate tumor rejecting immune cells such as effector T cells in tumors. Additionally, this project will couple the sdAb with collagen binding domain receptor so called leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) that bind to collagen in the tumor, therefore sustain tumor retention. This project “ReTenTion” will fill a gap for a strong need for new ICI molecules capable of addressing immunosuppressive in TME, yet smaller than conventional ICIs, boosting passive delivery.