ADH-503 (GB1275, Leukadherin-1 choline) is a small-molecule allosteric agonist of CD11b that can render tumors more sensitive to checkpoint blockade.
ADH-503 rapidly decreased the genes involved in IL-1 signaling, increased the expression of cytokines involved in T cell and DC trafficking.
ADH-503 reduced the regulatory T cell (Treg) recruitment of cytokines CCL17 and CCL22 in PDAC-activated macrophages, down-regulated TGF-β1, IL-1α, and IL-1β and reduced alternative activation markers arginase-1 (Arg1), YM1, and Retnlα while upregulating type I interferons (IFNα1 and IFNβ) and T cell recruitment factors (CXCL9, CXCL10, and CXCL11).
ADH-503 reduced the numbers of total tumor-infiltrating CD11b+cells and subsets of CD11b+ monocytes, granulocytes, eosinophils, and macrophages on myeloid cells, improves T cell responses in vivo, induces the accumulation of CD103+ cDCs in the tumor.
ADH-503 impairs tumor growth and improves survival in orthotopic models and KPC GEMMs, also improves the efficacy of chemotherapy.