TSP-1 activator VT1021

A cyclic pentapeptide and stimulator of thrombospondin 1 (TSP-1; THBS1), with potential anti-angiogenic, immunomodulating and antineoplastic activities. Upon administration, TSP-1 activator VT1021 specifically stimulates TSP-1 expression in inflammatory myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME), which binds to TSP-1 receptors, mainly CD36 and CD47. This activates CD36-mediated signaling and induces apoptosis in tumor and endothelial cells, which may result in the inhibition of tumor cell proliferation. The binding of TSP-1 to CD47 prevents the interaction between CD47 and the signal regulatory protein alpha (SIRPalpha; SIRPa) that is expressed on phagocytic cells. This prevents CD47/SIRPa-mediated signaling and abrogates the CD47/SIRPa-mediated inhibition of macrophage activation and phagocytosis of cancer cells. In addition, VT1021 can reprogram the immunosuppressive TME, skewing macrophages from the immune suppressive M2 phenotype to an effector M1 phenotype, increasing the infiltration of cytotoxic T lymphocytes (CTLs) while decreasing regulatory T cells (Tregs) in the TME, thereby stimulating an anti-tumor immune response and further killing tumor cells.