Common lymphatic endothelial and vascular endothelial receptor 1 (CLEVER-1) (CLEVER-1)

Common lymphatic endothelial and vascular endothelial receptor 1 (CLEVER-1), also known as Stabilin-1, is a large multifunctional scavenger receptor and adhesion molecule primarily expressed on lymphatic endothelial cells and immunosuppressive M2-polarized macrophages (Kzhyshkowska et al., 2006). It plays a pivotal role in the regulation of immune homeostasis by facilitating the clearance of apoptotic cells and regulating the trafficking of leukocytes to tissues (Karikoski et al., 2014). In the context of oncology, CLEVER-1 is a significant immune checkpoint; its expression on tumor-associated macrophages (TAMs) promotes an immunosuppressive microenvironment that allows tumors to evade the immune system (Viitala et al., 2019). The soluble form of the receptor, sCLEVER-1, is a circulating variant that results from the shedding of the membrane-bound protein and serves as a potential systemic biomarker for monitoring disease progression and therapeutic response (Tadayon et al., 2021). Therapeutic targeting of CLEVER-1, most notably with the antibody bexmarilimab, aims to reprogram the tumor microenvironment by converting suppressive macrophages into an immunostimulatory phenotype, thus enhancing the efficacy of anti-tumor T-cell responses (Hollmén et al., 2020). By blocking the interaction between CLEVER-1 and its ligands, these therapies seek to transform "cold" non-responsive tumors into "hot" tumors susceptible to immune attack.

Other names

Stabilin-1STAB1FEEL-1Fasciclin EGF-like laminin-type EGF-like and link domain-containing scavenger receptor 1Soluble CLEVER-1sCLEVER-1

Bexmarilimab is a humanized monoclonal antibody that binds to the extracellular domain of CLEVER-1, preventing its immunosuppressive signaling and inducing a phenotypic switch in tumor-associated macrophages from a pro-tumoral M2-like state to a pro-inflammatory M1-like state, thereby stimulating anti-tumor T-cell activity.