CLEVER-1 Immune Checkpoint Molecule for Drug Development

Overview of Clever-1

Clever-1 (Common lymphatic endothelial and vascular endothelial receptor-1, also known as Stab1, Feel-1, and Stabilin-1), is a large and multifunctional glycoprotein receptor. It is expressed by sinusoidal endothelial cells in the adrenal cortex, liver, lymph nodes, and spleen. Indeed, the Clever-1 is expressed on the efferent and afferent arms of the lymph node lymphatic endothelium, subsets of immunosuppressive macrophages and circulating monocytes to a greater extent. Furthermore, pregnant women's placental macrophages also abundantly express the Clever-1, and this has been considered to promote immunosuppression allowing the mother's immune system to tolerate fetal antigens. Clever-1 is an acknowledged scavenger receptor that plays a role in the scavenging of apoptotic cells and molecules, and potential cancer antigens. Meanwhile, it is involved in angiogenesis, cell adhesion, and lymphocyte transmigration.

Structure of Clever-1

Clever-1 is encoded by the gene named Stab1, and the genomic nucleotide sequencing suggested that Clever-1 is a very large (approximately 270-280 kDa) and high evolutionary conservation type-I transmembrane protein with a large extracellular multidomain nature containing one X-link homology region, seven fascicles-like domains, and numerous EGF-like domains (act the function of cell/matrix interactions and homotypic adhesion). Stab1 contains 69 exons, which provides several potentialities for alternative splicing, and there are more than two isoforms of Clever-1 that have been found at the protein level and may manifest as cell-type specific.

Functions of Clever-1

Clever-1 with its distinctive ligand involved in sophisticated physiological clearance processes. For example, clever-1 can bind, internalize, and target degradation-modified forms of LDL, such as oxLDL and its analog acetylated acLDL using the classical endocytic pathway for the trafficking of extracellular ligands. Clever-1 performed the function of internalizing and clearing of secreted protein acidic and rich in cysteine (SPARC, a universal regulate molecule of tissue remodeling) through the extracellular EGF-like domain containing the sequence FHGTAC. Clever-1 plays the function of prohibiting the immune response against the tumors cells by mediating a fast removal and degradation action of those self-unneeded components including SPARC, underlying cancer antigens, advanced glycation end products (AGEs), and so on.

Clever-1 normally acts as an immunosuppressive molecule on monocyte by directly or indirectly regulates the ability of monocytes to polarise T cells into Th1 upon the stimulation of antigens. Recent studies also highlight its immunologic impact on tumor-associated macrophage (TAM) polarization. The blocking of Clever-1 expression on monocytes or macrophages appears a transformation, a change from the immunosuppressive M2 macrophages to the immunostimulatory M1 macrophages. This transformation has the ability to promote the macrophages to produce more TNF-α and support antibody production. Moreover, recent ex vivo and In vivo studies on vascular and lymphatic endothelial cells have shown that Clever-1 is involved in lymphocyte transmigration, and can mediate leukocyte and cancer cell trafficking via the lymphatic system into the draining lymph nodes and lymphocyte homing to the spleen.

Fig.1 A schematic representation of multiple functions of Clever-1.¹

Preclinical and Clinical Development of Drugs Targeting Clever-1

Clever-1 is a very versatile molecule, and there is much preclinical evidence unveiling that targeting Clever-1 is active in innate and adaptive T cell responses, and the clever-1 blocking agent targeting tumor immunotherapy has been particularly attractive in recent years. Studies in multiple solid tumor models found that removal of the clever-1 from macrophages can significantly delay tumor growth, implying clever-1 as a novel target in clinical cancer evaluation and immunotherapy. There are already some clever-1 inhibitors involving solid tumors currently in phase I/II clinical trials.

Services at Creative Biolabs

Creative Biolabs is a worldwide company with extensive scientific and medical expertise. If you are interested in Clever-1 and any other immune checkpoints and looking for a reliable partner, Creative Biolabs will be your best choice. Our comprehensive services for worldwide customers include but are not limited to:

• Custom Immune Checkpoint Protein Development
• Antibody Development for Immune Checkpoints
• Immune Checkpoint Targeted Peptide Development
• Immune Checkpoint Targeted Small Molecular Drug Development
• Biomarker Development for Immune Checkpoint Inhibitor (ICI)
• Immune Checkpoint Assays
• Preclinical Research on Immune Checkpoint Drugs

Please refer to our Services Overview for more information, and do not hesitate to contact us for more details. We are delighted to furnish comprehensive information about our offerings.

Reference

1. Hollmén, et al. "New tools to prevent cancer growth and spread: a 'Clever'approach." British journal of cancer 123.4 (2020): 501-509.

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