CD46

What is CD46?

Human CD46, also known as membrane cofactor protein (MCP), belongs to the family of complement activation regulator (RCA) proteins and is a type I transmembrane glycoprotein that is expressed on most tissues as four major isoforms derived by alternative splicing of a single gene.  CD46 is widely distributed on most of the normal cell surface, including hematopoietic cell lines, fibroblasts, epidermal cells, endothelial cells and stellate cells, but the number of cells expressed on different types of cells is Different.

The function of CD46

CD46 is an intrinsic cofactor for the factor-I-mediated cleavage of C3b and C4b. Intrinsic refers to the fact that CD46 efficiently aids in cleaving C3b or C4b that is deposited on the same cell as CD46 itself. The cleavage of C3b produces the fragment C3bi, which is unable to support further complement activation. The cleavage of C4b by factor I and CD46 produces the fragments C4c and C4d. C4c is liberated into the extracellular milieu whereas C4d, incapable of continuing the complement cascade, remains attached to the target. CD46 is most effective in controlling the amplification loop of the alternative pathway. It may be involved in the fusion of the spermatozoa with the oocyte during fertilization.

Additionally, CD46 also acts as a costimulatory factor for T-cells which induces the differentiation of CD4+ into T-regulatory 1 cells. T-regulatory 1 cells suppress immune responses by secreting interleukin-10, and therefore are thought to prevent autoimmunity.

CD46 and Disease

A large number of studies have demonstrated that CD46 is associated with a variety of immune-inflammatory diseases. Sandra et al. found that high expression of CD46 in people who have quit smoking prevent emphysema and chronic obstructive pulmonary disease caused by autoimmune and inflammatory reaction.

Currently, more than 60 disease-associated mutations in CD46 have now been identified. The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified.

CD46 Clinical Drug Information

So far, there are four drugs about CD46 in clinical trial, including Enadenotucirev (launched by PsiOxus Therapeutics, Merck Sharp & Dohme), Carcinoembryonic antigen-expressing measles virus (launched by National Cancer Institute), AugmAb (launched by BRIM Biotechnology, PAI Life Sciences) and FOR-46 (launched by University of California San Diego). Except Enadenotucirev, The research of other three drugs are at phase I, and Enadenotucirev is at phase II.

Regard reading: CD46, A Complement Regulator

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