CD6 is a type I transmembrane glycoprotein that belongs to the highly conserved scavenger receptor cysteine-rich superfamily (SRCR-SF). It is expressed on all developing and mature T lymphocytes. Due to its unique functional epitopes, CD6 has multiple complex functions. CD6 participates in lymphocyte activation and differentiation following adhesion to antigen-presenting cells . The interaction between CD6 and its ligands is crucial in the pathogenesis of various autoimmune diseases and cancers.

CD6 expression distribution

CD6 is primarily expressed on T cells and NK cells, with smaller amounts on B cells, dendritic cells, and macrophages. CD6 expression is typically low on immature thymocytes but increases with thymocyte maturation, reaching its highest expression on mature single-positive thymocytes (CD4 or CD8).

(Data source: Uniprot)

The structure of CD6

CD6 is a type I transmembrane protein composed of an extracellular domain, a transmembrane region, and a long cytoplasmic tail. Its extracellular region contains three scavenger receptor cysteine-rich (SRCR) domains and a membrane-proximal stalk, while its intracellular region contains phosphorylation sites. The three SRCR domains (highly conserved across species) are responsible for its interaction with multiple CD6 ligands.

(Data source: Chappell PE, et al. Structure. 2015)

CD6 ligand

CD6 ligands primarily include CD166/ALCAM, CD318, and CD44. CD44 is a potential new ligand recently discovered through proximity labeling. The membrane-proximal SRCR domain of CD6 binds to the N-terminal domain of CD166, while CD318 binds to the third extracellular SRCR domain of CD6. Monoclonal anti-CD6 antibodies can target the interaction between CD6 and its ligands, CD166 and CD318, and hold promise for the treatment of tumor immunotherapy and autoimmune diseases.

CD166 is expressed by a variety of cell types, including activated T cells, monocytes, epithelial cells, fibroblasts, and cancer cells. CD166 has been implicated in the pathogenesis of lupus nephritis, rheumatoid arthritis, Sjögren's syndrome, and inflammatory bowel disease.

CD318 is expressed by epithelial cells of both normal and cancer cells and is involved in inflammatory responses, autoimmunity, and cancer. Overexpression of CD318 is strongly associated with adverse outcomes in many cancers, including breast, lung, colorectal, ovarian, renal, prostate, and pancreatic cancers.

(Data source: Gurrea-Rubio M, et al. Front Immunol. 2025)

CD6-targeted therapy

Alzumab ( Itolizumab ) is a monoclonal antibody targeting CD6. It was approved for marketing in India in January 2013. In December 2019, the FDA granted it Fast Track designation for lupus nephritis. In October 2019, Exlimir announced the initiation of a Phase Ib clinical trial of itolizumab (EQ001) in patients with lupus nephritis and provided an update on its ongoing clinical programs.

(Data source: Gurrea-Rubio M, Fox DA, Castresana JS. Cells . 2025)

UMCD6 has a unique dual effect of blocking the CD6/CD318 interaction . It is an anti-CD6 monoclonal antibody known to block T cell-dependent autoimmunity by affecting the differentiation of effector CD4+ T cell subsets, while also activating the anti-cancer cytotoxic properties of CD8+ T and NK cells . The drug is currently in preclinical development.

(Data source: Gurrea-Rubio M, et al. Front Immunol. 2025)