DNAM-1/CD226 Immune Checkpoint Molecule for Drug Development

Immune Checkpoint DNAM-1/CD226

DNAX Accessory Molecule-1 (DNAM-1), also known as Cluster of Differentiation 226 (CD226), is a kind of adhesion molecule expressed in a wide range of cells, including natural killer (NK) cells, NK T cells, T cells, a subset of B cells, dendritic cells, hematopoietic precursor cells, platelets, and monocytes.

ALTERNATE NAME CD226, PTA-1(outdated)
CELL TYPE AFFECTED NK cells, T cells, B cells, NK T cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes, etc.

Structure of DNAM-1/CD226

DNAM-1/CD226 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein, which is a member of the immunoglobulin (Ig) superfamily. It consists of 1) two extracellular Ig-like domains CD226-D1 and CD226-D2) of the V set, 2) a transmembrane domain of 28 aa, 3) eight N-glycosylation sites, and 4) a 60 aa cytoplasmic domain with three putative sites of phosphorylation by intracellular kinases.

Overall structure of the two IgV-like domains CD226 in human. (Wang, et al., 2019)Fig.1 Overall structure of the two IgV-like domains CD226 in human.1

Functions of DNAM-1/CD226

DNAM-1/CD226 is the only stimulatory receptor in the Ig superfamily. Since there is no tyrosine-based activation motif (which is recognized as essential for activating signal transduction of stimulatory molecules) in the intracellular domain of DNAM-1/CD226, it performs downstream signal transduction by phosphorylation of intracellular phosphorylation sites and association with integrin lymphocyte function-associated antigen. DNAM-1/CD226 plays broad roles in cellular adhesion, and regulation of NK cell functions. It is also reported to be involved in the crosstalk between T lymphocytes and NK cells, lysing activated T lymphocytes in graft versus host disease. Additionally, it is demonstrated that DNAM-1/CD226 can improve NK and T cell-mediated cytotoxicity against virus-infected cells and certain tumors.

DNAM-1/CD226 Immune Checkpoint Molecule for Drug Development

Different from all the known inhibitory Ig-like molecules, the unique mechanism and potential in predicting prognosis and immunotherapy response of DNAM-1/CD226 has drawn great interest. As induction of the expression of DNAM-1 and its ligand provides a prospective strategy for immune checkpoint drug development, many preclinical trials are currently being performed.

Table 1 Preclinical trials in promising target of DNAM-1/CD226.2

Treatment Immune cells Tumor Results
Anti-DMAN-1 or anti-PVR antibodies NK Neuroblastoma monoclonal antibody-mediated masking of either DNAM-1 (on NK cells) or PVR (on neuroblasts) resulted in strong inhibition of tumor cell lysis
Anti-DMAN-1 or anti-PVR antibodies NK Tumor cell lines The ability of NK-mediated lysis of tumor cells mediated by DNAM-1 engage with its ligands that were downregulated by antibody-mediated masking of the receptor or its ligands
anti-CD226 antibody NK Hepatoma Crosslinking CD226 with the anti-CD226 antibody regulates miR-30c-1* expression, which promotes NK cell cytotoxicity against hepatoma cells by targeting HMBOX1
DNAM-1 agonist NK Melanoma, experimental autoimmune encephalomyelitis DNAM-1 agonist could activate DNAM-1 modifies the bidirectional crosstalk of NK cells with CD155 DC, which can suppress CNS autoimmunity and strengthen tumor surveillance
Anti-CD226 antibody Tregs Allogeneic skin transplant CD226 antibody promoted Treg expansion, reduced inflammation, and prolonged allogeneic graft survival
Anti-CD226 antibody γδT Hepatocellular carcinoma Anti-DNAM-1 antibody-mediated masking experiments that γδT cells cytotoxicity against HCC cells, as well as IFN-γ production, were decreased
CD226 agonist antibody CD8+ T pancreatic ductal adenocarcinoma CD226 agonist antibody-mediated activation of CD226 augments the effect of TIGIT or PD-1 blockade on CD8 T-cell responses

Services at Creative Biolabs

With sufficient experience and proven R & D capabilities, Creative Biolabs provides professional immune checkpoint drug development services. Our technology platforms offer a full range of DNAM-1/CD226 immune checkpoint molecule drug development services, including but not limited to:

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  1. Wang, Han, et al. "Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5." Proceedings of the National Academy of Sciences 116.3 (2019): 988-996.
  2. Wu, Baokang, et al. "Poliovirus receptor (PVR)-like protein cosignaling network: new opportunities for cancer immunotherapy."Journal of Experimental & Clinical Cancer Research 40 (2021): 1-16.

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