Inducible T-cell co-stimulator (ICOS, CD278) is an activating co-stimulatory immune checkpoint expressed on activated T cells. It can induce T-cell proliferation, survival, and differentiation, and regulate multiple T-cell functions. Its ligand, ICOSL, is expressed on antigen-presenting cells and somatic cells, including tumor cells in the tumor microenvironment. Binding of ICOS to its ligand triggers downstream pathways that regulate T-cell proliferation and survival. ICOS can serve as a biomarker for predicting and monitoring responses to T-cell-mediated immunotherapy.

Structure of ICOS

ICOS is a type I transmembrane glycoprotein composed of 199 amino acids and possessing a variable immunoglobulin (IgV) domain. ICOS exists as a disulfide-linked homodimer on the T cell surface. The FDPPPF motif (consisting of amino acids 114-120) in the FG loop of ICOS forms key interactions with residues in the CC' and C'D loops of ICOS-L, including hydrogen bonds and aromatic stacking. Binding of ICOS to its ligand, ICOSL, triggers cellular signaling.

(Data source: Rujas E, et al. Nat Commun. 2020)

Signaling pathways and regulation of ICOS in Tregs:

The ICOS-ICOSL interaction promotes the generation, proliferation, survival, and suppressive capacity of regulatory T cells (Tregs) through a complex signaling pathway. First, ICOS activation promotes Foxp3 transcription, favoring NFAT binding to FOXP3 rather than AP-1, and upregulating FOXP3 downstream regulatory genes such as Il-10 and Tgf-β. Second, ICOS participates in inducing PI3K recruitment to the YMFM motif in its cytoplasmic tail and inducing Akt phosphorylation. Akt activation induces Bcl-2 expression and inhibits the production of pro-apoptotic Bcl-2 family proteins, thereby promoting the survival of ICOS+ Tregs. Furthermore, ICOS activates mTORC1 signaling, which is hypothesized to mediate protein synthesis and metabolism in Tregs. Furthermore, ICOS expression increases CXCR3 expression, promoting the migration of Tregs into inflamed tissues.

(Data source: Li DY, et al. Front Immunol. 2020)

Dual roles of ICOS in tumors

ICOS has both pro-tumor and anti-tumor effects in tumors; ICOS promotes the activation of anti-tumor cytotoxic T cells, thereby exerting anti-tumor effects. ICOS also promotes the function and maintenance of regulatory T cells (Tregs), which can suppress immune cells and thus promote tumor evasion of immune surveillance.

(Data source: Amatore F, et al. Expert Opin Biol Ther. 2020)

ICOS targeted drugs:

Currently, no ICOS antibodies have been approved for marketing globally. Feladilimab (GSK3359609), developed by GSK, has made the most rapid clinical progress. Feladilimab is a humanized, non-T cell-depleting IgG4 antibody, meaning it activates ICOS without consuming T cells. This helps further enhance T cell immune responses and has the potential to improve the efficacy of immune checkpoint inhibitors. However, in August 2021, GSK announced the discontinuation of the trial.

Acazicolcept, a CD28/ICOS bispecific antibody developed by Alpine, is currently in Phase II clinical development for the treatment of systemic lupus erythematosus (SLE). By simultaneously blocking two key co-stimulatory pathways, acazicolcept has the potential to improve outcomes for patients with severe autoimmune/inflammatory diseases.

(Data source: Alpine's official website)

Xencor's investigational Izuralimab (ICOS/PD-1) bispecific antibody is designed to promote tumor-selective T cell activation. In preclinical studies, the synergistic effects of PD-1 blockade and ICOS co-stimulation significantly enhanced T cell proliferation, activation, and anti-tumor activity in vivo. Currently in Phase II clinical trials, this antibody is primarily intended for the treatment of advanced sarcomas, central nervous system diseases, and metastatic melanoma.

(Data source: New Drug Intelligence Database)