Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a cell surface glycoprotein receptor involved in the costimulatory signaling of T cell receptor (TCR)-mediated T cell activation. CD26 possesses serine exopeptidase activity and can cleave a variety of substrates, such as chemokines, growth factors, fibronectin, neuropeptides, and incretin hormones (gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)), to regulate various physiological processes. It is also involved in inflammatory processes, including cancer, obesity, and type 2 diabetes. Furthermore, DPP-4 is negatively correlated with bone mineral density, suggesting a potential link to osteoporosis.

Expression distribution of DPP4

DPP4 is primarily expressed in proximal intestinal cells, prostate glandular cells, syncytiotrophoblasts, serous gland cells, and cytotrophoblasts, and is expressed to a lesser extent in T cells, B cells, granulocytes, dendritic cells, macrophages, Hofbauer cells, and Langerhans cells.

(Data source: Uniprot)

Structure of DPP4 and its receptor

DPP4 is a transmembrane protein with a total length of 766 amino acids, consisting of a short cytoplasmic tail, a transmembrane hydrophobic segment, and an extracellular domain. In addition to its membrane-bound form, DPP4 can also be cleaved from the cell membrane and released into plasma and other body fluids, resulting in a soluble form lacking the cytoplasmic and transmembrane domains. Because the catalytic domain is located in the extracellular region, soluble DPP4 retains enzymatic activity. The extracellular domain is further divided into three regions: a glycosylated region, a cysteine-rich region, and a catalytic region (or C-terminal region). The glycosylated region and the cysteine-rich region participate in the enzyme's non-enzymatic functions and interact with other proteins, such as adenosine deaminase (ADA), caveolin-1, streptokinase, and plasminogen, as well as extracellular matrix components, such as collagen and fibronectin.

(Data from Torrecillas-Baena B, et al. Stem Cell Rev Rep. 2022)

Functions of DPP4

DPP4 is a multifunctional protein with both enzymatic and non-enzymatic functions. It is involved in immune regulation, fibrosis, and the progression of autoimmune diseases, and has dual effects (pro-inflammatory and anti-inflammatory, pro-fibrotic and anti-fibrotic).

Enzyme activity function

DPP4 changes the biological activity of substrates with N-terminal X-Pro or X-Ala sequences (such as glucagon-like peptide-1 (GLP-1), chemokine CXCL12, SDF-1, etc.) .

Non-enzymatic function

DPP4 acts as a positive regulator of T cell coactivation by binding to at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T cell proliferation and NF-kappa B activation in a TCR/CD3-dependent manner. Interaction with ADA also regulates lymphocyte-epithelial cell adhesion, which is associated with FAP and involves degradation of the pericellular matrix, as well as endothelial cell migration and invasion into the matrix. It may participate in lymphatic endothelial cell adhesion, migration, and lumen formation. When overexpressed, it enhances cell proliferation, a process inhibited by GPC3.

T cells: act as co-stimulatory molecules for Th1 and Th17 cells, promoting the secretion of pro-inflammatory cytokines (such as IFN-γ and IL-17); inhibiting Treg cell function.

B cells: involved in B cell activation, DNA synthesis and immunoglobulin secretion.

NK cells: maintain cytotoxicity and mediate CD16-dependent lytic responses.

Dendritic cells (DCs): modify macrophage-derived chemokines, thereby attracting Th1 cells. DPP4 regulates adenosine concentration and inflammatory responses in the VAT microenvironment by binding to adenosine deaminase ( ADA ) .

Macrophages: Promote T cell proliferation by regulating adenosine concentration in the microenvironment.

(Data source: Huang J, et al. Front Immunol. 2022)

The relationship between DPP4 and disease

DPP-4 is produced by bone marrow mesenchymal cells, liver, and adipose tissue, and receptor activator of nuclear factor κB ligand (RANKL) induces DPP-4 expression in osteoclasts, leading to decreased GLP-1 levels and increased blood glucose levels. Furthermore, DPP-4 cleaves various sites on chemokines, interleukins, and other cytokines actively involved in bone remodeling . DPP-4 may indirectly regulate bone remodeling by interacting with multiple peptide substrates on osteocytes, including GLP-1, glucagon-like peptide-2 (GLP-2), GIP, NPY, and PYY.

(Data source: Pechmann LM, et al. Diabetol Metab Syndr. 2024)

DPP4-targeted therapy

The primary treatment for DPP4 is small molecule inhibitors, and few antibody drugs are currently in clinical development. YS-110 is the only monoclonal antibody currently in clinical development. A Phase 1 clinical trial of YS110 found that weekly doses of up to 6 mg/kg were generally well tolerated and demonstrated promising efficacy in 33 patients with advanced or refractory CD26-expressing tumors, including malignant mesothelioma, renal cell carcinoma, and urothelial carcinoma.

ZHB015, developed by ZonHonbio, is a bispecific T cell binder targeting DPP4. Its Phase 1 clinical trial application has been approved by the National Medical Products Administration.