Integrin αVβ6 (ITGAV: ITGB6) is a receptor for fibronectin and cellular actin. It recognizes the RGD sequence in its ligands. Internalization of integrin α-V/β-6 via clathrin-mediated endocytosis promotes cancer cell invasion. ITGB6 is a key subunit controlling the expression of the entire heterodimer αvβ6. ITGB6 directly binds to LAP-TGFβ via the αvβ6 integrin, triggering TGFβ maturation and release. This in turn induces regulatory T cell differentiation and inhibits CD8⁺ T cell activity, creating an immunosuppressive microenvironment. It plays a crucial role in cancer regulation .
Expression distribution of ITGB6
ITGB6 is mainly expressed in epithelial cells, such as basal respiratory cells, alveolar cell type 2, exocrine gland cells, alveolar cell type 1, collecting duct cells, and duct cells.
(Data source: Uniprot)
ITGB6 is overexpressed in a variety of solid tumors, such as bladder cancer, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma ( HNSCC ) , pancreatic cancer, etc.
(Data source: Uniprot)
Structure and function of ITGB6
ITGB6 is located on chromosome 2q24-q31 and is encoded by ITGB6. This protein forms a heterodimer with integrin αv (ITGAV), termed integrin αvβ6. Each subunit consists of a large extracellular head, a flexible leg, a transmembrane segment, and a short cytoplasmic tail. While ITGAV primarily recognizes ligands, ITGB6 transduces signals by binding to other cellular signaling molecules and proteins. Furthermore, ITGB6 is sometimes referred to as the rate-limiting subunit because its presence restricts the activity of integrin αvβ6. ITGB6 is a key subunit regulating the expression of the entire heterodimer αvβ6, and its structural specificity may account for the unique functions of integrin αvβ6.
The latent TGF-β1 complex binds to the extracellular matrix via LTBP. Integrin αvβ6 recognizes and binds to the RGD tripeptide in LAP, releasing TGF-β1. TGF-β1 is a key ligand that induces integrin αvβ6 to promote fibrosis and cancer.
(Data source: Uniprot)
(Data source: Zhang Z, et al. Apoptosis. 2024)
The role of ITGB6 in cancer
ITGB6 expression is increased on the surface of cancer cells and plays a role in promoting cancer cell growth and spread. It regulates lipid metabolism by activating the PI3K pathway, promotes cancer cell apoptosis through the ERK pathway, promotes angiogenesis and cancer cell proliferation through the FAK pathway, and promotes epithelial-mesenchymal transition through the Smad pathway.
(Data source: Zhang Z, et al. Apoptosis. 2024)
Targeted therapy of ITGB6
Sigvota tug vedotin is an ITGB6 -targeting antibody-drug conjugate developed by Pfizer . It consists of three components: a monoclonal antibody targeting IB6 (integrin beta-6), the microtubule-disrupting agent MMAE (monomethyl austin E), and a protease-cleavable mc-vc (maleimide-caproyl-valine-citrulline) linker, which covalently links MMAE to the antibody, enabling preferential release of MMAE within target cells . 1 A randomized, Phase 3, open-label study is currently evaluating Sigvota tug vedotin versus docetaxel in previously treated adult patients with non-small cell lung cancer (Be6A Lung-01 study).
(Data source: Pfizer official website)
PF-08046876 is another ADC developed by Pfizer. PF-08046876 utilizes the same antibody backbone from sivotatug vedotin and is specific for IB6 but does not bind to other alpha-v family members. These results suggest that PF-08046876 is a promising ADC for the treatment of multiple cancers and support further clinical development. A Phase 1 first-in-human study is planned to evaluate the safety and anti-tumor activity of PF-08046876.
JSKN022 is a first-of-its-kind multispecific antibody- drug conjugate (ADC) developed by Alphamab Oncology. It targets both PD-L1 and αVβ6 antigens, combining immunotherapy mechanisms with ADC technology. This novel therapy utilizes a glycosyl-specific linker to achieve precise drug loading, using a cleavable linker to deliver the patented TOPO1 inhibitor Alphatecan into the body for improved stability and efficacy. Clinical evaluations have confirmed the clinical feasibility of this approach, and preliminary data indicate that its unique targeting mechanism poses no significant safety concerns. JSKN022 is expected to provide a new treatment option for cancer patients who are resistant to or ineffective against PD-1/PD-L1 inhibitors.
(Data source: ASCO)
