New Momentum for Integrin Drugs: Integrin αvβ6

Function and Signaling Pathway of Integrin αvβ6

Integrin αvβ6 (hereinafter referred to as αvβ6) belongs to the integrin family of proteins. As one of the epithelial cell surface receptors, it mainly participates in cell proliferation, adhesion, and migration, promoting tissue repair and wound healing, and regulating cell adhesion during epithelial remodeling. The hallmark function of αvβ6 is the activation of TGFβ1, also known as tgf β1, which regulates innate immune surveillance in the lungs, skin, and gastrointestinal tract, maintaining the quiescence of epithelial stem cells. Research has shown that the lack of αvβ6 can result in enamel hypoplasia, periodontal disease, and hair loss, while overexpression can promote fibrosis and epithelial-mesenchymal transition, leading to cancers, especially those prone to metastasis. Importantly, αvβ6 is specifically expressed in proliferating epithelial cells and not in normal epithelial cells, making it a potential new target for integrin-based drugs due to its restricted expression and clearer separation from normal cells.

Figure 1. Integrin αvβ6 Signaling Pathway[1]

 

αvβ6 consists of two subunits, αv and β6, forming one of the integrin heterodimers built from α and β subunits. It is one of the integrins that can bind to the RGD sequence. Its ligands include transforming growth factor (TGFβ1/3), fibronectin, vitronectin, tenascin-C, and viral capsid proteins. Notably, β6 is the rate-limiting subunit that can only form a dimer with αv. Therefore, the expression and activity of αvβ6 depend on β6. Additionally, the cytoplasmic C-terminus of β6 has an extra 11 amino acids unique among all β subtypes, which may influence the function of αvβ6 on multiple levels. This could enhance its stability, allow more effective binding with the α subunit, or alter interactions between the β6 subunit and other signaling molecules, thereby better regulating downstream pathways and possibly serving as a new drug design target.

From an integrin structure perspective, conformational switching around the RGD-binding region can be stabilized by divalent cation binding sites, which helps explain shifts in receptor affinity during activation. These conformational changes propagate through the transmembrane region and into the β6 cytoplasmic tail, where signaling and adaptor recruitment occur. Because αvβ6 is composed of α and β subunits, differences in subunit pairing and tail sequence can influence downstream outcomes.

Figure 2. Structure of Integrin αvβ6[2]

How αvβ6 connects the extracellular matrix to intracellular signaling

Upon integrin activation, αvβ6 can undergo integrin clustering and organise integrin adhesion complexes at focal adhesions on the cell surface. These adhesion complexes physically couple the actin cytoskeleton and other cytoskeletal proteins to the extracellular matrix, supporting stable cell adhesion and directional cell migration. This process often involves talin binding to the integrin β tails, enabling talin mediated integrin activation and helping drive adhesion formation. Through this integrin mediated adhesion, signals initiated at the extracellular domains can be transmitted to intracellular adaptors, supporting coordinated adhesion and movement in epithelial tissues.

Downstream, αvβ6 can signal through focal adhesion kinase and integrin linked kinase, coordinating integrin signaling with pathways such as mitogen activated protein kinase and extracellular signal regulated kinase, which interact with growth factors and growth factor receptor signaling to support epithelial dynamics. In disease contexts, this coupling can contribute to increase cell proliferation, altered cell survival, and changes in cell biology linked to inflammation and fibrosis. These mechanisms also relate to tissue repair suggests roles where αvβ6 activation supports repair programs but may become dysregulated in chronic injury.

Development of Targeted Drugs

Drugs targeting αvβ6 or β6 mainly focus on antibodies and ADCs, reflecting broader efforts in targeting integrin pathways for solid tumors. Notable examples include Seagen's SGN-B6A and Harpoon's ITGB6 ProTriTAC.

Figure 3. Mechanism of SGNB6A[3]

 

SGN-B6A uses an ADC design, targeting only integrin β6, increasing specificity and reducing harm to normal cells. At the 2023 ASCO, the phase 1 results of SGN-B6A in treating advanced solid tumors showed encouraging anti-tumor activity and durable efficacy in patients with heavily pre-treated non-small cell lung cancer (NSCLC), esophageal cancer (EC), and head and neck squamous cell carcinoma (HNSCC), with acceptable and manageable safety. This approach is relevant for tumour types where carcinoma cells show high αvβ6 expression and where cancer cell migration contributes to aggressive spread and cancer progression.

Table 1. Phase I Clinical Trial Results of SGNB6A in Advanced Solid Tumors[4]

 

ITGB6 ProTriTAC consists of antibodies against ITGB6, CD3, and Albumin, with a masking peptide and a tumor-specific enzyme-cleavable linker between the CD3 and Albumin antibodies. This design ensures that the drug is activated only in tumor tissues, reducing off-target toxicity. After cleavage, the remaining part without the Albumin antibody has a shorter half-life, facilitating rapid clearance and further improving safety. ITGB6 ProTriTAC is currently in preclinical research, targeting solid tumors, and has shown good anti-tumor activity in mouse models, including contexts where tumor growth and tumor progression depend on invasive properties and extracellular matrix degradation.

Figure 4. ProTriTAC Design Principle[5]

  

Table 2. Some αvβ6 Targeting Drugs in Clinical Trials

 

Furthermore, radiological imaging diagnostics like PET/CT detection are also research directions for αvβ6, aiding in early cancer detection and better stratified treatment options. Imaging agents in clinical research include 18F-FP-R01-MG-F2 (Early Phase 1) and 18F-αvβ6-BP (Phase 1),  which can help assess αvβ6 distribution in primary lesions and metastatic sites, including in breast cancer and breast carcinoma cohorts where epithelial integrins may correlate with invasive behavior.

Figure 5. Principle of Radiological Imaging Agents Targeting αvβ6[6]

 

KACTUS High-Quality Integrin αvβ6 Products

The development of αvβ6 drugs has moved towards reducing TGFβ in the tumor microenvironment, lowering PD-L1 expression in tumor cells, biomarker evaluation, and combination therapy. This may offer opportunities for more precise therapeutic effects, new indication choices, and fewer side effects. To support integrin-related drug development, KACTUS has developed high-quality αvβ6 proteins, including species-chimeric αvβ6, to better apply in immune processes and improve antibody development efficiency. These reagents support studies on integrin function, integrin activation, and ligand interactions, including the fibronectin receptor role of alpha v beta 6 and related forms such as integrin alpha v beta and integrin avb6.

 

Product Validation Examples

Figure 6. Immobilized Human ITGAV&ITGB6, His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for Biotinylated Human Latent TGF beta 1, His Tag with the EC₅₀ of 63.3 μg/ml determined by ELISA.

Figure 7. Immobilized Mouse&Human Chimeric ITGAV&ITGB6, His Tag at 2 μg/ml (100 μl/well) on the plate. Dose response curve for Biotinylated Human Latent TGF beta 1, His Tag with the EC₅₀ of 26.5 ng/ml determined by ELISA.

 

Available Proteins

Catalog Number	Product Information
ITG-HM4V6	Human Integrin αvβ6 Heterodimer, His-Avi Tag
ITG-HM4V6B	Biotinylated Human Integrin αvβ6 Heterodimer, His-Avi Tag
ITG-MM1V6	Mouse Integrin αvβ6 Heterodimer, His Tag
ITG-HM1V6	Human&Mouse Chimeric Integrin αvβ6 Heterodimer, His Tag
ITG-RM1V6	Rhesus macaque Integrin αvβ6 Heterodimer, His Tag
TG1-HM401	Human Latent TGF beta 1, His Tag
LAP-HM4B1	Human LAP (TGF beta 1), His Tag
TGF-HM103	Human Latent TGF beta 3, His Tag
VTN-HM101	Human Vitronectin, His Tag

Click the catalog number for product details

 

References

[1] Niu J, Li Z. The roles of integrin αvβ6 in cancer. Cancer Lett. 2017 Sep 10;403:128-137. doi: 10.1016/j.canlet.2017.06.012.

[2] Sowmya G, Khan JM, Anand S, Ahn SB, Baker MS, Ranganathan S. A site for direct integrin αvβ6·uPAR interaction from structural modelling and docking. J Struct Biol. 2014 Mar;185(3):327-35. doi: 10.1016/j.jsb.2014.01.001.

[3] https://seagenmedicalaffairs.com/

[4] https://meetings.asco.org/abstracts-presentations/218493/poster

[5] https://doi.org/10.1158/1538-7445.AM2023-2927

[6] Ludwig BS, Kessler H, Kossatz S, Reuning U. RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field. Cancers (Basel). 2021 Apr 4;13(7):1711. doi: 10.3390/cancers13071711.