Sigvotatug Vedotin: A Breakthrough in Integrin αvβ6 ADC Therapy for Solid Tumors

At the 2025 JPM, Pfizer announced that its integrin αvβ6-targeting ADC candidate, Sigvotatug Vedotin (PF-08046047, also known as SGN-B6A), has advanced to Phase III clinical trials for PD-L1 high-expressing NSCLC. With its promising anti-cancer activity, the drug has emerged as a potential "First-in-Class" integrin β6 ADC therapy in 2025.

Sigvotatug Vedotin: Mechanism and Clinical Progress

Sigvotatug Vedotin is an ADC targeting integrin αvβ6-positive tumor cells. Its engineered antibody ensures high specificity, while a protease-cleavable linker delivers microtubule inhibitor MMAE (monomethyl auristatin E). Upon internalization, MMAE disrupts microtubule, inhibits cell division and ultimately leading to tumor cell death. At ASCO 2024, Pfizer presented Phase I clinical data showing a confirmed objective response rate (cORR) of 19.5%, with a median duration of response (mDOR) of 8.4 months. Notably, in non-squamous NSCLC patients who had not received prior taxane therapy, the cORR increased to 32.5%, and the mDOR extended to 11.6 months, demonstrating strong anti-tumor activity and encouraging efficacy. This improvement was particularly significant in taxane-nave non-squamous NSCLC patients. Given these promising Phase I results, Pfizer opted to advance Sigvotatug Vedotin directly into Phase III clinical trials by passing Phase II.

Integrin: Key Players in Tumor Development and Metastasis

Integrins are critical in cancer progression, influencing proliferation, angiogenesis, invasion and metastasis, immune evasion, metabolic regulation, apoptosis resistance, and inflammatory responses. By interacting with the extracellular matrix (ECM) and signaling pathways, integrins not only drive tumor cell growth and neovascularization but also enhance migratory capacity, facilitating distant organ colonization. Moreover, integrins modulate the immune microenvironment, influence tumor metabolic adaptation, and play a key role in drug resistance, making them a crucial focus in cancer research and targeted therapy development.

Due to the critical role of integrins in cell adhesion and tumor migration, early integrin-targeted therapeutics primarily focused on small-molecule inhibitors and blocking antibodies. However, these agents do not directly induce tumor cell death, leading to limited efficacy as monotherapies. Clinical data have shown that while drugs such as Intetumumab, Abituzumab, and Cilengitide demonstrated favorable safety profiles, their therapeutic benefits remained modest. As a result, research efforts have shifted toward enhancing tumor-killing activity, driving the development of next-generation therapies targeting Integrin αvβ6 and Integrin αvβ8. These include ADCC-enhanced antibodies, ADCs, and T-cell engagers (TCEs), marking a major innovation leap that is turning the tide in integrin-targeted cancer therapy!

Innovative Integrin-Targeted Therapies in Development

• Madwell 2MW4991: An ADCC-enhanced integrin αvβ8-specific blocking antibody with sub-nM affinity for αvβ8 and no binding to other integrins. It blocks αvβ8-mediated TGF-β release and exhibits potent anti-tumor activity in tumor models such as CT26 and EMT6. It significantly promotes immune cell infiltration and enhances the sensitivity of immune-excluded tumors to PD-1 inhibitors. Non-primate model studies demonstrate its favorable safety profile and metabolic stability.1

• Pfizer SGN-B6A: An ADC drug developed by Seagen (now part of Pfizer), targeting integrin αvβ6. SGN-B6A is composed of an αvβ6 antibody, MMAE (monomethyl auristatin E), and a mc-vc linker with a drug-to-antibody ratio (DAR) of 4. This drug specifically binds to integrin αvβ6 and does not interact with other integrins, enabling significant internalization within 4 hours. Integrin αvβ6 is highly expressed in various solid tumors, including non-small cell lung cancer (NSCLC), head and neck cancer, and esophageal cancer, and is associated with poor prognosis. SGN-B6A utilizes a protease-cleavable linker to conjugate the αvβ6 antibody with the microtubule-disrupting agent MMAE, demonstrating potent anti-tumor activity. Preclinical studies have shown its efficacy across a range of tumor models.2

• Harpoon Therapeutics CD3 x ITGB6 TCE: A bispecific TCE under development by Harpoon Therapeutics, based on the ProTriTAC™ platform, targeting integrin αvβ6 and CD3. Integrin αvβ6 is highly expressed in various solid tumors, such as non-small cell lung cancer (NSCLC), head and neck cancer, and esophageal cancer, and is associated with poor prognosis. This TCE aims to specifically kill αvβ6-expressing tumor cells by recruiting and activating T cells, while optimizing its half-life to enhance efficacy and reduce toxicity. Preclinical studies have demonstrated significant anti-tumor activity in various tumor models with high αvβ6 expression. It holds potential as a new strategy for immune therapy in solid tumors.3

>>> Product Recommendation: Click to View CD3 TCE Development Tools

Comprehensive Integrin-Targeted Drug Development Solutions

To meet the drug development needs for integrin-targeted therapies in both oncology and non-oncology indications, ACROBiosystems has launched a comprehensive range of high-quality biopharmaceutical development tools. These tools are designed to support drug development applications from the molecular to the cellular level, ensuring precision and efficacy across all stages of the process.

•  24 Integrin Heterodimer Subtype Proteins: High-quality recombinant proteins, including heterodimers and monomers, with high purity and activity for immune assays, antibody screening, and functional validation of candidate drugs.

•  Integrin α4β7: MAdCAM-1 [Biotinylated] Inhibitor Screening ELISA Kit: Detects inhibitors of ITG α4β7-MAdCAM-1 binding. It effectively quantifies the inhibitory effects of candidate molecules on the binding between ITG α4β7 and its receptor MAdCAM-1. With high sensitivity and strong specificity, this kit is ideal for high-throughput screening in drug development, helping researchers quickly identify promising Integrin α4β7-targeted inhibitors and ensure QC release.

•  Integrin αVβ6 Overexpression Cell Lines: The overexpressing cell lines for Integrin αVβ6 antigen stably expresses the protein on the surface of host cells for long-term use. Supports antibody drug activity screening (cell-level binding and blocking) and evaluating CAR molecule cytotoxicity, providing essential tools for drug development and functional testing.

ACROBiosystems performs batch-by-batch quality control on all products, verifying properties such as purity and binding activity, and provides free protocols to streamline integrin-targeted drug development.

References

1. Cuicui Guo, Zhen Han, Xiaowei Cen, Hai Wu, Jinchao Zhang, Xun Gui; Abstract 6349: 2MW4991, a novel ADCC-enhanced integrin αvβ8 blocker, exhibits high anti-tumor potency and was well tolerated in cynomolgus monkeys. Cancer Res 15 March 2024; 84 (6_Supplement): 6349. https://doi.org/10.1158/1538-7445.AM2024-6349

2. Lyon RP, Jonas M, Frantz C, Trueblood ES, Yumul R, Westendorf L, Hale CJ, Stilwell JL, Yeddula N, Snead KM, Kumar V, Patilea-Vrana GI, Klussman K, Ryan MC. SGN-B6A: A New Vedotin Antibody-Drug Conjugate Directed to Integrin Beta-6 for Multiple Carcinoma Indications. Mol Cancer Ther. 2023 Dec 1;22(12):1444-1453. doi: 10.1158/1535-7163.MCT-22-0817. PMID: 37619980; PMCID: PMC10690100.

3. https://www.merck.com/news/merck-completes-acquisition-of-harpoon-therapeutics-inc/