Sigvotatug vedotin

Sigvotatug vedotin (development codes SGN-B6A, PF-08046047) is an investigational antibody-drug conjugate (ADC) designed for the treatment of various solid tumors.^[1] Developed by Seagen (now part of Pfizer), sigvotatug vedotin is composed of a monoclonal antibody directed against integrin beta-6 (IB6), conjugated to the cytotoxic payload monomethyl auristatin E (MMAE) via a protease-cleavable linker.^[1]

The drug is, as of August 2025, in late-stage clinical development, including Phase III trials for non-small cell lung cancer (NSCLC), where it has shown promising activity in heavily pretreated patients.^[2]

Sigvotatug vedotin represents a significant advancement in targeted cancer therapy, particularly for patients with limited treatment options in the second-line and subsequent settings.^[3] In NSCLC, second-line treatment options offer limited benefit for patients whose disease has progressed after treatment with PD-(L)1 inhibitors and platinum-based chemotherapy, representing a substantial unmet medical need.^[2]

Sigvotatug vedotin is an antibody-drug conjugate composed of three key components: a monoclonal antibody targeting integrin beta-6, the cytotoxic agent monomethyl auristatin E (MMAE), and a protease-cleavable maleimidocaproyl-valine-citrulline (mc-vc) linker that covalently attaches MMAE to the antibody.^[1]

Integrin beta 6 (IB6) is a cell surface receptor that promotes cellular adhesion through interactions with the extracellular matrix, playing a major role in solid tumor pathogenesis and invasiveness.^[1] IB6 expression is normally low in healthy tissues but becomes highly upregulated during pathological processes, making it an attractive target for cancer therapy.^[4]

The mechanism involves selective binding of the antibody component to IB6-expressing cancer cells, followed by internalization of the ADC complex. Once inside the target cell, the protease-cleavable linker is cleaved by intracellular proteases, releasing MMAE within the cytoplasm.^[1] MMAE then disrupts microtubule polymerization, leading to cell cycle arrest and apoptosis of the cancer cell.^[4]

Integrin beta-6 is expressed in numerous solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal cancer, breast cancer, ovarian cancer, pancreatic cancer, bladder cancer, cervical cancer, gastric cancer, and cutaneous squamous cell carcinoma.^[1] Importantly, more than 90% of NSCLC tumors express IB6, making it a broadly applicable target in this indication.^[2]

IB6 expression correlates with poor outcomes in several cancer types and has been proposed as a negative prognostic marker based on multiple analyses.^[1] The high tumor selectivity and limited expression in normal tissues make IB6 an ideal target for antibody-drug conjugate therapy.^[4]

The initial clinical evaluation of sigvotatug vedotin was conducted in the Phase I study SGNB6A-001 (NCT04389632), an open-label, multicenter trial evaluating the safety, pharmacokinetics, and antitumor activity of the drug in patients with various solid tumors.^[5][6]

In NSCLC patients, sigvotatug vedotin demonstrated encouraging activity in heavily pretreated patients who had received prior therapies including PD-1/PD-L1 inhibitors, platinum-based chemotherapy, and targeted therapies where applicable.^[5] The drug showed a manageable safety profile with evidence of clinical benefit across multiple dose levels.^[5]

Based on the promising Phase I results, sigvotatug vedotin advanced to Phase III development with the Be6A Lung-01 study, a randomized, open-label trial comparing sigvotatug vedotin to docetaxel in patients with previously treated NSCLC.^[2] This study targets patients whose disease has progressed after treatment with PD-(L)1 inhibitors, platinum-based chemotherapy, and/or targeted therapy, representing a significant unmet medical need.^[2]

The Phase III trial was announced at the 2025 JPM Healthcare Conference and represents a potential first-in-class opportunity for an integrin αvβ6-targeting ADC in NSCLC.^[7][8][9]

Sigvotatug vedotin is also being evaluated in combination with pembrolizumab in ongoing Phase I studies, exploring the potential synergy between ADC therapy and immune checkpoint inhibitors.^[10] This combination approach is based on preclinical evidence suggesting that vedotin ADCs may have enhanced clinical activity when combined with checkpoint inhibitors.^[4]

Sigvotatug vedotin was originally developed by Seagen (formerly Seattle Genetics) under the designation SGN-B6A.^[4] The drug was developed as part of Seagen's vedotin ADC platform, which has produced several approved therapies in both hematologic and solid tumor indications.^[4]

In December 2023, Pfizer completed its acquisition of Seagen for approximately $43 billion, bringing sigvotatug vedotin and other investigational ADCs into Pfizer's oncology pipeline.^[7] Following the acquisition, the drug received the additional development code PF-08046047 within Pfizer's system.^[1]

Clinical studies have demonstrated that sigvotatug vedotin has a manageable safety profile consistent with other vedotin-based ADCs.^[5] The most commonly observed adverse events include those typical of MMAE-containing ADCs, such as peripheral neuropathy, fatigue, and gastrointestinal effects.^[5] The safety profile supports continued development across multiple tumor types and in combination with other anticancer agents.^[10]

As of August 2025, sigvotatug vedotin has investigational status and has not been approved by any regulatory agency for clinical use. The drug is being evaluated in multiple ongoing clinical trials across various solid tumor indications, with Phase III development underway in NSCLC.

• Antibody-drug conjugate
• Integrin beta 6
• Monomethyl auristatin E
• Non-small cell lung cancer
• Solid tumor
• Targeted therapy

• Pfizer Oncology Development Information
• Phase I Clinical Trial (SGNB6A-001) on ClinicalTrials.gov
• Phase III Clinical Trial (Be6A Lung-01) on ClinicalTrials.gov