Abstract 1522: SGN-B6A induces immunogenic cell death as an additional mechanism of action
Authors: Trang Vivian H. , Mazahreh Rebecca C. , Gosink John J. , Ulrich Michelle , Olson Devra , Ubben Allana , Allred Sean , Huang Li-Ya , Hensley Kelly , Treuting Piper M. , Klussman Kerry , Higgins Shaylin , Younan Patrick , Yumul Roma , Nazarenko Natalya , Lyon Robert P. 
Published: April 2023

Abstract
SGN-B6A is a novel investigational antibody-drug conjugate (ADC) directed to integrin beta-6 and uses the clinically validated vedotin drug-linker platform that delivers the microtubule disrupting agent, monomethyl auristatin E (MMAE). SGN-B6A is designed to bind and internalize the integrin beta-6/ADC complex from the surface of malignant cells and release the cytotoxic payload MMAE. We have previously demonstrated the antitumor activity of SGN-B6A in cell line-derived xenograft models originating from multiple carcinomas as well as patient-derived xenograft models of non-small cell lung cancer (NSCLC). Other clinically validated vedotin ADCs that deliver MMAE have been shown to induce immunogenic cell death (ICD) in preclinical models and have demonstrated promising clinical activity in combination with immunotherapy. Since the induction of ICD appeared to be a consequence of the activity of MMAE, and is independent of the antibody that delivers it, we hypothesized that this mechanism of action may also apply to SGN-B6A.
Consistent with this hypothesis, we observed that tumor cells treated with SGN-B6A in vitro showed key hallmarks of immunogenic cell death, including markers of endoplasmic reticulum (ER) stress, exposure of calreticulin, and release of ATP and high mobility group protein B1 (HMGB1). Further, in vivo studies demonstrated that treatment with SGN-B6A led to immune activation and recruitment of immune cells to the tumor environment. In an integrin beta-6-expressing syngeneic model, a vedotin ADC directed to integrin beta-6 has shown combinatorial activity with immunotherapy.
Preclinical models suggest that, like other vedotin ADCs, SGN-B6A induces immunogenic cell death which then promotes activation and recruitment of immune cells to the tumor. We have recently reported promising single-agent activity of SGN-B6A in non-small cell lung, head and neck squamous cell, and esophageal cancer observed in interim results of a phase I study (NCT04389632). The combination of SGN-B6A with immunotherapy may be utilized as a potential treatment for integrin-beta-6-expressing tumors including NSCLC, head and neck squamous cell carcinoma, and esophageal carcinoma. Altogether, our preclinical and initial clinical results support the ongoing evaluation of SGN-B6A as a single agent and in combination with immune checkpoint inhibitors.
Citation Format: Vivian H. Trang, Rebecca C. Mazahreh, John J. Gosink, Michelle Ulrich, Devra Olson, Allana Ubben, Sean Allred, Li-Ya Huang, Kelly Hensley, Piper M. Treuting, Kerry Klussman, Shaylin Higgins, Patrick Younan, Roma Yumul, Natalya Nazarenko, Robert P. Lyon. SGN-B6A induces immunogenic cell death as an additional mechanism of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1522.