Abstract 1281: SGN-B7H4V shows immunomodulatory activity through induction of immunogenic cell death
Authors: Gray Elizabeth E. , Ulrich Michelle , Epp Angela , Younan Patrick , Hensley Kelly , Allred Sean , Hahn Julie , Gahnberg Kristen , Treuting Piper M. , Gosink John J. , Thurman Robert , Smith Alyson J. , Schrum Jason , Nazarenko Natalya , Gardai Shyra J. 
Published: June 2022

Abstract
SGN-B7H4V is a novel investigational antibody-drug conjugate composed of a B7-H4-directed human monoclonal antibody conjugated to the validated vedotin drug linker, which incorporates the microtubule disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable peptide linkage. This vedotin drug linker system has been clinically validated by multiple ADC programs, including brentuximab vedotin, enfortumab vedotin, tisotumab vedotin, and polatuzumab vedotin. B7-H4 is an immune checkpoint ligand with elevated expression on a variety of solid tumor types, including breast, ovarian, and endometrial tumors. SGN-B7H4V is designed to bind and internalize the B7-H4/ADC complex from the surface of malignant cells and release the cytotoxic payload MMAE. The antitumor activity of SGN-B7H4V may be multimodal as SGN-B7H4V can induce tumor cell death through several mechanisms, including MMAE-mediated direct cytotoxicity and bystander killing as well as antibody-mediated functions including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Previously, vedotin ADCs have been described to elicit antitumor immune responses in part through induction of immunogenic cell death (ICD) mediated by the MMAE payload. These immunomodulatory effects potentially position vedotin ADCs to uniquely synergize with checkpoint inhibitors, supported by recent clinical activity observed when vedotin ADCs are paired with anti-PD1 agents. Here, we characterize SGN-B7H4V-mediated ICD and subsequent immunomodulatory activity. We also evaluate the contribution of SGN-B7H4V-induced immune activation to antitumor activity in combination with an anti-PD1 agent in an immunocompetent mouse model. In vitro, tumor cells treated with SGN-B7H4V showed several hallmarks of immunogenic cell death, including calreticulin exposure and release of ATP. In vivo, treatment of B7-H4-expressing tumors with SGN-B7H4V led to immune changes in the tumor microenvironment, including recruitment of macrophages and T cells. Finally, SGN-B7H4V drove robust, curative activity in an immunocompetent tumor model as a monotherapy and paired well with an anti-PD1 agent. Altogether, these data support the evaluation of SGN-B7H4V as a monotherapy in a first-in-human phase 1 clinical study and potential future clinical combinations with immunotherapies.
Citation Format: Elizabeth E. Gray, Michelle Ulrich, Angela Epp, Patrick Younan, Kelly Hensley, Sean Allred, Julie Hahn, Kristen Gahnberg, Piper M. Treuting, John J. Gosink, Robert Thurman, Alyson J. Smith, Jason Schrum, Natalya Nazarenko, Shyra J. Gardai. SGN-B7H4V shows immunomodulatory activity through induction of immunogenic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1281.