Abstract 2355: SGN-EGFRd2 binding and activity are agnostic to common EGFR extracellular resistance mutations acquired in response to anti-EGFR targeted antibody therapies

Abstract

Abstract SGN-EGFRd2 is an investigational bispecific antibody comprised of two camelid-derived humanized variable heavy chain only (VHH) domains, one targeting Vγ9Vδ2 (gamma delta) T cells and the other targeting the epidermal growth factor receptor (EGFR). Selective antitumor activity occurs when two conditions are met: 1) the molecule engages both EGFR-expressing tumor cells and gamma delta T cells and 2) butyrophilins, in complex with phosphoantigens (pAgs), are expressed by EGFR-positive tumor cells, resulting in gamma delta T cell directed tumor cell killing by activation, degranulation and secretion of cytolytic molecules. The tumor specific proximity of gamma delta T cells and expression of the butyrophilins/pAgs complex results in the killing of EGFR-expressing tumor cells but not EGFR-expressing normal cells. EGFR is an oncogenic receptor tyrosine kinase and target of several classes of therapeutic modalities, including antibodies. Two antibodies are currently approved for the treatment of EGFR-expressing, KRAS wild-type metastatic colorectal cancer (mCRC): cetuximab (CET) and panitumumab (PAN). Although these anti-EGFR therapies provide significant survival benefits to patients, the duration of response is transient, and most patients progress and develop secondary resistance [1]. One such escape mechanism is the acquisition of mutations in the extracellular domain (ECD) of EGFR, which prevent binding of therapeutic antibodies [2]. Because SGN-EGFRd2 will be tested on patients previously exposed to anti-EGFR therapeutic antibodies, it is paramount to assess its binding to EGFR ECD mutations identified in antibody resistant mCRC patients. EGFR-negative A2058 cells were transduced to express wild type EGFR and a panel of EGFR ECD resistance mutations (N=16). The binding specificity and kinetics of SGN-EGFRd2 were compared to CET and PAN by flow cytometry on engineered cell lines and biolayer interferometry, respectively. Results indicated SGN-EGFRd2 maintained the ability to bind to all tested EGFR ECD mutants, whereas CET and PAN were unable to bind several ECD mutants, as previously described [3,4]. SGN-EGFRd2 binding to EGFR ECD mutant cell lines induced the production of interferon gamma and expression of cell surface CD107a on gamma delta T cells, confirming functional engagement. In contrast to current anti-EGFR therapeutic antibodies, SGN-EGFRd2 binding and activity was unaffected by commonly identified EGFR ECD mutations. These findings highlight SGN-EGFRd2 as a novel molecule targeting wild-type EGFR and common EGFR ECD mutations identified in the mCRC setting. Citation Format: Liem Nguyen, Chun-Shu Wong, Serena Wo, Bryan Grogan, Daniel Diolaiti, Maria Corinna Palanca-Wessels, Astrid Clarke. SGN-EGFRd2 binding and activity are agnostic to common EGFR extracellular resistance mutations acquired in response to anti-EGFR targeted antibody therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2355.