Abstract 4255: Membrane interactomics (MInt) platform identifies EGFR and CDCP1 as effective co-targets for bispecific antibody drug conjugate IDP-001

EGFR is a biologically validated target which is overexpressed and activated in many human cancers and associated with poor prognosis. However, most current EGFR targeting therapies encompassing multiple modalities have shown limited therapeutic efficacy, frequently due to on-target toxicity in non-malignant tissues where EGFR is expressed. To improve selectivity via co-localization targeting over co-expression alone, we utilized InduPro’s proprietary MInt platform across multiple cancer cell systems to identify CDCP1 as a tumor associated proximity antigen to EGFR on tumor cells. Like EGFR, CDCP1 is over-expressed in multiple cancers and plays key roles in oncogenic signaling and malignant transformation (1). Moreover, EGFR signaling induces upregulation and cell surface localization of CDCP1 as well as inhibition of its degradation (2-3). We further demonstrate that EGFR and CDCP1 are co-expressed in many cancer types by immunohistochemistry, including high levels of co-expression in lung squamous cell carcinoma. IDP-001 is a novel MMAE-conjugated EGFR-CDCP1 bispecific antibody with low DAR. We find that bispecific EGFR x CDCP1 antibodies display enhanced selective internalization and cell killing through co-binding. IDP-001 is effective in vitro against a panel of cancer cell lines of varying target expression levels, including Osimertinib resistant EGFR mutant NSCLC. Importantly, IDP-001 has minimal activity against normal cells expressing both targets. CDCP1 is known to undergo cleavage in some settings, and we present data that confirms IDP-001 binds both intact and cleaved isoforms. Finally, we demonstrate in vivo efficacy of IDP-001 in a subcutaneous xenograft model. Collectively, our data supports that EGFR and CDCP1 are inherently proximal to each other in cancer cell lines and that IDP-001 shows pre-clinical efficacy in a variety of cancer settings and warrants further development. Refs: 1) Khan T et al., Cancer Res 81 (2021) 2259-2978. 2) Adams MN et al., Oncogene 34 (2015) 1375-83. 3) Law ME, et al. Breast Cancer Res 18 (2016) 80. Citation Format: Clare F. Malone, Anna de Regt, Chris May, Lydia Vignale, Kendall Johnson, Cody Scandore, Kalee Hansen, Sohpia Romero, Hayley Ma, Brian Woodruff, Ben Setter, Hengyu Xu, Carol L. Farr, Noah Dephoure, Heath Klock, Ertan Eryilmaz, Rob Oslund, Niyi Fadeyi, Pamela Holland, Scott Lesley. Membrane interactomics (MInt) platform identifies EGFR and CDCP1 as effective co-targets for bispecific antibody drug conjugate IDP-001 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4255.