Abstract 2933: IDP-001 is a potent bispecific ADC with in vivo activity against mouse xenograft tumor models expressing EGFR and CDCP1

Abstract EGFR is a clinically-validated target that is overexpressed and activated in many human cancers and associated with poor prognosis. However, ADCs targeting EGFR exhibit toxicity due to expression on healthy tissue (1), and EGFR can show heterogeneous tumor expression (2). We utilized InduPro’s proprietary MIntTM platform to identify proteins inherently proximal to EGFR on tumor cells. CUB domain-containing protein 1 (CDCP1) was identified as a TAPA (tumor associated proximity antigen) of interest. Like EGFR, CDCP1 is over-expressed in multiple cancers and plays key roles in oncogenic signaling and malignant transformation (3). IDP-001 is a novel MMAE-conjugated EGFR-CDCP1 bispecific antibody with low DAR. Here we report the preclinical in vivo assessment of IDP-001 in established tumor cell line-derived xenograft (CDX) models representing a range of target expression (measured by flow cytometry and immunohistochemistry) across multiple solid tumor indications. We also generated isogenic pairs of tumor cell lines with CDCP1 knocked out. IDP-001, along with versions of varying EGFR affinity, or monospecific derivatives thereof, were administered I.V. at a single dose in tumor-bearing mice. Unlike other EGFR ADCs, IDP-001 does not engage immune effector cells and has a serum half-life of ∼16 hours in mice. It is well tolerated at all doses evaluated, with no signs of body weight loss. Robust, dose-dependent anti-tumor activity was observed in tumor models with dual-target expression, regardless of expression level. Activity is reduced but not absent in CDCP1 knockout tumors and mice treated with EGFR or CDCP1 monospecific ADC controls, demonstrating more selective anti-tumor activity through co-binding. The activity of IDP-001 was also evaluated in patient-derived xenograft (PDX) models of squamous lung carcinoma, where a high degree of target co-expression is observed in clinical samples. IDP-001 is a first-in-class bispecific ADC with the potential for broad therapeutic activity and best-in-class efficacy. These encouraging in vivo results support advancement of IDP-001 to non-human primate studies. References 1. Dan-yun Ruan et al., JCO 42 (2024) 6013-6013. 2. Passaro A et al ESMO open vol. 5, 5 (2020) e000919. 3. Khan T et al., Cancer Res 81 (2021) 2259-2978. Citation Format: Hayley Ma, Sophia Romero, Anna de Regt, Clare Malone, Ben Setter, Brian Woodruff, Hengyu Xu, Rob Oslund, Niyi Fadeyi, Heath Klock, Ertan Eryilmaz, Pamela Holland, Scott Lesley. IDP-001 is a potent bispecific ADC with in vivo activity against mouse xenograft tumor models expressing EGFR and CDCP1 [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 2933.