Abstract 5445: Discovery and optimization of IDP-001, a bispecific ADC targeting 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). To engineer a next-generation bispecific EGFR ADC, we utilized InduPro’s proprietary MIntTM platform to identify proteins inherently proximal to EGFR on tumor cells. Among multiple proteins in proximity to EGFR, 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). Moreover, EGFR signaling induces upregulation and cell surface localization of CDCP1 as well as inhibition of its palmitoylation-dependent degradation (4). Here we report the development of IDP-001, a novel bispecific ADC targeting EGFR and CDCP1. To identify antibodies that display selective activity only on cells that express both EGFR and CDCP1, we generated antibodies to both targets and then combined them to form over 250 hIgG1-based 1+1 bispecific antibodies with diverse epitopes and affinities. This bispecific library was screened on internalization and cytotoxicity assays, yielding a lead candidate that bound domain III of EGFR with a kappa Fab and bound the membrane-distal domain of CDCP1 with an alpaca-derived VHH. We performed further sequence optimization to affinity tune and humanize this antibody, engineer its Fc, and conjugate it with a DAR of 2 via engineered cysteines to a vcMMAE drug linker to yield our final development candidate, IDP-001. IDP-001 incorporates several design principles that distinguish it from other EGFR ADCs, including possible higher tumor exposure and penetration because of its smaller size. Due to its format and conjugation strategy, IDP-001 exhibits excellent biophysical properties and is highly developable. IDP-001 has potent in vitro cytotoxic activity against cancer cell lines with varying target expression levels. IDP-001 is a first-in-class bispecific ADC with the potential for a wider therapeutic window and best-in-class efficacy. 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. 4. Adams MN et al., Oncogene 34 (2015) 1375-1383. Citation Format: Anna de Regt, Clare Malone, Payam Farahani, Ben Setter, Robert W. Gene, Carol F. Farr, Zachary Caldwell, Brian Woodruff, Gyuna Kim, Hengyu Xu, Heath Klock, Rob Oslund, Niyi Fedyi, Michael Hornsby, Pamela Holland, Scott Lesley. Discovery and optimization of IDP-001, a bispecific ADC targeting 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 5445.