Abstract 1558: HDP-201 - a novel multimeric linker exatecan-based ADC targeting Guanylyl cyclase C (GCC) for treatment of gastrointestinal malignancies

Abstract Background: HDP-201 is a novel multimeric linker ADC directed against GCC based on topoisomerase 1 inhibitor exatecan. GCC is highly expressed in gastrointestinal malignancies including gastric and colorectal cancers. The multimeric linker-payload featured with a solubility enhancer facilitates the delivery of more than one hydrophobic payload per conjugation site. HDP-201 employs a proprietary, site-specific conjugation technology based on cysteine-engineered and Fc-silenced antibodies which are devoid of Fc-mediated uptake. Methods: The cysteine-reactive multimeric exatecan-linker construct was synthesized at Heidelberg Pharma and site-specifically conjugated to engineered cysteine residues of a proprietary anti-GCC antibody, yielding ADCs with a DOL of 2.0 and a DAR of 4.0. HDP-201 potency was tested in cytotoxicity assays using a GCC-overexpressing HEK293-GUCY2C cell line. The anti-tumor efficacy was evaluated in subcutaneous HEK293-GUCY2C tumor models in female NOD SCID mice, and patient-derived xenografts (PDX) treated intravenously with single and multiple doses of HDP-201. Safety and tolerability of HDP-201 was assessed in cynomolgus monkeys. Results: HDP-201 showed favorable in vitro cytotoxicity, with nanomolar activity against the GCC-expressing cell line and no cytotoxicity against target-negative cells. A potent by-stander effect of HDP-201 was demonstrated in co-culture experiments with target-positive and -negative cells, indicating its potential to treat tumors with heterogenous target expression. In mouse xenograft models, intravenous HDP-201 single dose treatment resulted in complete tumor remission in HEK293-GUCY2C xenografts. In gastrointestinal PDX models, HDP-201 significantly inhibited tumor growth. Multiple dosing further enhanced this anti-tumor efficacy without impacting toxicity. In cynomolgus monkeys, a single intravenous dose of 60 mg/kg was well tolerated without severe clinical signs and only transient changes in hematology and serum chemistry parameters. Conclusion: Targeted delivery of topoisomerase 1 inhibitor to GCC-positive cells was achieved using HDP-201 comprised of an anti-GCC antibody conjugated to a multimeric linker-exatecan. HDP-201 showed target-specific potency, strong anti-tumor efficacy, and high tolerability in preclinical models. The use of HDP-201 in the therapy of GCC-positive gastrointestinal malignancies represents a promising approach in cancer treatment. Citation Format: Sarah Jane Neuberth, Christian Orlik, Hendrik Gruss, Christoph Mueller, Kristin Decker, Nick Neubacher, Marisa Schmitt, Anikó Pálfi, Irina Dranova, Michael Kulke, Andreas Pahl, Torsten Hechler HDP-201 - a novel multimeric linker exatecan-based ADC targeting Guanylyl cyclase C (GCC) for treatment of gastrointestinal malignancies [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 1558.