Abstract 2362: Preclinical efficacy and safety of M9140, a novel antibody-drug conjugate (ADC) with topoisomerase 1 (TOP1) inhibitor payload targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-expressing colorectal tumors

Abstract Background: M9140 is the first clinical-stage TOP1 inhibitor payload ADC directed against CEACAM5, which is expressed in colorectal cancer (CRC) and other cancer indications. M9140 is composed of a CEACAM5-specific antibody conjugated to eight, highly stable and hydrophilic ß-glucuronide-exatecan linker-payloads. After linker cleavage, the highly potent and membrane permeable TOP1 inhibitor exatecan is released. Methods: M9140 potency was tested in viability assays using cancer cell lines with different levels of CEACAM5 expression. Potency shift viability assays were conducted using two CRC cell lines, with zosuquidar used as multidrug resistance-1 (MDR-1) inhibitor. The M9140 bystander effect was assessed in co-culture experiments with CEACAM5-negative and -positive cancer cells. Antitumor efficacy and safety were evaluated in patient-derived xenograft (PDX) mouse models and in cynomolgus monkeys, respectively. Results: M9140 demonstrated specific binding to CEACAM5 and selective killing of target-positive cancer cells with potencies between 0.09 nM and 0.62 nM. A potent bystander effect of M9140 was demonstrated in co-culture experiments indicating the potential to treat tumors with heterogeneous target expression. Unlike other ADC payloads such as monomethyl auristatin E (MMAE) and the maytansine derivative DM4, exatecan potency was not affected by MDR-1 inhibition, indicating that this drug efflux resistance mechanism may not be relevant for exatecan. A single treatment with 10 mg/kg M9140 caused strong antitumor effects in all 14 CRC PDX models tested, with tumor stasis in 10 models and tumor regression in four models as the best response. The TOP1 inhibitor-based ADC M9140 caused strong antitumor efficacy with a tumor volume reduction of 74% and 88% as best response in two CRC PDX models where a maytansine-based CEACAM5 ADC was not effective. In cynomolgus monkeys, M9140 showed dose-dependent hematolymphoid and intestinal effects, consistent with exatecan payload, with no indication of any other toxicities such as interstitial lung disease (ILD) or ocular toxicity. Conclusions: M9140 demonstrated high potency, strong antitumor activity, and bystander effect in preclinical models. The side effect profile in monkeys was favorable and in line with the expected toxicity of exatecan. Notably, ILD and ocular toxicity, which are known adverse effects of deruxtecan and maytansine-based ADCs respectively, were absent. A first-in-human study to evaluate the safety, tolerability, pharmacokinetics, and preliminary clinical activity of M9140 in advanced solid tumors is ongoing (NCT05464030). Citation Format: Sabine Raab-Westphal, Felix Hart, Willem Sloot, Min Shan, Nicolas Rasche, Christiane Amendt, Jan Anderl. Preclinical efficacy and safety of M9140, a novel antibody-drug conjugate (ADC) with topoisomerase 1 (TOP1) inhibitor payload targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)-expressing colorectal tumors [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 2362.