Abstract 4890: A novel topoisomerase I inhibitor antibody-drug conjugate targeting CEACAM5 has potent anti-tumor activity in colorectal cancer models

Abstract

Carcinoembryonic antigen cell adhesion molecule 5, CEACAM5, is a glycosylphosphatidylinositol-anchored glycoprotein highly expressed on the cell surface of several epithelial tumors. CEACAM5 is expressed in virtually all colorectal cancer, ~90% of which to high levels while normal tissue expression is limited. The high prevalence of CEACAM5 expression in colorectal tumor cells prompted us to develop an investigational anti-CEACAM5 antibody-drug conjugate (ADC) for the potential treatment of CRC patients. We developed a novel ADC, by conjugating an anti-CEACAM5 antibody with a drug linker to a topoisomerase I inhibitor payload. The anti-CEACAM5 antibody was chosen based on its high selectivity for CEACAM5 and its potential to direct cytotoxic payloads to tumor. The topoisomerase I payload was optimized for potency, reduced PGP efflux and enhanced bystander activity. The novel anti-CEACAM5 topoisomerase I inhibitor ADC binds to CEACAM5 at nanomolar (nM) concentrations and kills CEACAM5-positive colon tumor cells with varying levels of CEACAM5 at sub-nM concentrations with no or very low cytotoxicity towards CEACAM5-negative cells. Mechanistically, the potent anti-tumor activity of the ADC is both mediated by direct internalization, processing, and release of the cytotoxic payload within the CEACAM5-expressing tumor cells, and by a bystander effect mediated by diffusion of the payload to the neighboring CEACAM5-negative tumor cells. The novel anti-CEACAM5 topoisomerase I inhibitor ADC is well tolerated in rats after repeated administration of 30 and 50 mg/kg/day, Q1W x 4. In vivo efficacy of this ADC at 1, 3 and 10 mg/kg (single administration) was evaluated in four CRC patient-derived xenografts (PDXs) models. The conjugate elicits potent and specific and dose dependent antitumor activity with complete regression (CR) at 10 mg/kg in the 4 models. This robust anti-tumor activity was further confirmed in a Single Mouse Trial of 16 CRC PDX models, consisting in the use of one animal per PDX model per treatment arm and for which the evaluation of efficacy was based on the criteria RECIST (Response Evaluation Criteria In Solid Tumors) used in clinic. In these criteria, the overall response rate includes complete response (CR) and partial response (PR) and the a disease control rate includes CR, PR and stable disease (SD). The ADC induces a disease control rate of 95% and an overall response rate of 50% following a single dose of 10 mg/kg. The outstanding anti-tumor activity across CRC PDX models and its favorable safety profile in rats support further evaluation of this investigational novel topoisomerase I ADC in CRC patients. Citation Format: Yves Baudat, Haley Neff-LaFord, Celine Nicolazzi, Dave Meyer, Johann Petur Sigurjonsson, Ryan Lyski, Valeria Fantin, Marie-Priscille Brun, Marielle Chiron, Stephanie Decary. A novel topoisomerase I inhibitor antibody-drug conjugate targeting CEACAM5 has potent anti-tumor activity in colorectal cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4890.