Targeting CEACAM5 with a Novel Maytansinoid-Antibody Conjugate: A Promising Therapeutic Approach for Multiple Cancers

The text focuses on the development and evaluation of an antibody-drug conjugate (ADC) targeting CEACAM5, a tumor marker particularly prominent in colorectal carcinomas. The research involved the generation of antibodies through immunization procedures using both human and monkey CEACAM5 extracellular domains, leading to the selection of a highly specific antibody with cross-reactivity to monkey CEACAM5. This antibody was found to internalize in tumor cells, which was a significant discovery given the literature's description of CEACAM5 as a poorly internalizing surface protein.

The selected antibody was then conjugated to the cytotoxic agent DM4 using a cleavable SPDB linker, resulting in the creation of SAR408701. This ADC demonstrated the ability to kill various CEACAM5-positive tumor cells at sub-nanomolar concentrations. Its in vivo efficacy was tested in patient-derived xenografts (PDXs) for colorectal, lung, and gastric tumors, showing strong and specific antitumor effects even at low doses and with repeat administrations.

SAR408701 was found to be well-tolerated in cynomolgus monkeys and exhibited a toxicity profile similar to other SPDB-DM4 ADCs. The preclinical data, along with the lack of target-mediated toxicity, suggests that SAR408701 could be an effective anticancer agent with a favorable therapeutic index, indicating its potential for further evaluation in clinical trials for CEACAM5-positive tumors.

The study was presented at the 106th Annual Meeting of the American Association for Cancer Research and published in the Cancer Research journal.