Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing

Abstract

Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such conjugates were prepared utilizing different dipeptides in the linkage including Gly-Gly, l-Val-l-Cit, and all four stereoisomers of the Ala-Ala dipeptide. The properties of AaMCs could be altered by the choice of dipeptide in the linker. Each of the AaMCs, except the AaMC bearing a d-Ala-d-Ala peptide linker, displayed more bystander killing in vitro than maytansinoid ADCs that utilize disulfide linkers. In mouse models, the anti-CanAg AaMC bearing a d-Ala-l-Ala dipeptide in the linker was shown to be more efficacious against heterogeneous HT-29 xenografts than maytansinoid ADCs that utilize disulfide linkers, while both types of the conjugates displayed similar tolerabilities.

A New Triglycyl Peptide Linker for Antibody–Drug Conjugates (ADCs) with Improved Targeted Killing of Cancer Cells

“…Upon ultimate release from the target cell, the CX ADC catabolite would be present mostly in the charged carboxylate form at the extracellular pH of approximately 7.4 and not readily diffuse into neighboring cells. In contrast, maytansinoid ADCs with alternate linkers such as disulfide or anilino peptide generated nonpolar catabolites with bystander-killing activity (22,36).…”

Antibody–Drug Conjugates: The Last Decade

“…Among them, Immunogen succeeded in developing mirvetuximab soravtansine ( Figure 12) [97][98][99]. This ADC is rather surprising because the release system in reducing conditions (sensitive to glutathione) was too sensitive (because of being unstable in plasma in the early development stage) and the corresponding linker was associated with a lack of success during the development of the ado-trastuzumab emtansine.…”

Recent advances of antibody drug conjugates for clinical applications

“…Plenty of highly potent drugs have been discovered including microtubule inhibitors, anthracyclines, and amatoxins, which may become important complements of auristatins and maytansinoids 75 , 76 , 77 , 79 , 80 . New generation linkers have been characterized in order to improve the therapeutic window of ADCs 13 , 57 , 118 , 119 , 120 . Future directions include bispecific ADCs that are designed to increase both potency and selectivity 121 , 122 , 123 , or deliver multiple classes of payloads 124 .…”