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

  • Bioconjug Chem. 2015 Nov 18;26(11):2261-78. doi: 10.1021/acs.bioconjchem.5b00430.
Wayne C Widdison  1 ,  Jose F Ponte  1 ,  Jennifer A Coccia  1 ,  Leanne Lanieri  1 ,  Yulius Setiady  1 ,  Ling Dong  1 ,  Anna Skaletskaya  1 ,  E Erica Hong  1 ,  Rui Wu  1 ,  Qifeng Qiu  1 ,  Rajeeva Singh  1 ,  Paulin Salomon  1 ,  Nathan Fishkin  1 ,  Luke Harris  1 ,  Erin K Maloney  1 ,  Yelena Kovtun  1 ,  Karen Veale  1 ,  Sharon D Wilhelm  1 ,  Charlene A Audette  1 ,  Juliet A Costoplus  1 ,  Ravi V J Chari  1
Affiliations
  • 1. ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
PMID: 26355774 DOI: 10.1021/acs.bioconjchem.5b00430
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.

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