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

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

Affiliation

  • 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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