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. Epub 2015 Sep 30.

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.

MeSH terms

  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacokinetics
  • Aniline Compounds / therapeutic use
  • Animals
  • Antineoplastic Agents, Phytogenic / chemistry*
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / therapeutic use
  • Maytansine / chemistry*
  • Maytansine / pharmacokinetics
  • Maytansine / therapeutic use
  • Mice
  • Neoplasms / drug therapy

Substances

  • Aniline Compounds
  • Antineoplastic Agents, Phytogenic
  • Immunoconjugates
  • Maytansine