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