Peptide-Cleavable Self-immolative Maytansinoid Antibody-Drug Conjugates Designed To Provide Improved Bystander Killing.

Published on Sep 27, 2019in ACS Medicinal Chemistry Letters3.975
· DOI :10.1021/ACSMEDCHEMLETT.9B00310
Juliet Costoplus4
Estimated H-index: 4
(ImmunoGen, Inc.),
Karen Veale4
Estimated H-index: 4
(ImmunoGen, Inc.)
+ 14 AuthorsWayne C. Widdison15
Estimated H-index: 15
(ImmunoGen, Inc.)
A new type of antibody–drug conjugate (ADC) has been prepared that contains a sulfur-bearing maytansinoid attached to an antibody via a highly stable tripeptide linker. Once internalized by cells, proteases in catabolic vesicles cleave the peptide of the ADC’s linker causing self-immolation that releases a thiol-bearing metabolite, which is then S-methylated. Conjugates were prepared with peptide linkers containing only alanyl residues, which were all l isomers or had a single d residue in one of the three positions. A d-alanyl residue in the linker did not significantly impair a conjugate’s cytotoxicity or bystander killing unless it was directly attached to the immolative moiety. Increasing the number of methylene units in the maytansinoid side chain of a conjugate did not typically affect an ADC’s cytotoxicity to targeted cells but did increase bystander killing activity. ADCs with the highest in vitro bystander killing were then evaluated in vivo in mice, where they displayed improved efficacy compare...
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