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

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

  • ACS Med Chem Lett. 2019 Sep 27;10(10):1393-1399. doi: 10.1021/acsmedchemlett.9b00310.
Juliet A Costoplus 1,  Karen H Veale 1,  Qifeng Qiu 1,  Jose F Ponte 1,  Leanne Lanieri 1,  Yulius Setiady 1,  Ling Dong 1,  Anna Skaletskaya 1,  Laura M Bartle 1,  Paulin Salomon 1,  Rui Wu 1,  Erin K Maloney 1,  Yelena V Kovtun 1,  Olga Ab 1,  Kate Lai 1,  Ravi V J Chari 1,  Wayne C Widdison 1
Affiliations

Affiliation

  • 1 ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
PMID: 31620224 DOI: 10.1021/acsmedchemlett.9b00310
Abstract

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 compared to previously described types of maytansinoid conjugates.

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