학술논문
Peptide-Cleavable Self-immolative Maytansinoid Antibody-Drug Conjugates Designed To Provide Improved Bystander Killing.
Document Type
Academic Journal
Author
Costoplus JA; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Veale KH; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Qiu Q; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Ponte JF; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Lanieri L; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Setiady Y; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Dong L; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Skaletskaya A; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Bartle LM; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Salomon P; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Wu R; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Maloney EK; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Kovtun YV; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Ab O; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Lai K; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Chari RVJ; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.; Widdison WC; ImmunoGen, Inc., 830 Winter Street, Waltham, Massachusetts 02451, United States.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1948-5875
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.
Competing Interests: The authors declare no competing financial interest.
(Copyright © 2019 American Chemical Society.)
Competing Interests: The authors declare no competing financial interest.
(Copyright © 2019 American Chemical Society.)