title: Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing.
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.
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Widdison
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Ponte
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Coccia
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Leanne
authors.initials: L
authors.lastname: Lanieri
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Yulius
authors.initials: Y
authors.lastname: Setiady
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Dong
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Skaletskaya
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: E Erica
authors.initials: EE
authors.lastname: Hong
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Rajeeva
authors.initials: R
authors.lastname: Singh
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Paulin
authors.initials: P
authors.lastname: Salomon
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Fishkin
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Luke
authors.initials: L
authors.lastname: Harris
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Erin K
authors.initials: EK
authors.lastname: Maloney
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Kovtun
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Veale
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Wilhelm
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Charlene A
authors.initials: CA
authors.lastname: Audette
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Costoplus
authors.affiliation: ImmunoGen Inc. , Waltham, Massachusetts 02451, United States.
authors.forename: Ravi V J
authors.initials: RV
authors.lastname: Chari
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008453:Maytansine / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy
chemical_list: D000814:Aniline Compounds; D000972:Antineoplastic Agents, Phytogenic; D018796:Immunoconjugates; D008453:Maytansine