title: Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates.
abstract: The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been elusive. Here we describe a bioreversible linkage based on a quaternary ammonium that can be used to connect a broad array of tertiary and heteroaryl amines to a carrier protein. Using a concise, protecting-group-free synthesis we demonstrate the chemoselective modification of 12 complex molecules that contain a range of reactive functional groups. We also show the utility of this connection with both protease-cleavable and reductively cleavable antibody-drug conjugates that were effective and stable in vitro and in vivo. Studies with a tertiary-amine-containing antibiotic show that the resulting antibody-antibiotic conjugate provided appropriate stability and release characteristics and led to an unexpected improvement in activity over the conjugates previously connected via a carbamate.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Leanna R
authors.initials: LR
authors.lastname: Staben
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Koenig
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Lehar
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Josefa
authors.initials: J
authors.lastname: Chuh
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Ng
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Fourie-O'Donohue
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Go
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Linghu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Segraves
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Gail D Lewis
authors.initials: GD
authors.lastname: Phillips
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Keyang
authors.initials: K
authors.lastname: Xu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Kozak
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Mariathasan
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Flygare
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Pillow
mesh_terms: D000588:Amines / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry; D002403:Cathepsins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D018796:Immunoconjugates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D012995:Solubility
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004337:Drug Carriers; D018796:Immunoconjugates; D004364:Pharmaceutical Preparations; D000644:Quaternary Ammonium Compounds; D002403:Cathepsins