2. Academic Validation
  3. Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates

Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates

  • Nat Chem. 2016 Dec;8(12):1112-1119. doi: 10.1038/nchem.2635.
Leanna R Staben 1,  Stefan G Koenig 1,  Sophie M Lehar 1,  Richard Vandlen 1,  Donglu Zhang 1,  Josefa Chuh 1,  Shang-Fan Yu 1,  Carl Ng 1,  Jun Guo 1,  Yanzhou Liu 1,  Aimee Fourie-O'Donohue 1,  MaryAnn Go 1,  Xin Linghu 1,  Nathaniel L Segraves 1,  Tao Wang 2,  Jinhua Chen 2,  BinQing Wei 1,  Gail D Lewis Phillips 1,  Keyang Xu 1,  Katherine R Kozak 1,  Sanjeev Mariathasan 1,  John A Flygare 1,  Thomas H Pillow 1
Affiliations

Affiliations

  • 1 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
  • 2 WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 27874860 DOI: 10.1038/nchem.2635
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.

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