Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity

  • ChemMedChem. 2020 Jan 7;15(1):17-25. doi: 10.1002/cmdc.201900497.
Thomas H Pillow  1 ,  Pragya Adhikari  1 ,  Robert A Blake  1 ,  Jinhua Chen  2 ,  Geoffrey Del Rosario  1 ,  Gauri Deshmukh  1 ,  Isabel Figueroa  1 ,  Karen E Gascoigne  1 ,  Amrita V Kamath  1 ,  Susan Kaufman  1 ,  Tracy Kleinheinz  1 ,  Katherine R Kozak  1 ,  Brandon Latifi  1 ,  Douglas D Leipold  1 ,  Chun Sing Li  2 ,  Ruina Li  1 ,  Melinda M Mulvihill  1 ,  Aimee O'Donohue  1 ,  Rebecca K Rowntree  1 ,  Jack D Sadowsky  1 ,  John Wai  2 ,  Xinxin Wang  2 ,  Cong Wu  1 ,  Zijin Xu  2 ,  Hui Yao  2 ,  Shang-Fan Yu  1 ,  Donglu Zhang  1 ,  Richard Zang  1 ,  Hongyan Zhang  2 ,  Hao Zhou  2 ,  Xiaoyu Zhu  2 ,  Peter S Dragovich  1
Affiliations
  • 1. Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
  • 2. Wuxi Apptec, 288 Fute Zhong Road Waigaoqiao Free Trade Zone, Shanghai, 200131, China.
PMID: 31674143 DOI: 10.1002/cmdc.201900497
Abstract

The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

Keywords
BRD4; antibodies; antibody-drug conjugate; chimeric protein degrader; drug delivery.
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