2. Academic Validation
  3. Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity

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

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z