Premium
Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity
Author(s) -
Pillow Thomas H.,
Adhikari Pragya,
Blake Robert A.,
Chen Jinhua,
Del Rosario Geoffrey,
Deshmukh Gauri,
Figueroa Isabel,
Gascoigne Karen E.,
Kamath Amrita V.,
Kaufman Susan,
Kleinheinz Tracy,
Kozak Katherine R.,
Latifi Brandon,
Leipold Douglas D.,
Sing Li Chun,
Li Ruina,
Mulvihill Melinda M.,
O'Donohue Aimee,
Rowntree Rebecca K.,
Sadowsky Jack D.,
Wai John,
Wang Xinxin,
Wu Cong,
Xu Zijin,
Yao Hui,
Yu ShangFan,
Zhang Donglu,
Zang Richard,
Zhang Hongyan,
Zhou Hao,
Zhu Xiaoyu,
Dragovich Peter S.
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900497
Subject(s) - in vivo , conjugate , chemistry , linker , small molecule , fusion protein , antibody , pharmacokinetics , bifunctional , pharmacology , combinatorial chemistry , biophysics , biochemistry , biology , recombinant dna , immunology , microbiology and biotechnology , mathematical analysis , catalysis , mathematics , computer science , gene , operating system
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.