Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity

• Published in: ChemMedChem Vol. 15; no. 1; pp. 17 - 25
• Main Authors: 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, Shang‐Fan, Zhang, Donglu, Zang, Richard, Zhang, Hongyan, Zhou, Hao, Zhu, Xiaoyu, Dragovich, Peter S.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 07.01.2020; Wiley Subscription Services, Inc
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; antibody-drug conjugate; Antigens; BRD4; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Chemical properties; Chemistry, Medicinal; chimeric protein degrader; Conjugates; Conjugation; Degradation; Drug Carriers - chemistry; drug delivery; Exposure; Female; Half-Life; Heterocyclic Compounds, 4 or More Rings - chemistry; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Lectins, C-Type - immunology; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Life Sciences & Biomedicine; Mice; Mice, SCID; Organic chemistry; Pharmacokinetics; Pharmacology; Pharmacology & Pharmacy; Protein Binding; Proteins; Proteolysis - drug effects; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Mitogen - immunology; Science & Technology; Surface Plasmon Resonance; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Xenograft Model Antitumor Assays; DRUG; STRATEGY; LETHAL ACTIVITY; drug delivery; DOSE-ESCALATION; antibody-drug conjugate; THERAPY; chimeric protein degrader; BROMODOMAIN INHIBITOR OTX015; PROTEIN-DEGRADATION; LYMPHOMA; antibodies; LEUKEMIA; KNOCKDOWN; BRD4
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900497

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. mAb‐Mediated delivery of protein degraders. A novel strategy for attaching chimeric degrader payloads to antibodies was developed using a self‐immolative disulfide linker. A conjugate prepared using this methodology displayed strong antigen‐dependent efficacy in xenograft tumor models. The corresponding unconjugated degrader was inactive in vivo when administered at a matched dose.