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Design, Synthesis, and In Vitro and In Vivo Evaluation of Cereblon Binding Bruton's Tyrosine Kinase (BTK) Degrader CD79b Targeted Antibody-Drug Conjugates.

Alan ZhangKatherine SeissLaurent LabordeSebastian Palacio-RamirezDaniel A GuthyMylene LanterJulien LorberAnna VulpettiLuca AristaThomas ZollerThomas RadimerskiClaudio ThomaChristina HebachWilliam R TschantzAlexei S KarpovGregory J HollingworthJoseph A D'AlessioStephane FerrettiMatthew T Burger
Published in: Bioconjugate chemistry (2024)
Antibody-drug conjugates (ADCs) are an established modality that allow for targeted delivery of a potent molecule, or payload, to a desired site of action. ADCs, wherein the payload is a targeted protein degrader, are an emerging area in the field. Herein we describe our efforts of delivering a Bruton's tyrosine kinase (BTK) bifunctional degrader 1 via a CD79b mAb (monoclonal antibody) where the degrader is linked at the ligase binding portion of the payload via a cleavable linker to the mAb. The resulting CD79b ADCs, 3 and 4 , exhibit in vitro degradation and cytotoxicity comparable with that of 1 , and ADC 3 can achieve more sustained in vivo degradation than intravenously administered 1 with markedly reduced systemic exposure of the payload.
Keyphrases
  • tyrosine kinase
  • monoclonal antibody
  • epidermal growth factor receptor
  • cancer therapy
  • nk cells
  • binding protein
  • drug delivery
  • magnetic resonance imaging
  • metal organic framework