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

  • Bioconjug Chem. 2024 Feb 21;35(2):140-146. doi: 10.1021/acs.bioconjchem.3c00535.
Alan Zhang  1 ,  Katherine Seiss  2 ,  Laurent Laborde  3 ,  Sebastian Palacio-Ramirez  4 ,  Daniel Guthy  3 ,  Mylene Lanter  3 ,  Julien Lorber  5 ,  Anna Vulpetti  5 ,  Luca Arista  5 ,  Thomas Zoller  5 ,  Thomas Radimerski  3 ,  Claudio Thoma  3 ,  Christina Hebach  3 ,  William R Tschantz  4 ,  Alexei Karpov  5 ,  Gregory J Hollingworth  5 ,  Joseph A D'Alessio  2 ,  Stephane Ferretti  3 ,  Matthew T Burger  1
Affiliations
  • 1. Global Discovery Chemistry, Novartis Biomedical Research, Cambridge, Massachusetts 02139 United States.
  • 2. Oncology Biotherapeutics, Novartis Biomedical Research, Cambridge, Massachusetts 02139 United States.
  • 3. Oncology, Novartis Biomedical Research, CH-4002 Basel, Switzerland.
  • 4. Novartis Biologics Center, Novartis Biomedical Research, Cambridge, Massachusetts 02139 United States.
  • 5. Global Discovery Chemistry, Novartis Biomedical Research, CH-4002 Basel, Switzerland.
PMID: 38265691 DOI: 10.1021/acs.bioconjchem.3c00535
Abstract

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.

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