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

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

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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