2. Academic Validation
  3. Antibody-peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins

Antibody-peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins

  • Nat Chem Biol. 2024 May 29. doi: 10.1038/s41589-024-01627-z.
Aaron Petruzzella 1 2,  Marine Bruand 1 2,  Albert Santamaria-Martínez 1 2,  Natalya Katanayeva 1 2,  Luc Reymond 3,  Sarah Wehrle 4,  Sandrine Georgeon 4,  Damla Inel 5 6,  Floris J van Dalen 7 8,  David Viertl 9 10,  Kelvin Lau 11,  Florence Pojer 11,  Margret Schottelius 9 12,  Vincent Zoete 2 5 6,  Martijn Verdoes 7 8,  Caroline Arber 5 6,  Bruno E Correia 13,  Elisa Oricchio 14 15
Affiliations

Affiliations

  • 1 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
  • 2 Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland.
  • 3 Institute of Chemical Sciences and Engineering (ISIC), Institute of Bioengineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
  • 4 Laboratory of Protein Design and Immunoengineering, School of Engineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
  • 5 Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
  • 6 Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
  • 7 Department of Medical Biosciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 8 Institute for Chemical Immunology, Nijmegen, The Netherlands.
  • 9 Translational Radiopharmaceutical Sciences, Departments of Nuclear Medicine and Molecular Imaging and of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland.
  • 10 In Vivo Imaging Facility, Department of Research and Training, University of Lausanne (UNIL), Lausanne, Switzerland.
  • 11 Protein Production and Structure Core Facility, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
  • 12 AGORA Pôle de Recherche sur le Cancer, Lausanne, Switzerland.
  • 13 Laboratory of Protein Design and Immunoengineering, School of Engineering, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. bruno.correia@epfl.ch.
  • 14 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. elisa.oricchio@epfl.ch.
  • 15 Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland. elisa.oricchio@epfl.ch.
PMID: 38811854 DOI: 10.1038/s41589-024-01627-z
Abstract

Cysteine cathepsins are a family of proteases that are relevant therapeutic targets for the treatment of different cancers and Other Diseases. However, no clinically approved drugs for these proteins exist, as their systemic inhibition can induce deleterious side effects. To address this problem, we developed a modular antibody-based platform for targeted drug delivery by conjugating non-natural peptide inhibitors (NNPIs) to Antibodies. NNPIs were functionalized with reactive warheads for covalent inhibition, optimized with deep saturation mutagenesis and conjugated to Antibodies to enable cell-type-specific delivery. Our antibody-peptide inhibitor conjugates specifically blocked the activity of cathepsins in different Cancer cells, as well as osteoclasts, and showed therapeutic efficacy in vitro and in vivo. Overall, our approach allows for the rapid design of selective Cathepsin inhibitors and can be generalized to inhibit a broad class of proteases in Cancer and Other Diseases.

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