Back
Full-text
Journal article

Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody.

  • Geiger M Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
  • Stubenrauch KG Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany.
  • Sam J Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
  • Richter WF Roche Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Jordan G Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany.
  • Eckmann J Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany.
  • Hage C Roche Pharma Research & Early Development, Roche Innovation Center Munich, Nonnenwald 2, 82372, Penzberg, Germany.
  • Nicolini V Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
  • Freimoser-Grundschober A Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
  • Ritter M Roche Diagnostics, CPS Research and Development, Nonnenwald 2, 82372, Penzberg, Germany.
  • Lauer ME Roche Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • Stahlberg H Center for Cellular Imaging and Nano Analytics, Biozentrum, University of Basel, 4070, Basel, Switzerland.
  • Ringler P Center for Cellular Imaging and Nano Analytics, Biozentrum, University of Basel, 4070, Basel, Switzerland.
  • Patel J Roche Sequencing, NimbleGen, Madison, WI, 53719, USA.
  • Sullivan E Roche Sequencing, NimbleGen, Madison, WI, 53719, USA.
  • Grau-Richards S Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
  • Endres S Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Lindwurmstraße 2a, Member of the German Center for Lung Research (DZL), 80337, Munich, Germany.
  • Kobold S Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Lindwurmstraße 2a, Member of the German Center for Lung Research (DZL), 80337, Munich, Germany.
  • Umaña P Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
  • Brünker P Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland.
  • Klein C Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952, Schlieren, Switzerland. christian.klein.ck1@roche.com.
Show more…
  • 2020-06-26
Published in:
  • Nature communications. - 2020
Animals
Antibodies, Bispecific
CD3 Complex
Cell Line, Tumor
Folate Receptor 1
GPI-Linked Proteins
Humans
Immunotherapy
Lymphocyte Activation
Mice
Molecular Targeted Therapy
Peptide Hydrolases
T-Lymphocytes
Xenograft Model Antitumor Assays
English T-cell bispecific antibodies (TCBs) crosslink tumor and T-cells to induce tumor cell killing. While TCBs are very potent, on-target off-tumor toxicity remains a challenge when selecting targets. Here, we describe a protease-activated anti-folate receptor 1 TCB (Prot-FOLR1-TCB) equipped with an anti-idiotypic anti-CD3 mask connected to the anti-CD3 Fab through a tumor protease-cleavable linker. The potency of this Prot- FOLR1-TCB is recovered following protease-cleavage of the linker releasing the anti-idiotypic anti-CD3 scFv. In vivo, the Prot-FOLR1-TCB mediates antitumor efficacy comparable to the parental FOLR1-TCB whereas a noncleavable control Prot-FOLR1-TCB is inactive. In contrast, killing of bronchial epithelial and renal cortical cells with low FOLR1 expression is prevented compared to the parental FOLR1-TCB. The findings are confirmed for mesothelin as alternative tumor antigen. Thus, masking the anti-CD3 Fab fragment with an anti-idiotypic mask and cleavage of the mask by tumor-specific proteases can be applied to enhance specificity and safety of TCBs.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/232653
Statistics
Document views: 31 File downloads:
  • Full-text: 0