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DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously

Author

Listed:
  • Roland Beckmann

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

  • Kristian Jensen

    (Roche Innovation Center Munich, Roche Diagnostics GmbH
    Bornspire)

  • Sebastian Fenn

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

  • Janina Speck

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

  • Katrin Krause

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

  • Anastasia Meier

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

  • Melanie Röth

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

  • Sascha Fauser

    (Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd)

  • Raymond Kimbung

    (Medicon Village)

  • Derek T. Logan

    (Medicon Village)

  • Martin Steegmaier

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

  • Hubert Kettenberger

    (Roche Innovation Center Munich, Roche Diagnostics GmbH)

Abstract

We report the development of a platform of dual targeting Fab (DutaFab) molecules, which comprise two spatially separated and independent binding sites within the human antibody CDR loops: the so-called H-side paratope encompassing HCDR1, HCDR3 and LCDR2, and the L-side paratope encompassing LCDR1, LCDR3 and HCDR2. Both paratopes can be independently selected and combined into the desired bispecific DutaFabs in a modular manner. X-ray crystal structures illustrate that DutaFabs are able to bind two target molecules simultaneously at the same Fv region comprising a VH-VL heterodimer. In the present study, this platform is applied to generate DutaFabs specific for VEGFA and PDGF-BB, which show high affinities, physico-chemical stability and solubility, as well as superior efficacy over anti-VEGF monotherapy in vivo. These molecules exemplify the usefulness of DutaFabs as a distinct class of antibody therapeutics, which is currently being evaluated in patients.

Suggested Citation

  • Roland Beckmann & Kristian Jensen & Sebastian Fenn & Janina Speck & Katrin Krause & Anastasia Meier & Melanie Röth & Sascha Fauser & Raymond Kimbung & Derek T. Logan & Martin Steegmaier & Hubert Kette, 2021. "DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20949-3
    DOI: 10.1038/s41467-021-20949-3
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