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

Beckmann, Roland ; Jensen, Kristian ; Fenn, Sebastian ; Speck, Janina ; Krause, Katrin ; Meier, Anastasia ; Röth, Melanie ; Fauser, Sascha ; Kimbung, Raymond LU and Logan, Derek T. LU orcid , et al. (2021) In Nature Communications 12(1).
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... (More)

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.

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Abstract (Swedish)
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... (More)
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. (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
issue
1
article number
708
pages
13 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85100096715
  • pmid:33514724
ISSN
2041-1723
DOI
10.1038/s41467-021-20949-3
language
English
LU publication?
no
additional info
Publisher Copyright: © 2021, The Author(s).
id
3f69b1d9-a89f-4f40-bc6b-3f8812dfe72f
date added to LUP
2022-02-18 08:52:01
date last changed
2024-06-19 08:15:03
@article{3f69b1d9-a89f-4f40-bc6b-3f8812dfe72f,
  abstract     = {{<p>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.</p>}},
  author       = {{Beckmann, Roland and Jensen, Kristian and Fenn, Sebastian and Speck, Janina and Krause, Katrin and Meier, Anastasia and Röth, Melanie and Fauser, Sascha and Kimbung, Raymond and Logan, Derek T. and Steegmaier, Martin and Kettenberger, Hubert}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-20949-3}},
  doi          = {{10.1038/s41467-021-20949-3}},
  volume       = {{12}},
  year         = {{2021}},
}