DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33514724.
- Also identified by DOI 10.1038/s41467-021-20949-3 and PMC identifier 7846786.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antibodies, Bispecific
- Choroidal Neovascularization
- Drug Development
- Immunoglobulin Fab Fragments
- Protein Engineering