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DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously.
- Source :
-
Nature communications [Nat Commun] 2021 Jan 29; Vol. 12 (1), pp. 708. Date of Electronic Publication: 2021 Jan 29. - Publication Year :
- 2021
-
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.
- Subjects :
- Amino Acid Sequence genetics
Animals
Antibodies, Bispecific genetics
Antibodies, Bispecific therapeutic use
Antibodies, Bispecific ultrastructure
Becaplermin antagonists & inhibitors
Binding Sites, Antibody genetics
Crystallography, X-Ray
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Immunoglobulin Fab Fragments genetics
Immunoglobulin Fab Fragments therapeutic use
Immunoglobulin Fab Fragments ultrastructure
Inhibitory Concentration 50
Intravitreal Injections
Male
Models, Molecular
Proof of Concept Study
Protein Conformation
Rats
Vascular Endothelial Growth Factor A antagonists & inhibitors
Antibodies, Bispecific pharmacology
Choroidal Neovascularization drug therapy
Drug Development methods
Immunoglobulin Fab Fragments pharmacology
Protein Engineering
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33514724
- Full Text :
- https://doi.org/10.1038/s41467-021-20949-3