Engineering antibodies with dual target capture

dutafabs, complexes VEGFA, PDGF
a) X-ray structure of the VP mat DutaFab in complex with PDGF-BB dimer. Fab in dark gray (heavy chain) and light gray (light chain). PDGF-BB dimer (beige) binds to the H-side of the DutaFab, interacting paratope (red surface). b) X-ray structure of the VP mat DutaFab in complex with VEGFA dimer. The VEGFA dimer (green) binds to the L-side of the DutaFab, interacting paratope (blue surface). c) Model of the ternary complex of the VEGF-PDGF DutaFab bound to its two targets simultaneously. d) Concomitant binding (SPR). Credit: Creative Commons Attribution 4.0 International License. Roland Beckmann.

In the sphere of human antibody therapeutics, the DutaFab platform shows broadening potential. Pharmaceutical giant Roche has developed ‘dual targeting’ Fab molecules containing two spatially independent binding sites for targeting distinct antigens. Their recent study, published in Nature Communications, demonstrates the high efficacy of these bispecific monoclonal antibodies for VEGFA and PDGF-BB growth factors related to blood vessel production.

Bispecific monoclonal antibodies are artificial proteins designed to treat disease and are considered a next generation solution to monospecific protein drugs. According to the study, engineering a bispecific antibody Fab (antigen-binding fragment) with structurally discrete binding sites or paratopes, on the same variable region has remained out of reach until now.

The structure allows for simultaneous binding of separate target antigens, thus opening up new avenues in optimized therapeutics. One given scenario is the effective neutralization of two targeted molecules with one Fab fragment.

As part of the design process of the DutaFabs, the crystalline structure of the DutaFab-VEGF complex was determined at beamline I911-3, the predecessor of BioMAX beamline at MAX IV Laboratory in Lund.

DutaFabs are the first molecule type developed with DutaMab technology, a platform invented by Roland Beckmann, co-founder of the Austrian-based biotech firm, Dutalys. Roche Holding acquired the rights for the breakthrough technology in 2014. The first DutaFabs phased in for clinical use in spring 2019.

Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor (PDGF-BB) are key components in drug design for macular degeneration and diabetic oedema. The new DutaFabs may enter clinical development in the foreseeable future, according to the authors.

 

Publication

Beckmann, R., Jensen, K., Fenn, S. et al. DutaFabs are engineered therapeutic Fab fragments that can bind two targets simultaneously. Nat Commun 12, 708 (2021). https://doi.org/10.1038/s41467-021-20949-3

Related articles

Gearing up for challenging proteins at MicroMAX
Floating droplets aid studies of challenging protein solutions