by Alexandre Bonvin, Utrecht University.
Merus, a biotech company based in Utrecht, the Netherlands, has recently announced the FDA approval of BIZENGRI®, a bifunctional antibody (zenocutuzumab-zbco) for treatment of NRG1+ Pancreatic Adenocarcinoma and NRG1+ Non–Small Cell Lung Cancer (NSCLC).
The approved therapeutic is based on their patented DEKK technology that enables the efficient production of bifunctional antibodies that contain two different heavy chains.
3D view of a bifunctional antibody. The two different heavy chains are indicated in wheat and light blue colors, while the similar light chains are shown in lime yellow.
DEKK refers to four charged substitutions (D:Asp, E:Glu, K:Lys) that were introduced into the Fc domains of the antibody. The general approach followed to develop these mutations and the crystal structure of the DEKK antibody Fc domains (PDB entry 5NSC) were published in 2017 in the Journal of Biological Chemistry by a team of Merus and Utrecht University researchers (De Nardis et al. 2017). The article describes, among others, how the BioExcel HADDOCK software was used, more than 10 years ago, to design and test those substitutions. HADDOCK was used in its refinement mode, to obtain the HADDOCK scores of the various combinations. This led to a number of candidates that favored the asymmetric assemblies of the heavy chains over the symmetric ones. These were extensively characterized by a battery of biochemical and biophysical methods leading ultimately to the patented DEKK version.
This nicely illustrates how molecular modelling software like the ones at the core of BioExcel can contribute to the early stages in the long path leading to the development of therapeutic antibodies.
De Nardis,LJ.A. Hendriks,E. Poirier, T. Arvinte, P. Gros, A.B.H. Bakker, J. de Kruif. A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1. J. Biol. Chem. 292, 14706-14717 (2017).
