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, and many others in Merus’ pipeline, 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 blueish-colors, while the similar light chains are shown in yellow (image courtesy of Merus)
DEKK refers to four charged substitutions (D:Asp, E:Glu, K:Lys) that were introduced into the Fc domains of the antibody. The BioExcel HADDOCK software was originally 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. The general approach and the crystal structure of the DEKK antibody Fc domains was published in 2017 in the Journal of Biological Chemistry (De Nardis et al. 2017) (PDB entry 5NSC).
Merus’s DEKK dimerization technology (image courtesy of Merus)
This nicely illustrates the long term impact that molecular modelling software like the ones at the core of BioExcel can have.
C. De Nardis, LJ.A. Hendriks, E. Poirier, T. Arvinte, P. Gros, A.B.H. Bakker and 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).
