Several approaches were followed.

1. The first approach included optimization of several surface loops of the ephrin-B2 protein interacting with the target. Modifications included both increase contact area as well as reduction of flexibility. 2 partially de novo candidates were created for which novel scaffolds were created for the target-interacting residues of EFNB2.
2. Such a partially de novo candidate was linked to an antibody described in literature, resulting in a chimeric protein targeting two sites on the target protein.