Over the years, we have investigated and engineered stable antibody frameworks with significantly better properties than natural ones. This work has been the basis of synthetic antibody libraries, which have given rise to many useful binders, being the basis of therapeutic development. It has also led to a stability-engineered antibody against EpCAM in our lab being now in phase 3 clinical trials. Using the directed evolution technologies, we have evolved extremely tight binders in vitro against proteins, peptides and small molecules, up to 1 pM (a monovalent scFv against the prion protein). Additionally, more fundamental questions have been addressed regarding the in vivo folding and stability, using scFv, Fab, IgG expressed in prokaryotic or eukaryotic cells. This work has helped to elucidate what features prevent misfolding and aggregation.
In recent years, we have used these capabilities to generate therapeutic IgGs, bispecific and multispecific antibodies of many formats and of different isotypes. Some of these constructs are on a trajectory to clinical trials. Moreover, these capabilities have been used to express IgGs in situ, using the Shielded Retargeted Adenovirus platform.