Protein Engineering (Margret Schottelius / Claudia Mendler)

Compared to intact antibodies, radiolabeled Fab-fragments show accelerated in vivo kinetics due to their reduced molecular mass. On the one hand, the enhanced blood clearance of such constructs leads to a fast reduction of background activity in the excretion organs, which is a prerequisite for high contrast imaging. On the other hand, it decreases the efficiency of tracer accumulation in tumor tissue due to reduced bioavailability, even at nanomolar affinities.

To be able to fully exploit the targeting potential of tumor-epitope binding Fab-fragments, it is necessary to prolong the circulation of the radioligand in the blood stream. This can be achieved by the expression of Fab-fusion proteins. The desired extention of plasma half-life is either based on specific binding of the Fab-contructs to plasma proteins (ABD) or on an adapted increase in molecular weight via conjugation with amino acid chains of variable length (PASylation).

First feasibility studies in normal mice have successfully demonstrated the applicability of this technology. The major focus of our actual studies lies on the transfer of this concept to Her2-binding Fab-fragments as well as their pharmacokinetic optimization, ideally allowing for fast and high contrast imaging of Her2-positive tumors. Furthermore, we plan to transfer this technology to further tumor-specific epitopes.

Based on the general concept of multifunctional fusion proteins (here: binding unit plus pharmacokinetic modifier) we will investigate further Her2-binding protein-anticaling constructs, which may open new perspectives for efficient pretargeting strategies with improved clinical practicability.