DSSS - The design of evolution and the evolution of design: Binding molecules in biomedicine

The lecture will highlight designed binding proteins and concentrate on two application areas.
First, to enable in vivo production of therapeutic proteins, we have combined several protein engineering technologies to devise a new platform, termed SHielded, REtargeted ADenovirus (SHREAD). It is based on virus-like particles that are devoid of any viral genes, but contain 36 kb of DNA that can encode multiple genes and complex regulatory regions. To target particular cells and organs, an adapter strategy has been devised, based on the DARPin platform, to selectively target any surface receptor of interest. To hide the particles from the immune system and to minimize liver targeting, a protein shield was developed covering the particles.
In vivo applications have included expressing therapeutic anti-tumor antibodies, therapeutic cytokines or bispecific T-cell engagers in situ, as well as infecting and reprogramming T-cells in vivo, and targeting of dendritic cells in lymph nodes to co-express cytokines there for highly efficient tumor vaccination.
Second, we challenge the paradigm of selection from large universal libraries to obtain binding proteins rapidly and efficiently - and we also challenge the paradigm of individually de novo designing each binder for each target. When it comes to linear epitopes, we found it possible to exploit the periodicity of peptide bonds and create a completely modular system, based on a binding protein design that shares the same periodicity, using Armadillo Repeat Proteins.
Using orthogonal approaches of design, selection, evolution, biophysical testing, and structure determination, significant progress has been reached toward the creation of a system of modular binding proteins that are modular and complementary to a given peptide sequence. We believe that this technology can provide a new paradigm of creating binding proteins for many challenges in biomedical research.