Description

Future Biologics: Exploiting the Opportunities for Protein Engineering

Andreas Plückthun

Department of Biochemistry, University of Zurich, Switzerland

Future biologics should open up areas of application that expand on today’s possibilities. This will be illustrated in several key areas. First, the possibility of engineering geometry can be used to exert extremely strong effects on receptor signaling, such as a pan-HER inhibition (1,4). Using similar linking strategies, novel ways of bridging cells in a controllable way may have important implications in immune oncology. Second, intracellular targets may gradually come within reach. A key challenge is to engineer and correctly assess the cell- and receptor-specific uptake and transport to the cytoplasm of desired cells (3). Using systems inspired by engineered bacterial toxins (3), levels can now be reached which are much higher than with positively charged peptides, and more importantly, allow cell-specific uptake. Third, viral delivery may open up new avenues to administer cocktails of therapeutic proteins in a localized manner, not by creating replication-proficient “oncolytic” viruses, but instead by engineering viruses, able to target predesigned cell types (5), which can be used to produce therapeutic proteins in vivo, at locations where they are needed. For such applications, protein modules are needed which very robustly fold, are very stable and can be generated to specifically bind to any target, and are compatible with in vivo applications because of their low immunogenicity. For these reasons, we have developed alternative scaffolds such as the Designed Ankyrin Repeat Proteins (DARPins) to pick up these ideas (2), and reduce them to practice.

1. Tamaskovic R. et al. (2016). Nature Communications 7, 11672.

2. Plückthun, A. (2015). Annu. Rev. Pharmacol. Toxicol. 55, 489-511.

3. Verdurmen, W. P. et al. (2015). J. Control. Release 200, 13-22.

4. Jost, C. et al. (2013). Structure 21, 1979-1991.

5. Dreier, B. et al. (2013). Proc. Natl. Acad. Sci. U. S. A. 110, E869-877.