Synthetic approaches to modulate and understand activation of the human complement system

Abstract

Immunotherapeutics induce clearance of malignant cells, this can be achieved by recruitment of complement of the human innate immune system via monoclonal antibodies. Such monoclonal antibodies have had clinical success and are under continuous development. Similarly, bispecific complement agonists function to activate the complement system, however their molecular properties/structures differ from monoclonal antibodies. Furthermore, due to their novelty, there is a limited understanding in what drives efficient complement activation by these bispecifics.

In this thesis we have investigated and developed bispecific C1 agonists, which have been studied using minimal synthetic systems. Using these systems the geometry and affinity of the bispecifics were modified in a systematic manner to unravel the effect of these parameters on complement activation. Furthermore we showcase a first-in-class peptide agonist that can bind C1 of complement. These insights have provided a deeper understanding of these novel complement agonist and should aid the development of therapeutics in this class further.