The aim of the project is to develop therapeutic antibodies for the treatment of Klebsiella pneumonia infections, focusing on antibody therapies that boost the host immune system. The functionality of antibodies in human immune protection against invading bacteria critically depends on the antibody's capacity to activate the complement system. Complement is a large protein network in plasma that directly kills Gram-negative bacteria via ring-structured pores or labels bacteria for phagocytosis by immune cells. Here we will investigate the potential of complement-enhancing antibodies as herapeutic interventions against Klebsiella infections. We will combine advanced sequencing and de novo top-down mass spectrometry to identify antibody repertoires form healthy individuals and patients. To specifically identify antibodies with strong complement-activating potential, we choose a non-biased approach in which functional assays drive the antibody selection process. Furthermore, since mutations in the Fc region of antibodies can strengthen this hexameric rearrangement, we will use this patented technology to further potentiate the complement-inducing activity of antibodies against Klebsiella pneumoniae. Most promising antibodies or antibody combinations will be analyzed in murine infection models. Altogether, this work will improve basic understanding of host immune mechanisms against bacteria and lead to novel strategies for treatment of Klebsiella pneumoniae infections. This project is part a bigger collaboration between the group of prof. dr. Rooijakkers, the group of prof. dr. Heck, and Genmab as main commercial partner.
Sjors van der Lans