Therapeutic efficacy of anti-viral IgG with enhanced Fc effector functions (GRK2504 TP C07)

Monoclonal antibodies limiting viral spread upon infection are a promising approach to counteract the major health burden posed by viral pandemics e.g. COVID-19. Mechanistically, antibodies of the immunoglobulin G (IgG) class may have neutralizing activity by preventing target cell binding via their Fab fragment. Fc mediated effector functions have, in addition, increasingly been recognized to contribute to protection against SARS-CoV-2 and other viral pathogens. The complement cascade and Fc receptors expressed on immune cells can thus enhance inactivation and clearance of opsonized viral particles by phagocytosis or antibody-dependent cellular cytotoxicity (ADCC). 

Within this project we therefore aim to decipher the contribution of IgG Fc domain dependent effector functions for the protective activity of Influenza A specific IgG and identify variants with enhanced clinical efficacy. We will generate IgG variants against Type 1 Influenza A Hemagglutinin of different subclasses, Fc mutations and epitope locations. The influence of Fc activity and epitope location will be evaluated in vitro including analysis of their neutralization capacity, binding kinetics, complement and FcR dependent immune cell activation. Selected Fc-effector functions important in Influenza pathogenesis will be studied in detail. We will ultimately assess the therapeutic potential of selected IgG candidates in an in vivo challenge assay employing humanized mice.