Targeting subcellular trafficking behaviour for the design of therapeutic antibodies Event

Event details

The central role of FcRn in regulating IgG persistence and transport provides opportunities for targeting this receptor in multiple different diagnostic and therapeutic situations. The engineering of IgGs with higher affinity for FcRn can be used to produce antibodies with longer in vivo half-lives due to increased recycling within cells, but only if the pH dependence of the IgG-FcRn interaction is retained. Conversely, engineered IgGs with higher affinity for FcRn at both acidic and near neutral pH act as potent inhibitors of FcRn and drive wild type IgG into lysosomes. Consequently, such antibodies (‘Abdegs’, for antibodies that enhance IgG degradation) can lower the levels of endogenous IgG, providing a pathway for the treatment of antibody-mediated autoimmunity. In addition, we have recently generated engineered Fc-antigen fusions that selectively deliver antigen-specific antibodies into lysosomes (called ‘Seldegs’, for selective degradation). We have also generated engineered, tumour-specific antibodies with altered endosomal trafficking behaviour. Following conjugation to cytotoxic drugs to form antibody-drug conjugates (ADCs), these antibodies are more effective in delivering their toxic payload to target cells, resulting in a potential strategy to circumvent the dose-limiting toxicities that frequently reduce the therapeutic efficacy of current ADCs.