University of Virginia Health System

The long-term goal of our research is to provide an experimental foundation for the general treatment of infectious diseases through use of heteropolymer (HP)-sensitized human erythrocytes (RBCs). We have prepared bi-specific cross-linked monoclonal antibodies (HPs) with specificity for both selected targeted pathogens and the human erythrocyte C3b complement receptor (CR1). These HPs facilitate rapid and quantitative in vitro binding of targeted pathogens to CR1 on human and other primate RBCs. The use of HPs allows us to bypass the complement opsonization requirement for binding of immune complex substrates to CR1. Virtually any potential pathogen can be selectively bound to RBCs by this procedure. The HPs facilitate in vivo binding of innocuous prototype pathogens to primate RBCs, and these RBC-bound substrates and HP are rapidly cleared from the circulation without any lysis or sequestration of the RBCs. This result is a manifestation of one of the body's natural defenses, the RBC-based immune complex clearance mechanism. This mechanism allows for the safe and rapid neutralization and clearance of complement-opsonized pathogens bound to CR1 on human and non-human primate RBCs. We are now investigating whether virulent pathogens will be bound in vivo to RBCs via appropriately constructed HPs, and then rapidly and safely cleared from the circulation. Selected particulate pathogens include several bacteria and viruses. We are also developing general approaches for the treatment of cancer based on the interaction of cancer cells with the complement sysstem. In the presence of serum and normal human IgM and/or specific monoclonal antibodies, large amounts of the complement activation product, C3bi, covalently bind to the cancer cells. We are using monoclonal antibodies specific for cell-associated C3bi to facilitate tumor cell targeting and killing.