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.

Selected References

Taylor RP, Lindorfer MA. (2010) "Antigenic modulation and rituximab resistance." Semin Hematol. 47:124-32. [PubMed]

Daubeuf S, Lindorfer MA, Taylor RP, Joly E, Hudrisier D. (2010) "The direction of plasma membrane exchange between lymphocytes and accessory cells by trogocytosis is influenced by the nature of the accessory cell." J Immunol. Feb 184:1897-908. Epub 2010 Jan 20. [PubMed]

Aue G, Lindorfer MA, Beum PV, Pawluczkowycz AW, Vire B, Hughes T, Taylor RP,Wiestner A. (2010) "Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia." Haematologica. 95:329-32. Epub 2009 Aug 13. [PubMed]

Pawluczkowycz AW, Beurskens FJ, Beum PV, Lindorfer MA, van de Winkel JG, ParrenPW, Taylor RP. (2009) "Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX." J Immunol. Jul 183:749-58. Epub 2009 Jun 17. [PubMed]

Beum PV, Lindorfer MA, Taylor RP. (2008) "Within peripheral blood mononuclear cells, antibody-dependent cellular cytotoxicity of rituximab-opsonized Daudi cells is promoted by NK cells and inhibited by monocytes due to shaving." J Immunol. Aug 181:2916-24. [PubMed]

Taylor RP, Lindorfer MA. (2008) "Immunotherapeutic mechanisms of anti-CD20 monoclonal antibodies." Curr Opin Immunol. 20:444-9. Epub 2008 Jul 1. [PubMed]

Beum PV, Lindorfer MA, Beurskens F, Stukenberg PT, Lokhorst HM, PawluczkowyczAW, Parren PW, van de Winkel JG, Taylor RP. (2008) "Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis." J Immunol. Jul 181:822-32. [PubMed]

Wang SY, Racila E, Taylor RP, Weiner GJ. (2008) "NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement." Blood. Feb 111:1456-63. Epub 2007 Nov 16. [PubMed]