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

Lindorfer MA, Nardin A, Foley PL, Solga MD, Bankovich AJ, Martin EN, HendersonAL, Price CW, Gyimesi E, Wozencraft CP, Goldberg JB, Sutherland WM, Taylor RP. (2001) "Targeting of Pseudomonas aeruginosa in the bloodstream with bispecific monoclonal antibodies." J Immunol. Aug 167:2240-9. [PubMed]

Lindorfer MA, Schuman TA, Craig ML, Martin EN, Taylor RP. (2001) "A bispecific dsDNAxmonoclonal antibody construct for clearance of anti-dsDNA IgG in systemic lupus erythematosus." J Immunol Methods. Feb 248(1-2):125-38. [PubMed]

Hahn CS, French OG, Foley P, Martin EN, Taylor RP. (2001) "Bispecific monoclonal antibodies mediate binding of dengue virus to erythrocytes in a monkey model of passive viremia." J Immunol. Jan 166:1057-65. [PubMed]

Reinagel ML, Taylor RP. (2000) "Transfer of immune complexes from erythrocyte CR1 to mouse macrophages." J Immunol. Feb 164:1977-85. [PubMed]

Craig ML, Bankovich AJ, McElhenny JL, Taylor RP. (2000) "Clearance of anti-double-stranded DNA antibodies: the natural immune complex clearance mechanism." Arthritis Rheum. 43(10):2265-75. [PubMed]

Sokoloff MH, Nardin A, Solga MD, Lindorfer MA, Sutherland WM, Bankovich AJ, ZhauHE, Chung LW, Taylor RP. (2000) "Targeting of cancer cells with monoclonal antibodies specific for C3b(i)." Cancer Immunol Immunother. 49(10):551-62. [PubMed]

Nardin A, Schlimgen R, Holers VM, Taylor RP. (1999) "A prototype pathogen bound ex vivo to human erythrocyte complement receptor 1 via bispecific monoclonal antibody complexes is cleared to the liver in a mouse model." Eur J Immunol. 29:1581-6. [PubMed]

Craig ML, Reinagel ML, Martin EN, Schlimgen R, Nardin A, Taylor RP. (1999) "Infusion of bispecific monoclonal antibody complexes into monkeys provides immunologic protection against later challenge with a model pathogen." Clin Immunol. 92:170-80. [PubMed]

Nardin A, Lindorfer MA, Taylor RP. (1999) "How are immune complexes bound to the primate erythrocyte complement receptor transferred to acceptor phagocytic cells?" Mol Immunol. Sep-36(13-14):827-35. [PubMed]

Kuhn SE, Nardin A, Klebba PE, Taylor RP. (1998) "Escherichia coli bound to the primate erythrocyte complement receptor via bispecific monoclonal antibodies are transferred to and phagocytosed by human monocytes in an in vitro model." J Immunol. May 160(10):5088-97. [PubMed]

Nardin A, Sutherland WM, Hevey M, Schmaljohn A, Taylor RP. (1998) "Quantitative studies of heteropolymer-mediated binding of inactivated Marburg virus to the complement receptor on primate erythrocytes." J Immunol Methods. Feb 211(1-2):21-31. [PubMed]