Human Monoclonal Antibody Therapy for Rhodesiense Sleeping Sickness. (360G-Wellcome-093008_Z_10_Z)

Human African Trypanosomiasis remains a serious health problem in Central Africa and treatment has been largely untouched by the advent of modern medicine. The chemotherapy used is based on drugs introduced between 40 and 90 years ago that have severe side effects including a few percent mortality. There is a desperate need for new medicines. Most trypanosomes cannot infect humans due to a primate-specific innate immunity mechanism based on apolipoprotein L-1 (apoL-1), a component of a subse t of high density lipoprotein (HDL) particles. Receptor mediated endocytosis of HDL and trafficking of the apoL-1 to the lysosome results in cell death. Trypanosoma brucei rhodesiense, one of the two human infective subspecies, counteracts the action of apoL-1 through the production of the SRA protein which binds to apoL-1 and prevents its action. The objective of this application is to produce and test a new therapeutic based on human monoclonal antibodies that bind SRA and block the bindi ng of apoL-1, thus rendering the trypanosome susceptible to killing by apoL-1. The use of human antibodies for the treatment of disease is an emerging technology that is characterized by dramatic on target efficacy, and little or no off-target effects.