Development of human monoclonal antibodies for the treatment of Chagas' Disease

Abstract

Chagas' disease, caused by the parasite Trypanosoma cruzi, affects 7 to 8 million people worldwide. The condition can be debilitating, and even life-threatening, to those that develop cardiomyopathy or one of the digestive forms of the disease, making it a significant burden to health care and society at large. Treatment options for patients are still limited to two drugs, both of them with important side effects and limited efficacy. It is therefore urgent to develop therapeutic alternatives for Chagas' disease. Our group has been studying a multigene family present in the parasite's genome, called gp85/trans-sialidase gene family. Proteins encoded by this gene group are important in the invasion process of the host cell by the parasite, promoting the adhesion to membrane proteins and the extracellular matrix of the host. Monoclonal antibodies raised against selected members of this family of proteins are able to prevent host cell invasion. Unfortunately, to date, none of these antibodies have been shown to broadly neutralize all family members and inhibition levels vary from 46-96%, depending on which strain and form of the parasite were used (metacyclic or tissue-cultured derived trypomastigotes). To address this issue, we have identified two highly conserved motifs within the gp85 proteins, called TS9 and FLY, both important for parasite infection. These sequences promote parasite's adhesion to host cells, therefore playing an important role in the invasion process. Since these sequences are present in all gp85 proteins, they are ideal candidates as targets for broadly neutralizing monoclonal antibodies. In this project, we propose the use of antibody phage and yeast display technology to isolate and characterize human monoclonal antibodies against the peptide motifs TS9 and FLY. These antibodies will find important applications as drug candidates for the development of new effective therapies for individuals afflicted by this devastating disease. (AU)