The goal of this project is to develop a family of marketable therapeutic drugs for treating mulitple sclerosis (MS) that is directed at the specific autoimmune responses characteristic of particular patient subgroups. This work will be carded out as a collaboration between OHSU and Virogenomics, Inc. a Portland biotech company which has licensed this technology. The key to this novel therapeutic concept is the Recombinant T cell Ligand or RTL, a single chain protein consisting of the two outermost domains of the so-called DR2 isoform of the human MHC II gene family and along with a covalently linked autoimmune peptide. The version of the RTL family that has yielded our first candidate for development contains the myelin oligodendrocyte glycoprotein peptide fragment MOG 35-55. This peptide is found to be one of the dominant autoantigens in up to 60% of MS patients of northern European descent. We have developed an animal model for testing this drug that is based on inducing experimental autoimmune encephalomyelitis (EAE) in a transgenic mouse expressing the human DR2 (DRB 1*1501) allele using the MOG peptide as the inducing antigen. Administration of a single dose of MOG35-55 in CFA leads to chronic EAE in these animals, including paralysis with associated white matter lesions. EAE induced in this manner can be effectively treated with eight doses of the RTL compound. The first two specific goals of this Phase I project are to perform experiments in this animal model that will allow us to optimize the treatment regime and choose the exact peptide construct that will be used in preparation for human clinical trials. A dose range study and a maximum tolerated dose study are planned. An additional goal is to explore alternative ways of expressing the recombinant protein in order to create a process effiecient enough to prepare gram quantities of the drug for preclinical and clinical testing
