Novel Therapeutics for Multiple Sclerosis
Need and Opportunity for a Novel Approach
MS is an autoimmune disease in which the myelin insulation on nerves is attacked by the patient’s own immune cells. Established drugs for MS are non-specific immune and inflammatory modulators that modestly affect symptoms and remissions. Newer MS drugs disrupt the normal immune process by affecting T cell trafficking but their potent, nonspecific activity has led to serious infections.
The challenge is to develop a disease-targeted therapy that is effective in MS, yet preserves immune function.
Provid’s strategy is molecular targeting of the disease-associated MHC class II molecule, HLA-DR2. In over 60% of MS patients, autoreactive immune T cells are triggered by myelin fragments presented by the MHC class II molecule, HLA-DR2
Target DR2 = Target MS
(a) | (b) | |
Myelin peptide MBP 82-98 (yellow) in binding groove of HLA-DR2 (DRB1*1501; Smith, Pyrdol, Gauthier, Wiley, Wucherpfennig J Exp Med 1998) | Model of PV-267 (red) in DR2 binding site. |
PV-267 is a small molecule peptide mimetic designed by Provid on the basis of the structural biology of MHC class II molecules. PV-267 is a potent DR2 inhibitor that blocks antigen binding (2 nM) and T cell activation and is effective in MS animal models (EAE in DR2 transgenic mice). PV-267 is immunologically "inert" except as a blocker. It is selective for DR2, thus preserving other immune function and is stable toward cathepsin enzymes found in antigen presenting cells and is fully stable in plasma.