Multiple Sclerosis

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

Myelin peptide MBP 82-98   Model of PV-267 (red) in DR2 binding site.
(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.

The DR2 selectivity and mechanism of PV-267 suggests a novel biomarker approach to the clinical development of the compound for MS.