Development of DRα1-MOG-35-55 for treatment of DR2 negative MS subjects

DESCRIPTION provided by applicant Our laboratory discovered and is developing partial p MHC class II constructs pMHC as a possible immunotherapy for multiple sclerosis MS pMHC containing the extracellular domains of the MS risk factor HLA DR linked covalently to the encephalitogenic peptide of myelin oligodendrocyte glycoprotein pDR MOG can reverse CNS inflammation and clinical signs of MOG peptide induced experimental autoimmune encephalomyelitis EAE in DR transgenic mice The pDR MOG construct for humans termed Recombinant T cell receptor Ligand or RTL was found to be safe and well tolerated in a Phase safety trial in MS subjects and is soon to be tested in a Phase II tria in progressive MS Our preclinical studies showed that pDR MOG can specifically inhibit cognate DR restricted MOG reactive T cells and to a lesser extent bystander T cells reactive to other myelin peptides RTL blocks the binding and downstream inflammatory effects of a key pathogenic factor in EAE and MS called macrophage migration inhibitory factor MIF to CD the invariant chain Ii of MHC class II that serves as the major MIF receptor on immune cells Additionally the down modulation of CD expression by RTL may serve as an important biomarker of drug efficacy Currently the FDA requires that patients receiving RTL express the same HLA DR type as that intrinsic to RTL in order to avoid potentially harmful transplantation andquot mismatchesandquot after repeated dosing andquot Matchingandquot for HLA DR would allow treatment of of MS subjects with RTL Americans but produces an unmet need for an effective pMHC treatment for the remaining who express a variety of other HLA DR types To address this need we here propose to evaluate the potency and immunogenicity of a novel derivative pMHC construct DR MOG that retains the primary binding region for CD and the MOG peptide found in RTL but lacks the DR domain Due to its universal expression DR MOG would be a andquot matchandquot for all human recipients and would thus nicely complement RTL and address the unmet need of treating HLA DR negative patients To fully evaluate possible differences and limitations of each we will compare potency immunogenicity and CD modulation of the two constructs in andquot matchedandquot transgenic DR vs andquot mismatchedandquot transgenic DR recipient mice with EAE The ultimate goal of this study is to position the DR MOG drug to address the unmet need and provide coverage for DR negative MS subjects to complement the more advanced development of RTL for use in DR positive MS subjects

PUBLIC HEALTH RELEVANCE This project will evaluate suitability of a novel therapeutic called DR MOG for the possible treatment of of subjects with multiple sclerosis MS who do not carry the HLA DR genetic risk factor for disease susceptibility DR MOG has the ability block the activity of a potent cytokine called macrophage migration inhibitory factor MIF that is involved in MS and can be studied in an animal model for MS known as experimental autoimmune encephalomyelitis EAE The Aims will evaluate the ability of DR MOG to reverse clinical and histological signs of EAE in transgenic HLA DR mice that are representative of HLA DR negative MS subjects determine the level of neutralizing antibodies induced during treatment and assess a new biomarker for efficacy of DR MOG called CD the MIF receptor in preparation for possible human clinical trials in MS