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-DR2, linked covalently to the encephalitogenic 35-55 peptide of myelin oligodendrocyte glycoprotein (pDR2/MOG-35-55) can reverse CNS inflammation and clinical signs of MOG-35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic mice. The pDR2/MOG-35-55 construct for humans (termed Recombinant T-cell receptor Ligand or RTL1000) was found to be safe and well tolerated in a Phase 1 safety trial in MS subjects and is soon to be tested in a Phase II tria in progressive MS. Our preclinical studies showed that pDR2/MOG-35-55 can specifically inhibit cognate DR2-restricted MOG-35-55 reactive T cells and to a lesser extent bystander T cells reactive to other myelin peptides. RTL1000 blocks the binding and downstream inflammatory effects of a key pathogenic factor in EAE and MS, called macrophage migration inhibitory factor (MIF), to CD74, the invariant chain (Ii) of MHC class II that serves as the major MIF receptor on immune cells. Additionally, the down-modulation of CD74 expression by RTL1000 may serve as an important biomarker of drug efficacy. Currently, the FDA requires that patients receiving RTL1000 express the same HLA-DR2 type as that intrinsic to RTL1000 in order to avoid potentially harmful transplantation mismatches after repeated dosing. Matching for HLA-DR2 would allow treatment of ~50% of MS subjects with RTL1000 (~250,000 Americans), but produces an unmet need for an effective pMHC treatment for the remaining 50% (~250,000) 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?1-MOG-35-55, that retains the primary binding region for CD74 and the MOG-35-55 peptide found in RTL1000, but lacks the DR2?1 domain. Due to its universal expression, DR?1-MOG-35-55 would be a match for all human recipients and would thus nicely complement RTL1000 and address the unmet need of treating HLA-DR2 negative patients. To fully evaluate possible differences and limitations of each, we will compare potency, immunogenicity and CD74 modulation of the two constructs in matched (transgenic DR2+) vs. mismatched (transgenic DR4+) recipient mice with EAE. The ultimate goal of this study is to position the DR?1-MOG-35-55 drug to address the unmet need and provide coverage for DR2 negative MS subjects to complement the more advanced development of RTL1000 for use in DR2 positive MS subjects.
This project will evaluate suitability of a novel therapeutic called DR?1-MOG-35-55 for the possible treatment of ~50% of subjects with multiple sclerosis (MS) who do not carry the HLA-DR2 genetic risk factor for disease susceptibility. DR?1-MOG-35-55 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?1-MOG-35-55 to reverse clinical and histological signs of EAE in transgenic HLA-DR4 mice that are representative of HLA- DR2 negative MS subjects, determine the level of neutralizing antibodies induced during treatment and assess a new biomarker for efficacy of DR?1-MOG-35-55 called CD74, the MIF receptor, in preparation for possible human clinical trials in MS.
| Benedek, Gil; Chaudhary, Priya; Meza-Romero, Roberto et al. (2017) Sex-dependent treatment of chronic EAE with partial MHC class II constructs. J Neuroinflammation 14:100 |
| Yang, Liu; Liu, Zhijia; Ren, Honglei et al. (2017) DR?1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury. Metab Brain Dis 32:1395-1402 |
| Meza-Romero, Roberto; Benedek, Gil; Jordan, Kelley et al. (2016) Modeling of both shared and distinct interactions between MIF and its homologue D-DT with their common receptor CD74. Cytokine 88:62-70 |
