Phase 1 Trial: Tolerance To MS Autoantigens Using Peptide-Coupled PBMCs
Two Forms of MS
Multiple sclerosis (MS) is a degenerative inflammatory disease of the brain and spinal cord, with symptoms typically starting between ages 20 and 40. MS falls into two major forms. The most common, accounting for 85%–90% of cases, is relapsing-remitting MS (RRMS), which usually progresses to secondary progressive MS (SPMS) over time. The second form, primary progressive MS (PPMS), accounts for roughly 10%–15% of cases. It presents with disability from disease onset and progresses steadily, with little to no remission. It’s still not clear what drives these different disease courses, and there’s limited understanding of what causes the complex variation in immune abnormalities seen among MS patients.
Myelin Antigens and Epitope Spreading
Although the cause of MS remains unclear, it’s widely thought to be driven by CD4+ T-cell autoreactivity to self-antigens in the central nervous system (CNS), particularly myelin antigens. Three myelin sheath proteins are recognized as key autoantigens in MS: myelin basic protein (MBP), myelin oligodendrocyte protein (MOG), and proteolipid protein (PLP). Earlier studies suggest epitope spreading may occur during the immune response to these three antigens in relapsing-remitting MS models — an idea supported by the fact that MS patients show different target myelin epitopes, possibly reflecting changes in the specificity of the T-cell pathogenic response over time.
These observations point to epitope spreading as a factor in MS, and may explain the disappointing results from several MS clinical trials that targeted a single antigen or peptide epitope. In other words, those earlier trials targeted pathogenic T-cells reactive against just one target antigen — without accounting for how the specificity of the pathogenic response changes over time.
A Phase 1 Trial of Antigen-Coupled Cell Tolerance
Antigen-coupled cell tolerance is a therapeutic approach that aims for antigen-specific T-cell tolerance by coupling target peptides to carrier agents. In a study published in Science Translational Medicine, Lutterotti’s group reported promising results from their first-in-man MS clinical trial. They demonstrated antigen-specific tolerance using autologous myelin peptide-coupled cells, delivered as a single infusion of autologous peripheral blood mononuclear cells (PBMCs) that served as carrier cells.
Seven myelin peptides believed to be key targets of autoreactive CD4+ T-cells in MS (MOG1–20, MOG35–55, MBP13–32, MBP83–99, MBP111–129, MBP146–170, and PLP139–154) were chemically bound to the surface of patient-isolated PBMCs, using the chemical cross-linker 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), then reinfused back into the patient. Lutterotti’s group validated the safety and feasibility of this approach in nine MS patients, and reported promising tolerability: patients’ immune autoreactivity to myelin peptides dropped by 50 to 75 percent. All nine patients showed T-cell reactivity to at least one of the seven targeted myelin peptides — seven were RRMS patients, and two were SPMS patients.
What the Results Show
These results support the epitope-spreading hypothesis: MS patients initially make antibodies against one or a few myelin proteins, but as the disease progresses, the autoimmune response spreads to other myelin sheath epitopes. Lutterotti’s team makes the case that future therapies need to target not just specific antigens, but also the ability to inhibit epitope spreading — ideally before the CD4+ T-helper cell autoreactivity diversifies.
Next Steps for Antigen-Specific MS Therapy
This study is a significant step toward an effective strategy for treating MS and other T-cell-driven autoimmune disorders. That said, this therapeutic method still needs to be tested in a much larger, geographically diverse population to confirm the efficacy holds across most or all MS subtypes. Phase II of this clinical trial is planned for the near future, and should reveal more about the technique’s long-term safety and efficacy. For now, this study sets a clear requirement for future antigen-specific therapies: the ability to target not just previously activated autoreactive T-cells, but also naïve autoreactive T-cells specific to multiple myelin epitopes.
Further Reading:
Antigen-Specific Tolerance by Autologous Myelin Peptide–Coupled Cells: A Phase 1 Trial in Multiple Sclerosis
