The T-Cell Attack on Myelin
The attack against MS patients’ myelin by their own immune system occurs through the activation of myelin-specific T cells (MRTCs) specifically directed against myelin protein components. The current understanding of MS pathogenesis involves T-cell-mediated inflammatory activity followed by selective demyelination (erosion of the myelin coating of the nerve fibers), then neurodegeneration. While both healthy individuals and MS patients have autoreactive T cells that recognize a variety of self-antigens [e.g., myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG)], these cells form part of the normal T-cell repertoire and do not cause autoimmune disease.
Individuals, however, with predisposing genetic backgrounds have increased susceptibility to activation and clonal expansion of myelin-autoreactive T cells. In MS patients these usually dormant cells become activated outside the CNS, possibly by recognizing epitopes that are common to autoantigens and foreign antigens, such as bacterial proteins, at the same time.
Once activated, the cells may cross the blood-brain barrier and infiltrate the healthy tissue of the brain and spinal cord. The ensuing cascade of pathogenic events eventually destroys the myelin sheath and prevents normal nerve impulse conduction.
Activated MRTCs in MS patients initiate destructive responses when a receptor on their surfaces binds to myelin components, causing Type 1 helper T cells (Th1 cells) to produce pro-inflammatory cytokines such as Interferon gamma and lymphotoxin; Th-1 type reactions are generally associated not only with inflammatory immune responses but also delayed hypersentitivity reactions.
While MRTCs from normal individuals induce Type 2 helper cells associated with antinflammatory effects, the myelin-reactive T cells from MS patients provoke pro-inflammatory Th-1-mediated responses.
The biofirms discussed below are developing therapeutics aimed at controlling MS-specific aspects of immune activation and responses. These include, for example, blocking the interaction between T cells and myelin antigens necessary for triggering Th-1 type responses and inducing immune responses against myelin-reactive T cells to reduce their numbers. In theory, these approaches would avoid compromising the immune system and allow normal immune surveillance mechanisms to operate.
PharmaFrontiers’ (www.pharmafrontierscorp.com) Tovaxin consists of MRTCs removed from an individual MS patient’s blood, expanded in cell culture in the presence of three myelin-derived peptides (MBP, PLP, and MOG) recognized by myelin auto-reactive T cells, then irradiated, rendering the cells nonreplicative but viable. When these attenuated MRTCs are injected subcutaneously into the MS patient, the body recognizes them as foreign and mounts an immune response against them, destroying not only the injected cells, but also the circulating, myelin autoreactive T cells carrying the peptide-specific T-cell receptor molecules.
The myelin-reactive T cells comprising Tovaxin, once returned to the patient via subcutaneous injection, stimulate anti-idiotypic and anti-ergotypic [a response that recognizes the state of activation of T cells irrespective of their TCR specificity] responses, differentiating this therapy from other products, explains Jim C. Williams, Ph.D., PharmaFrontier’s COO.
The key to the technology, continues Dr. Williams, is that Tovaxin can dampen or eliminate Th-1 type responses and increase Th-2 responses, and induce cytotoxic lymphocytes to destroy MS-specific pathogenic cells.
Two years ago, according to Dr. Williams, the reaction to autologous therapy was very cool in the investment community. Since then, we have amassed a lot of clinical data suggesting this approach may have significant promise in the treatment of MS, he says.
PharmaFrontiers has also developed a monitoring procedure that, points out Dr. Williams, will help us determine whether, pre-therapy, patients have the cells we use to make the vaccine. We also plan to use the assay to determine how long, post-vaccination, MRTC cells remain depleted.
The company is focusing on developing a vaccination schedule that maintains anti-myelin T-cell depletion for a year.
In PharmaFrontiers’ Phase I/II studies, Tovaxin (administered to MS patients in four injections over 3 months annually) reduced relapses more than 90% with virtually no side effects, according to the company. Additionally, approximately 40% of the MS patients treated with Tovaxin experienced a reversal of disability, while the remainder of patients (except for one relapse) experienced no progression of disease.
Based on the results of the Phase I/II studies, the company will begin a Phase IIb clinical trial to study Tovaxin therapy in 2006. The trial will enroll 150 patients (100 treated, 50 placebo) with early-stage disease, where the company expects that Tovaxin therapy will be most likely to have its greatest impact. The primary endpoint will be lesion evaluation (the total number of gadolinium-enhancing lesions) using MRI with a secondary endpoint being annual Artielle ImmunoTherapeutics (www.artielle.com) is developing autoimmune therapeutics based on Recombinant T-cell Receptor Ligands (RTLs). Artielle licensed RTL technology from the Oregon Health & Science University (OHSU), and says that the ligands, recombinantly produced proteins that comprise part of the MHC class II receptor molecule of antigen-presenting cells, can be tailored to treat a range of autoimmune diseases.