Therapeutic vaccines are antigen-specific agents that inhibit an unwanted immune response to prevent progression of, or eliminate, existing disease. Unlike prophylactic vaccines, developing therapeutic vaccines poses a significant challenge because they can require multimodal immunomodulatory activity to modulate complex pathogenic disease pathways. This is particularly true in autoimmune disorders, including multiple sclerosis, which has complex pathogenesis that, although not fully understood, appears to involve dysfunction of both innate and adaptive immune processes. The glatiramoid, glatiramer acetate (Copaxone®), a nonbiologic, complex, heterogenous mixture of synthetic polypeptides, is currently the only approved therapeutic peptide for treatment of multiple sclerosis. Glatiramer acetate has an enormous number of potentially active epitopes (estimated to be ~1030) in the polypeptides mixture. The epitopes in glatiramer acetate have not been identified, but they appear to act as altered peptide ligands of encephalitogenic epitopes within myelin basic protein, a suspected autoantigen implicated in multiple sclerosis. Peptide epitopes in glatiramer acetate compete with autoantigens for binding with major histocompatability complex molecules on antigen-presenting cells, thereby altering the functional outcome of T cell signaling from inflammatory to anti-inflammatory responses. Other therapeutic vaccines designed to more selectively compete with myelin antigens for receptor binding have been shown effective in animal models of multiple sclerosis but toxic in human patients in clinical trials. The partially random structure of glatiramer acetate and potentially huge number of antigenic sequences may be integral to safety and efficacy by influencing multifactorial immune processes and surmounting challenges related to inter- and intra-individual heterogeneity of T cell responses and the phenomenon of epitope spreading. Follow-on generic versions of glatiramer acetate have been made available to multiple sclerosis patients outside the United States. Analyses of these glatiramoids indicate they have different biological and immunological activity from that of Copaxone®, illustrating the difficulty of replicating complex glatiramoids and of developing safe, effective peptide vaccines in general. Reviewed here are some of the major mechanisms of glatiramer acetate activity on innate and adaptive immune pathology and considerations for development of future therapeutic peptide vaccines for multiple sclerosis.
keywords: Autoimmune disease, glatiramer acetate, glatiramoid, multiple sclerosis, peptide, copolymer, therapeutic, vaccine