Beyond copolymer 1

Copolymer 1, also called glatiramer acetate, is an unusual therapeutic compound, a heterogeneous mix of polypeptides containing the four amino acids Y, E, A, and K in definite ratios but with no uniform sequence. Although its mode of action remains controversial, this preparation clearly helps retard the progression of human multiple sclerosis (MS) and of the related autoimmune condition, studied in mice, experimental autoimmune encephalomyelitis (EAE). Copolymer 1 is presented on class II MHC molecules, including the HLA-DR2 type that is associated with increased risk of MS. This MHC molecule binds a defined auto-epitope from myelin basic protein (MBP) and presents it to CD4 T cells, initiating an immune response against myelin in the CNS. Fridkis-Hareli et al. reexamined the structure of the DR2 peptide-binding groove and concluded that the selection of amino acids used in Copolymer 1 was far from optimal if the goal was to compete against presentation of MBP peptides. Here they show that YFAK and FAK copolymers, among others, bind DR2 with higher affinity than does YEAK (copolymer 1), allowing them to compete successfully against an endogenous autoantigenic peptide. These formulations were more effective than Copolymer 1 at suppressing the activation of T cells bearing DR2-restricted, MS patient?derived T cell receptors. Crucially, the novel copolymers were also dramatically more effective at suppressing EAE. Thus, mice injected with either a defined antigenic peptide or whole spinal cord homogenate normally initiate inflammatory and cytolytic responses in the CNS. While Copolymer 1 reduced the incidence of this disease and delayed its onset in most cases, several of the novel copolymers prevented it entirely. Given the precedent of Copolymer 1?s safety and efficacy in people with MS, the use of other copolymers, perhaps optimized to target an individual?s MHC haplotype, seems an attractive scenario for MS and perhaps other autoimmune diseases.

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