Preclinical and Pharmacological Studies of AG284, a Soluble HLA‐DR2:Myelin Basic Protein Peptide Complex for the Treatment of Multiple Sclerosis

The recent approvals of Betaseron, Avonex, and Copaxone have improved treatment options for multiple sclerosis (MS), but these therapeutics delay the progression of disease in only ~30% of the patient population. There remains an unmet need for MS therapeutics, and several new drugs enter clinical testing each year in an attempt to meet this need (37,38). This review summarizes the development of an antigen-specific therapeutic comprised of a solubilized major histocompatibility complex (MHC) molecule bearing an autoantigenic peptide of myelin basic protein, called AG284, and the initiation of its phase I clinical trial in MS. The combination of MHC molecule, peptide, and detergent excipient in AG284 presented several unique challenges in the formulation of this drug and in the analysis of its biodistribution and stability. Furthermore, the considerable polymorphism of MHC molecules complicated preclinical efficacy studies, as well as tests of toxicity and immunogenicity. Other challenges that were also encountered in other recent MS clinical trials included a dearth of simple, sensitive surrogate markers, particularly for tracking T-cell reactivity. The preclinical testing and trial design of AG284 reviewed here illustrate several of the challenges likely to face other antigen-specific therapeutics, and some of the solutions detailed herein may have applications for similar trials in other diseases.