chapter  37
3 Pages

A Phase I trial of solubilized DR2: MBP(84-102) (AG284) in multiple sclerosis

Converging lines of evidence suggest that multiple sclerosis (MS) is an immunemediated disease of the central nervous system (CNS).1 T cells cloned from patients with MS respond to myelin basic protein (MBP) peptide fragment 84-102 (MBP(84-102)) by proliferating and secreting pro-inflammatory cytokines that may directly or indirectly damage myelin.2 AG284 is a complex, solubilized in n-dodecyl-β-malto-side, that is comprised of human leukocyte antigen (HLA) DR2 non-covalently bound to MBP(84102) in the peptide-binding groove. Pre-incubation with AG284 reduces the proliferative response of a DR2-restricted, MBP(84-102)-reactive T-cell clone, derived from a MS patient, to MBP(84-102) in the presence of autologous irradiated antigen-presenting cells (APCs), to 20-30% of control levels.3 We hypothesized that the solubilized HLA-DR2: MBP(84-102) complex AG284 might render MS patients’ autoreactive T cells unresponsive to MBP(84-102), thereby preventing the formation of new MS lesions and clinical expression of disease activity. To prepare for a trial of clinical efficacy of AG284 in MS, we tested the safety and tolerability of this product in a randomized, placebocontrolled, double-blinded, dose-escalation trial in 33 patients with secondary progressive multiple sclerosis (SPMS).4 A full report of the methods and results of this study are reported elsewhere.5