Antibodies to glatiramer acetate do not interfere with its biological functions and therapeutic efficacy

Abstract

G latiramer acetate (GA) previously known as C opolymer 1 (Cop 1), a synthetic amino acid copolymer, suppresses experimental autoimmune encephalomyelitis (EAE) and shows a beneficial effect in relapsing-remitting type of multiple sclerosis (MS). G A acts as a specific immunomodulator by binding to MHC C lass II molecules, inducing specific T suppressor (Ts) cells and interfering with T cell responses to myelin antigens. MS patients treated with GA developed GA reactive antibodies, which peaked at three months and decreased at six months. In order to find out whether anti-G A antibodies may neutralize the therapeutic effect of GA, we tested both polyclonal (mouse and human) and monoclonal G A specific antibodies for their ability to interfere with the biological activity of GA in several assay systems. None of the antibodies interfered with GA activities either in vitro (binding to MHC molecules and T cell stimulation) or in vivo (blocking of EAE). Furthermore, 53 samples of sera obtained from 34 MS patients that participated in the open label trial in Israel, and all developed G A specific antibodies, were tested for their ability to inhibit the proliferation response of GA specific Ts cell clone and to interfere with G A competitive inhibition of the response to peptide 84-102 of myelin basic protein (MBP). None of the sera inhibited and some even enhanced the in vitro activities of G A. Furthermore, representative MS sera with high titer of G A reactive antibodies did not neutralize the biological activities of G A and did not inhibit Th2 cytokine secretion by human G A specific clone. These results are consistent with the findings that the therapeutic effect of GA is not affected by GA reactive antibodies and is sustained upon long term treatment.