Prevention of passively transferred experimental autoimmune myasthenia gravis by Fab fragments of monoclonal antibodies directed against the main immunogenic region of the acetylcholine receptor

The muscle acetylcholine receptor loss, responsible for the clinical sympto ms of myasthenia gravis, is due mainly to mechanisms dependent on the bival ent character of the anti-receptor antibodies. In cell culture, univalent F eb fragments of monoclonal antibodies (mAbs) directed against the main immu nogenic region (MIR) of the acetylcholine receptor are able to protect the receptor against the action of the intact antibodies. To investigate the po tential therapeutic use of this approach, we examined the ability of the Fa b fragment of anti-MIR mAb195 (Fab195) to protect the receptor in vivo agai nst two anti-MIR mAbs. Because of the rapid clearance of Fab fragments from the circulation, Lewis rats were treated repeatedly with Fab195. The Fab f ragment significantly protected muscle receptors against antibody-mediated loss and was very efficient in providing protection against clinical sympto ms when its administration was commenced before, simultaneously with, or 2 h after, mAb injection. Twenty-four hours after mAb injection, the protecte d rats only showed mild myasthenic symptoms, whereas those which only recei ved intact antibodies were moribund or dead. These results suggest that, on ce modified to ensure their low immunogenicity and a long half-life, anti-M IR Fab fragments might be useful in the specific immunotherapy of myastheni a gravis. (C) 2000 Elsevier Science B.V. All rights reserved.