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 symptoms of myasthenia gravis, is due mainly to mechanisms dependent on the bivalent character of the anti-receptor antibodies. In cell culture, univalent Fab fragments of monoclonal antibodies (mAbs) directed against the main immunogenic region (MIR) of the acetylcholine receptor are able to protect the receptor against the action of the intact antibodies. To investigate the potential therapeutic use of this approach, we examined the ability of the Fab fragment of anti-MIR mAb195 (Fab195) to protect the receptor in vivo against two anti-MIR mAbs. Because of the rapid clearance of Fab fragments from the circulation, Lewis rats were treated repeatedly with Fab195. The Fab fragment significantly protected muscle receptors against antibody-mediated loss and was very efficient in providing protection against clinical symptoms when its administration was commenced before, simultaneously with, or 2 h after, mAb injection. Twenty-four hours after mAb injection, the protected rats only showed mild myasthenic symptoms, whereas those which only received intact antibodies were moribund or dead. These results suggest that, once modified to ensure their low immunogenicity and a long half-life, anti-MIR Fab fragments might be useful in the specific immunotherapy of myasthenia gravis.
Papanastasiou
D
D
Department of Biochemistry, Hellenic Pasteur Institute, 127 Vas. Sofias Avenue, Athens, Greece.
Poulas
K
K
Kokla
A
A
Tzartos
S J
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D007135:Immunoglobulin Variable Region / Q000187:drug effects / Q000276:immunology*; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007135:Immunoglobulin Variable Region; D011950:Receptors, Cholinergic