In vitro characterization of an acetylcholine receptor-transferrin fusion protein for the treatment of myasthenia gravis.
SHG2210, a fusion protein containing the N-terminus of human nicotinic acetylcholine receptor α (AchR-α; aa1-210) and human transferrin (TF), was characterized as a potential therapeutic for myasthenia gravis (MG) caused predominately by α subunit autoantibodies. SHG2210 was shown to be able to bind to α subunit autoantibodies and the TF receptor (TFR). SHG2210 and SHG2210-anti-AchR antibody complex are internalized through TFR-mediated endocytosis. The SHG2210 and SHG2210-anti-AchR antibody complex is present in Lamp1-positive lysosomal compartments after internalization; however, neither SHG2210 nor SHG2210-antibody complex is present in Rab11-positive recycling endosomes. SHG2210 bound to α subunit of AChR autoantibodies may be cleared by the lysosome, resulting in short cellular half-life relative to SHG2210. SHG2210 is shown to have a protective effect on antigenic modulation of the AChR induced by serum from select patients with MG, suggesting that a fusion protein approach may be an effective therapeutic for treating MG.
Keefe
Dennis
D
Department of Research, Shire Human Genetic Therapies, Lexington, MA 02421, USA. dkeefe@shire.com
Parng
Chuenlei
C
Lundberg
Dianna
D
Ray
Satyajit
S
Martineau-Bosco
Jennifer
J
Leng
Charan
C
Tzartos
Socrates
S
Powell
Jan
J
Concino
Michael
M
Heartlein
Michael
M
Lamsa
Justin
J
Josiah
Serene
S
D001667:Binding, Competitive / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000276:immunology*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000276:immunology*; D011990:Receptors, Transferrin / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D014168:Transferrin / Q000235:genetics / Q000276:immunology*
D011978:Receptors, Nicotinic; D011990:Receptors, Transferrin; D011994:Recombinant Proteins; D014168:Transferrin