In vitro characterization of an acetylcholine receptor–transferrin fusion protein for the treatment of myasthenia gravis

Abstract

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.

Keywords::

• Myasthenia gravis
• acetylcholine receptor
• transferrin
• antigenic modulation

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.