Nihon’s new drug candidate NPO-15 for the treatment of Myasthenia Gravis has been adopted by AMED’s Drug Discovery Support Program for Orphan drug prior to the Designation
Project titleDevelopment of a new treatment agent for Myasthenia Gravis (NPO-15)
AffiliationNihon Pharmaceutical Co., Ltd.
Drug Discovery Support Program for Orphan Drug Prior to the Designation
Myasthenia Gravis (MG)
(Information from the website of Japan Intractable Disease Center as of May 2019)
Further information on AMED
Expected dual action of NPO-15
Myasthenia Gravis (MG) is an autoimmune neurological disease which results from pathogenic autoantibodies that destroys nicotinic acetylcholine receptors on the side of postsynaptic membrane of the neuromuscular junction. This prevents nerve impulses from triggering muscle contractions to cause muscle weakness and fatigue. MGs are classified into systemic MG and ocular MG, and 80 to 85% of all MGs are positive for anti-acetylcholine receptor antibody (anti-AChR antibody).
NPO-15 is a recombinant Fc fusion protein consists of the human acetylcholine receptor α1 subunit extracellular domain (AChR domain) and human IgG1 Fc domain (IgG1 Fc domain). Thanks to this molecular design and mechanism of action, this targets anti-AChR antibody-positive patients.
In the AChR domain, there is a recognition sequence of anti-AChR antibody, a pathogenic autoantibody, which binds to the anti-AChR antibody by antigen-antibody reaction. This binding action acts as a decoy effect, and autoantibody neutralizing activity is exhibited in the patient's blood or in the neuromuscular junction.
The other IgG1 Fc domain has an Fc receptor binding site, which is a sequence deeply involved in antibody-dependent cellular cytotoxicity (ADCC). NPO-15 binds to autoantibody-producing B cells (pathogenic B cells), and then IgG1 Fc binds to Fc receptors so that it is exhibited to exert ADCC activity against the pathogenic B cells via effector cells such as natural killer cells.
NPO-15 has a unique molecule to be expected to have dual mechanisms of action, i.e., neutralizing activity against anti-AChR antibody and cytotoxic activity against pathogenic B cells.