19 Jun Hope for Rare Neuropathy By Targeting Specific Autoantibodies
MedicalResearch.com Interview with:
Pascal Hänggi, PhD
Chief Scientific Officer
Polyneuron Pharmaceuticals
MedicalResearch.com: What is the background for this study?
Response: Anti-MAG neuropathy is a rare form of acquired demyelinating neuropathy. The disease onset normally presents after the age of 50 years and is 2.7 times more frequent in men than in women, with a prevalence of about 1 in 100,000. It is caused by the production of monoclonal anti-MAG IgM antibodies that recognize the HNK-1 epitope. The myelin-associated glycoprotein MAG is a mediator for the formation and maintenance of the myelin sheaths. There is strong evidence that the binding and deposition of anti-MAG IgM autoantibodies on myelin sheath is responsible for the demyelination, which clinically manifests itself as a peripheral neuropathy affecting primarily sensory nerves. However, the causes and the exact mechanisms behind the expansion of anti-MAG IgM producing B-cell and plasma cell clones are not fully understood.
Most off-label treatments aim to reduce pathogenic autoantibody titers by depleting autoantibody-producing B cell clones which interfere with antibody-effector mechanisms, or physically remove autoantibodies from the circulation. Most frequently, the anti-CD20 monoclonal antibody rituximab is used to treat anti-MAG neuropathy patients. However, all of these treatment options often lack of selectivity, efficiency, or can induce severe adverse effects in some patients.
Polyneuron has designed PN-1007 to highly selectively target the IgM autoantibodies that cause anti-MAG neuropathy. PN-1007 is a glycopolymer that mimics the natural HNK-1 carbohydrate epitope found on myelin of peripheral nerves and binds to the circulating disease-causing antibodies. By eliminating these pathogenic antibodies, PN-1007 may protect the integrity of the neuronal myelin sheaths of anti-MAG neuropathy patients.
MedicalResearch.com: What are the main findings of these reports?
Response: In the Journal of Neurochemistry paper, entitled “Selective inhibition of anti‐MAG IgM autoantibody binding to myelin by an antigen specific glycopolymer”, Polyneuron and collaborators found that PN-1007 selectively bound anti‐MAG IgM autoantibodies and prevented the binding of patients’ anti‐MAG IgM antibodies to myelin of non‐human primate sciatic nerves.
In a dose titration study in mice, intravenous administration of PN-1007 was able to efficiently remove all anti-MAG IgM antibodies, strongly supporting the anticipated effective dose range for the upcoming phase I/IIa study in patients.
The mechanism of anti-MAG IgM removal in vivo was further verified by comparing PN-1007 treatment with that of a CD20+ B cell depleting monoclonal antibody. CD20+ B cell depletion was found to not affect the anti-MAG IgM titers in the immunological mouse model whereas weekly treatment with PN-1007 abrogated the MAG binding within less than an hour from administration. Moreover, further studies supported the favourable safety profile of PN-1007 in mice and ex vivo with human leukocytes and B cells of anti-MAG neuropathy patients. PN-1007 did not induce or lead to the release of murine and human cytokines and chemokines, and did not activate antibody-producing cells of patients ex vivo.
MedicalResearch.com: What is happening next as a result of these studies?
Response: These and other preclinical optimization studies have enabled us to move towards clinical studies. Later in 2020, Polyneuron will begin evaluating PN-1007 in a phase I/IIa study in anti-MAG neuropathy patients.
Citation:
Butrint Aliu, Delphine Demeestere,Emilie Seydoux.,Jose Boucraut, Emilien Delmont, Alexandre Brodovitch, Thomas Oberholzer, Shahram Attarian, Marie Théaudin, Pinelopi Tsouni, Thierry Kuntzer, Tobias Derfuss, Andreas J. Steck, Beat Ernst, Ruben Herrendorff, Pascal Hänggi
First published:09 April 2020
https://doi.org/10.1111/jnc.15021
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Last Updated on June 19, 2020 by Marie Benz MD FAAD