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You are here: Home / Archives for generalized myasthenia gravis

Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases

February 1, 2023 by Janice Reichert

Summary written by Alicia Chenoweth, PhD, King’s College London

Antibody Engineering & Therapeutics, held in December 2022, offered many opportunities to hear exciting and informative presentations by experts in the field, including Dr. Hans de Haard, Chief Scientific Officer at argenx.

Dr. de Haard’s talk, Efgartigimod: A Novel FcRn Antagonist in the Treatment of Autoimmune Diseases, detailed the mechanism of action and clinical trial results of the FcRn antagonist efgartigimod. Efgartigimod is a human IgG1 Fc fragment with five “Abdeg” mutations (M252Y, S254T, T256E, H433K, N434F) to increase its affinity for FcRn at both low pH and neutral pH (1,2). It is designed to outcompete the binding of serum IgG for FcRn, leading to degradation of the unbound IgG and recycling of efgartigimod back to the surface of the cell to be released back into circulation.

Dr. de Haard discussed the findings of a recent publication in which the biochemical, structural, and in vivo properties of efgartigimod and a full-length antibody counterpart containing the same Abdeg mutations were compared (3). Crystallographic studies of FcRn in complex with the full-length antibody demonstrated that the antigen-binding fragment projects towards the membrane, leading to a potential steric clash hindering binding. This hypothesis was confirmed using a bioassay measuring receptor occupancy, showing that efgartigimod gave a better FcRn occupancy and had improved uptake compared to the full-length antibody. Furthermore, in cynomolgus monkeys, the Fc fragment gave a much faster clearance of tracer antibody and a more potent pharmacodynamic effect compared to full-length antibody. Thus, the Fc fragment was determined to be the better performing FcRn antagonist over the full-length antibody due to improved blocking of IgG recycling in vitro and the more potent PD effect in vivo.

[Read more…]

Filed Under: Antibody Engineering & Therapeutics Tagged With: antibody therapeutics, efgartigimod, generalized myasthenia gravis

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