Investigating the Effects of Pre-Existing Anti-PEG Antibodies on Mircera

摘要

Polyethylene glycol (PEG) is often conjugated with therapeutic molecules such as proteins, liposomes and nanoparticles due to its biocompatibility and ability to prolong the half-life of therapeutic drugs. Several studies have reported that IgM antibodies with specificity for PEG can be induced by PEGylated nanoparticles and cause accelerated blood clearance, which may compromise the effectiveness of PEGylated drugs. We recently found that around 40% of healthy Han Chinese in Taiwan already has pre-existing antibodies against PEG in their circulation. However, the clinical impact of pre-existing anti-PEG antibodies on PEGylated drugs is still unclear. Here, we aim to characterize the effects of pre-existing anti-PEG antibodies on Mircera (methoxy polyethylene glycol-epoetin beta), an erythropoietin receptor activator often used to treat patients with anemia associated with chronic kidney diseases in Taiwan. We showed that pre-existing anti-PEG antibodies in healthy individuals from Taiwan could bind Mircera. Further, pre-injecting IgG and IgM anti-PEG monoclonal antibodies in mice to mimic pre-existing antibodies in healthy individuals dose-dependently accelerated the clearance of Mircera from the circulation. Biodistribution studies revealed that cleared Mircera largely accumulated in the liver and spleen. Pre-existing anti-PEG antibodies also blocked the bioactivity of Mircera as measured by red blood cell maturation. These findings indicate that pre-existing anti-PEG antibodies may hinder the therapeutic activity of Mircera. In the future, the pre-existing anti-PEG antibodies in patients may be important references for physicians to prescribe PEGylated drugs.