FDA guidelines to Industry on PEGylated Protein drug immunogenicity

Immune responses to therapeutic protein products may pose problems for both patient safety and product efficacy. Immunologically based adverse events, such as anaphylaxis, cytokine release syndrome, and cross-reactive neutralization of endogenous proteins mediating critical functions, have caused sponsors to terminate the development of what otherwise may have been efficacious therapeutic protein products.

Pegylation of therapeutic protein products has been found to diminish their immunogenicity via similar mechanisms to those by glycosylation that indirectly alters protein immunogenicity by minimizing protein aggregation, as well as by shielding immunogenic protein epitopes from the immune system. Immune responses to the polyethylene glycol (PEG) itself have been recognized and have caused loss of product efficacy and adverse safety consequences. Anti-PEG antibodies have also been found to be cross-reactive between pegylated products.For pegylated therapeutic protein products, the ADA assay should be able to detect both the anti-protein antibodies and antibodies against the PEG moiety.

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