Immunogenicity of recombinant human proteins: causes and consequences

Abstract

Antibodies develop to varying degrees during treatment with human proteins, including insulin, growth hormone, granulocyte-macrophage colony-stimulating factor, factor VIII, erythropoietin, and interferons. These antibodies may reduce the clinical efficacy of these agents by blocking or neutralizing their biologic activity and may have other biologic effects. For example, antibodies develop in 20 % to 40% of patients with severe hemophilia treated with human factor VIII; the presence of these antibodies can result in tolerance to the clotting effects of this agent. Similarly, a proportion of patients treated with interferon alpha develop antibodies, which inhibit its therapeutic effects. Therefore, it is important to test for neutralizing antibodies during treatment with these agents, particularly in patients who are unresponsive to treatment or have breakthrough disease. This article reviews the incidence and clinical impact of antibodies that develop in response to some of the commonly used protein therapeutic agents.

Tailoring recombinant protein quality by rational media design

“…The glycan profile was determined once a day, starting on culture day 3 until the end of the run. The fucosylated species FA2-the main glycan peak-and the two galactosylated species, including the mono-galactosylated form FA2G1 (sum of FA2 [3]G1 and FA2 [6]G1) as well as the di-galactosylated glycan, FA2G2, in function of time are presented in figure 8.5. The cells readily expressed galactosylated mAb at the beginning of the culture.…”

“…However, the model is not capable to predict the final glycan fingerprint at the very end of the fed-batch process. To assess the prediction quality of the four major glycan species, FA2, FA2 [6]G1, FA2 [3]G1, and FA2G2, the observed versus predicted value plots in figure 8.12 provided insight at each specific glycan value. The predicted points of FA2 [3]G1 lie rather closely to the diagonal line, whereas for the points of the other three species form a curve.…”

“…To assess the prediction quality of the four major glycan species, FA2, FA2 [6]G1, FA2 [3]G1, and FA2G2, the observed versus predicted value plots in figure 8.12 provided insight at each specific glycan value. The predicted points of FA2 [3]G1 lie rather closely to the diagonal line, whereas for the points of the other three species form a curve. Both at the extremes and in the middle the prediction error is larger as the larger distance between the points and the line indicates.…”

“…Patients have benefited ever since from safer and more efficacious drug products due to recombinant analogs rather than proteins of animal origin, which enabled substantial purity improvements 3 . The advent of biotherapeutics revolutionized the landscape of the healthcare sector, and as a consequence of the great improvements they brought about, the biologics market has massively grown 4 , resulting in tripling of new biological license applications in the beginning of the 21 st century and reached all-time records in 2012, 2014 and 2015, exceeding twelve per year 5 .…”

“…Contrary to the proteins of animal origin, recombinant analogs of insulin from E.coli cultures and human growth hormone produced in mammalian cells have provided the patients with access to safer and more efficacious drug products from the advent of biotechnology until today. They enabled purity improvements of insulin preparations, for instance, and patients treated with this biotherapeutic displayed lower prevalence and titers of anti-insulin antibodies 3 . While recombinant drugs are in general well tolerated and their advantages largely outweigh the downsides, their safety and efficacy can be severely impaired by the development of immunogenic reactions against the therapeutic protein 243 .…”