Immunogenicity and other problems associated with the use of biopharmaceuticals

Abstract

Biopharmaceuticals are used widely for the treatment of cancer, chronic viral hepatitis, inflammatory, and autoimmune diseases. Biopharmaceuticals such as interferons are well tolerated for the most part with the most common adverse events observed being 'flu-like' symptoms that resolve rapidly after initial treatment. Prolonged treatment is associated, however, with more serious adverse events including leucopenia, thrombocytopenia, and neuropsychiatric effects, which may necessitate dose reduction or even cessation of treatment in some patients. Recombinant growth factors, such as erythropoietin (EPO), granulocyte colony-stimulating factor, or granulocyte macrophage colony-stimulating factor, are for the most part well tolerated, although severe complications have been reported in patients with cancer or chronic kidney disease treated with EPO. Similarly, treatment of patients with cancer with high doses of interleukin-2 is associated with significant toxicity. Treatment of chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and Crohn's disease, with antitumor necrosis factor-alpha monoclonal antibodies is associated with an increased risk of granulomatous infections and, in particular, tuberculosis. The monoclonal antibody, natalizumab, that targets alpha4 integrins is effective in the treatment of multiple sclerosis but is associated with the activation of JC virus and development of progressive multifocal leukoencephalopathy. Repeated administration of recombinant proteins can cause a break in immune tolerance in some patients resulting in the production of a polyclonal antibody response that can adversely affect pharmacokinetics and clinical response. In addition, neutralizing antibodies that cross react with nonredundant essential proteins such as EPO can cause severe autoimmune reactions.

Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of RG7667, a Combination Monoclonal Antibody, for Prevention of Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients

“…These findings were not unexpected, as clinical immunogenicity to recombinant monoclonal antibody therapeutics is not uncommon (24)(25)(26)(27). The clinical relevance of this observation is unknown, as there was no measurable effect upon RG7667 pharmacokinetics.…”

Rheumatoid Arthritis: A Brief Overview of the Treatment

“…Nonetheless, biologics pose the problem of serious side effects, such as increased risk of infections. Other common side effects include neurologic diseases like multiple sclerosis and lymphoma [27-29]. …”

Parallel experimental design and multivariate analysis provides efficient screening of cell culture media supplements to improve biosimilar product quality

“…The clusters 1–4 in the groups 1 and 2 showed variation larger than the control runs, while for cluster 5, no group featured a clear variation compared to the controls. A decrease in aggregate levels during cell culture to circumvent undesired immunogenicity is an important objective (Moore and Leppert, ; Tovey and Lallemand, ). Each group increased the range of protein aggregation compared to the controls.…”