The immunogenicity of biopharmaceuticals. Lessons learned and consequences for protein drug development.

Most biopharmaceuticals, including those proteins that are more or less identical to native human proteins, induce antibodies in a significant fraction of patients. The main factors contributing to immunogenicity are impurities and the presence of aggregates. Sequence divergence from the native proteins only plays a minor role except in proteins from microbial, plant or distant vertebrate origin. In the majority of cases the antibodies have no biological or clinical effects. The most common clinical effect is the loss of efficacy of the biopharmaceutical. Serious complications of immunogenicity are rare. The best method to prevent immunogenicity is optimizing production, purification and formulation of the biopharmaceutical protein to generate soluble, non-aggregated, native protein free of contaminating adjuvants. The best way to predict immunogenicity in humans is evaluation in immune tolerant transgenic mice.