Clinical Aspects of Immunogenicity to Biopharmaceuticals

The range of biopharmaceuticals available is steadily increasing. The first generation of products were copies of naturally occurring growth factors, or hormones or cytokines. With the development of new techniques, such as pegylation and glycosylation, second-generation biopharmaceuticals with increased bioavailability and higher therapeutic index are available. Most biopharmaceuticals induce immune responses. The theoretical basis for immunogenicity to biopharmaceuticals is based either on their foreign nature, being of exogenous origin (neo-antigens or non-self-antigens), or on their similarity to self-molecules (self-antigens). In both cases, clinical manifestation of immunogenicity depends on the activation of antibodysecreting B cells. Besides this, many factors contribute to immunogenicity, such as product-related factors and host-related factors. These are discussed in more detail in Chapter 5. Immunogenicity can cause a range of consequences, as summarized in Table 2.1. In many cases, antibodies against biopharmaceuticals have little or no consequences. In some cases, they can cause a loss of efficacy of the therapeutic proteins, but the most dangerous effect occurs when autoimmunity is directed against the endogenous molecule (Kromminga and Schellekens 2005). On the next pages, the different effects of antigenicity and immunogenicity will be discussed, and each type of effect will be illustrated by examples.