Antibodies immunogenicity risk

Adalimumab is used to reduce signs and symptoms and progression of rheumatoid arthritis and psoriatic arthritis. It could be administered alone or in combination with methotrexate. The recommended dose for adults is 40 mg by subcutaneous injection, administered every other week. The most common side effect associated with the administration of adalimumab is injection site reaction. The most serious side effects resulting from treatment with this antibody include increased risk of infections and malignancies and neurological disorders. Additional side effects are the production of autoantibodies, immunogenicity and GI disorders. 

The definition of risk is the probability times the consequences (Figure 20.1). So the probability of an immune response is not synonymous with its risk. A high risk can be associated with a relative high probability, but also with a low probability if the consequences are severe. For example, the probability of an immune response to epoetin is rather low, but one of the consequences, antibody-induced severe anemia, is severe [3], This makes the risk of immunogenicity of epoetins relatively high. 

The route of administration influences the likelihood of an antibody response independent of the mechanism of induction. The probability of an immune response is the highest with subcutaneous administration, less probable after intramuscular administration and intravenous administration is the least immunogenic route. There are no studies comparing parenteral and nonparenteral routes of administration. Flowever, as both mucosal tissues and the skin are immune competent organs designed to keep invaders out of the body, intranasal, pulmonary, and transdermal administration of therapeutic proteins may increase the risk of an immune response as compared to parenteral routes. 

To evaluate the biological consequences of antibodies, patients with positive responses should be monitored for their impact on the pharmacokinetic and pharmacodynamic effect of the therapeutic protein. Also the effect on adverse events and possible neutralization of the endogenous protein, in cases where human proteins are administered at pharmacological doses, should be monitored. When the consequences of the immunogenicity are known, the risk can be established. 

A variety of possibilities to reduce the risk of immunogenicity of a therapeutic antibody exist, and have been employed. 

Chimeric antibodies are hybrid molecules combining the antigen-specific variable domain of the mouse antibody fused to the constant regions of a human IgG molecule (Fig. 1.4). This reduces the risk of immunogenicity somewhat, and the human Fc domain prolongs the serum half-life and is more effective in triggering the effector systems of complement and Fc receptors. 

---