Therapeutic proteins in general induce an immune response, especially when administered as multiple doses over prolonged periods. Non-human therapeutic proteins such as asparaginase and streptokinase induce antibodies by the classical immune reaction and their primary immunogenic factor is the degree of non-self. Human therapeutic proteins such as the interferons and GM-CSF breakdown immune tolerance and protein aggregation is their main factor inducing antibodies. Many other factors influence the level of immunogenicity of proteins, such as storage conditions,contaminants or impurities in the preparation, downstream processing, dose and length of treatment, as well as route of administration, appropriate formulation and disease status and concomitant treatment of patients. Clinical manifestations of antibodies directed against the protein include loss of efficacy, cross neutralization of endogenous proteins and general immune system effects, such as anaphylaxis or serum sickness.