There are cases, however, in which antibodies were found to be neutralizing, which can negate the effect of the therapy or when cross-reacting with the endogenous protein, deplete the effect of this protein. The clinical effects of such cases are significant, and can result in a more severe disease and a need for acute intervention. Several potential mechanisms can cause immunogenicity of therapeutic proteins such as aggregates, molecular mimicry, adjuvants, neo-antigens, and modification of the protein. Epoetin is an example of one display of this mechanism.
The number of biotechnology-derived therapeutic proteins now available includes over 75 products representing 65 different types of molecules.2 In spite of the fact that biopharmaceuticals currently have only a small share of the pharmaceutical market, their medical impact is enormous. Examples of deficiency correction are recombinant human-insulin therapy for diabetes mellitus, therapy with factor VIII in patients with hemophilia A, and recombinant human erythropoietin (epoetin) therapy for the treatment of anemia. An example of a biopharmaceutical that alters disease processes is the use of recombinant interferons in patients with multiple sclerosis, hepatitis, and cancer.
In some cases antibodies may be neutralizing, which can negate the effect of the therapy.6-16 Cross-reaction with the endogenous protein can deplete the effect of this protein.17-19 This effect has been observed in the management of anemia in chronic kidney disease patients, where cross-reactive neutralizing antibodies were found to inhibit the activity of both the administered epoetin and the patient's own residual erythropoietin.18,19 This created a more severe anemia, called pure red-cell aplasia (PRCA), characterized by an almost complete absence of red-blood-cell precursors in bone marrow.18,19 In the majority of reported cases of PRCA, the presence of anti-erythropoietin antibodies has been confirmed, resulting in the condition named antibody-mediated PRCA (Ab+PRCA).