Assessment of Immunogenicity

Immunogenicity assays are conducted early in drug development to support pharmacology and toxicology studies. The concentration of antibody in blood or serum is detected with a semiquantitative assay such as an enzyme-linked immunosorbent assay (ELIS A). ELIS A is an analytical tool in which the antigen, in this case a protein pharmaceutical, is coated on the surface of a test tube (solid support), allowing antigen-specific binding of a specific serum antibody. An enzyme-linked diagnostic antibody that recognizes the presence of a specific antibody then is added to the test tube along with an enzyme substrate that produces an intensity of color proportional to the amount of binding. By measuring the color intensity, an analyst can assess the antibody concentration in serum raised by the protein drug. This method allows screening of any antibody that binds to the therapeutic protein (binding antibody) in the sera of blood samples from a large number of patients.

However, not all antibody detected by ELISA corresponds to the antibody molecule that blocks the biological activity or active sites of the therapeutic protein. These neutralizing (blocking) antibodies are only a small fraction of the binding antibody population. Different cell- and receptor-based neutralizing antibody assays are developed for different protein drugs.

It is essential to evaluate potential immunogenicity of a therapeutic protein throughout clinical trials. Therefore, in planning for sample collection during clinical trials for biotechnology products, clinical investigators often consider collecting blood samples at multiple predetermined time points for immunological assays. Availability of these blood samples allows the investigators to determine the immunogenicity of the protein drug. It also reveals the time course and extent of the immune response in the population. Additional pharmacokinetic data, collected before and after induction of antibody, allow the assessment of clinical impact of immune responses generated against the administered protein. For example, a decrease in the biologic activity of a therapeutic protein after induction of an antibody response signifies the presence of drug-neutralizing antibodies.

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