Biomarkers For The Immunogenicity Of Therapeutic Proteins

Two classes of biomarkers are used to indicate the clinical consequences of immunogenicity of therapeutic proteins:

1. General: persisting levels of neutralizing antibodies

2. Specific: loss of activity of endogenous homolog; increase in specific disease marker; decrease in efficiency marker

Biomarkers are also used to indicate the loss of efficiency of therapeutic proteins by antibodies:

1. Monoclonal antibodies: increase in side effects

2. Other therapeuticproteins: loss of side effects

Structural properties are the main primary factors of the induction of antibodies [18] . Therapeutic proteins of nonhuman origin will induce antibodies in the majority of patients after a limited number of applications. The degree of nonself and the presence of T-cell epitopes and the relative lack of immune tolerance are predictors of the antibody response.

Human homologs are less likely to be immunogenic. The best structural predictor of breaking tolerance is the presence of aggregates. The only animal model available for this type of immunogenicity is immune-tolerant transgenic mice. Induction of antibodies to human proteins usually occurs only after prolonged exposure. Independent of whether the protein is self or nonself, the possible immune modulating effect of the therapeutic protein, concomitant immune suppressive therapy, and the immune status of the patients are important predictors of an antibody response.

Antibody formation is by definition the marker for the immunogenicity of therapeutic proteins. The role of the cellular immunity is largely unknown and may be absent in the case of breaking B- cell tolerance. The occurrence of clinical consequences is in the majority of cases associated with relative high and persisting levels of neutralizing antibodies. In some cases the occurrence of neutralizing antibodies is preceded by binding antibodies, which may interfere with the pharmacokinetics of the proteins.

As discussed extensively, skin reactions cannot be seen as signs of the immu-nogenicity of proteins. Often, the loss of efficacy by neutralizing antibodies is difficult to assess because the diseases involved are chronic diseases with an unpredictable development and the proteins have only a limited effect. In these cases surrogate markers for efficacy may be monitored. Also, the effect on the side effects may be used as a marker. If the side effects are caused by the pharmacodynamic effect of the protein drugs, the loss of side effects is indicative of the development of neutralizing antibodies. If the side effect is the result of immune complexes, their appearance is associated with the induction of antibodies.

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