Mechanisms Of Antibody Induction

There are two main mechanisms by which antibodies are induced by therapeutic proteins (Table 1). If the proteins are of completely of foreign origin, such as asparginase or streptokinase, and the first generation mAbs derived from murine cells or partly foreign such as chimeric or humanized mAbs, the antibody response is comparable to a vaccination reaction. Often a single injection is sufficient to induce high levels of neutralizing antibodies, which may persist for a considerable length of time.

The other mechanism is based on breaking B-cell tolerance, which normally exists, to self-antigens, such as human immunoglobulins or products such as epoetins and the interferons. For breaking B-cell tolerance, prolonged exposure to proteins is necessary. In general, it takes months before patients produce antibodies, which are mainly binding and disappear when treatment is stopped.

To induce a classical immune reaction a degree of nonself is necessary. The trigger for this type of immunogenicity is the divergence from the comparable human proteins. The triggers for breaking tolerance are quite different. The production of these auto- antibodies may occur when the self- antigens are exposed to the immune system in combination with a T-cell stimulus or danger signal such as bacterial endotoxins, microbial DNA rich in GC motifs or denatured proteins. This mechanism explains the immunogenicity of biophar-maceuticals containing impurities. When tolerance is broken with this type of mechanism, the response is often weak with low levels of antibodies with low affinity.

To induce high levels of IgG, the self-antigens should be presented to the immune system in a regular array form with a spacing of 50 to 100 Á, a supra-molecular structure resembling a viral capsid [ 2] . Apparently the immune system has been selected to reach vigorously to these types of structures which

TABLE 1 Main Markers of Immunogenicity of Therapeutic Proteins
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