Immunogenicity studies antibody response

Immunogenicity is a substantial complication for preclinical safety assessment studies. Antibodies can invalidate the animal model species. Antibody production alone, however, should not necessarily prohibit the conduct of these studies. The effect on pharmacokinetics and pharmcodynamics needs to be measured and evaluated. The potential consequences of the antibodies on endogenous molecules also needs to be evaluated. Secondary effects, such as antibody deposition, should be measured. The lack of ability to predict absolute human immunogenicity does not preclude the use of animals to assess the relative potential for an immune response. 

Immunogenicity is an important issue to consider for biopharmaceuticals as it can limit toxicity testing. An immune response to the biopharmaceutical is expected because the test agents are human proteins administered to animals, and the response can limit the duration of the toxicity studies. Antibodies to a test agent can neutralize its activity and thus reduce exposure. In addition antidrug antibodies can potentially cause toxicity such as deposition of immune complexes in the kidney. This issue is discussed further in Chapter 10. 

The route of administration influences the likelihood of an antibody response independent of the mechanism of induction. The probability of an immune response is the highest with subcutaneous administration, less probable after intramuscular administration and intravenous administration is the least immunogenic route. There are no studies comparing parenteral and nonparenteral routes of administration. Flowever, as both mucosal tissues and the skin are immune competent organs designed to keep invaders out of the body, intranasal, pulmonary, and transdermal administration of therapeutic proteins may increase the risk of an immune response as compared to parenteral routes. 

Because most monoclonal antibodies that have been studied for tissue targeting are from mouse or, occasionally, from rat, the problem of antibody production to such foreign proteins always exists. While murine-derived mAbs are well tolerated for acute therapy, their use in chronic therapy is limited, due to severe human anti-mouse antibody response (HAMA) [231]. The HAMA response is elicited due to the foreign nature of the antibody itself. Molecular engineering is being utilized to replace the foreign components of the murine antibody with human antibody sequences to overcome their immunogenicity [232]. 

Hong also studied the immunological activity of the ferredoxins, and we were very surprised to find that these proteins were immunogenic in rabbits. These are relatively small proteins, and I think they are among the smallest that have been shown to elicit an antibody response. The antibody is very specific for the ferredoxin, and in this case we made one... 

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