Research project
In vivo tracking and biodistribution of protein aggregates
Therapeutic proteins have revolutionized the treatment of many severe diseases like multiple sclerosis, haemophilia, diabetes and many more. Unfortunately, even recombinant proteins with structures (almost) identical to those of their endogenous counterparts often induce the formation of anti drug antibodies (ADA). These ADA may decrease the plasma half life, reduce the activity of the therapeutic protein or even completely block it.
In the first two cases the therapy design has to be adjusted to compensate for the loss of drug activity, which will increase the therapy cost. In the latter, the protein has to be replaced by another drug (if available). Moreover, production of ADA might carry direct risk for patient’s health. In rare cases ADA can cross-react with endogenous proteins, which may lead to severe, even life-threatening, side reactions. Many approaches are being developed to predict and to eliminate protein immunogenicity. However, the predictive value of those approaches is hampered by a lack of full understanding as to why ADA are developed in the first place.
Many factors have been identified that contribute to the risk of ADA formation. Origin of the protein, therapy design, patient’s genetic background, type of disease, impurities and contamination of formulated drug may increase the risk of ADA. However, an increasing number of reports stress the importance of protein aggregates as the major risk factor leading to ADA production. Protein aggregates have been shown to increase the immunogenicity of many therapeutic proteins like growth factors, interferons alpha and beta, insulin and monoclonal antibodies. However, not all types of aggregates are equally immunogenic. For example, it was shown that aggregates of a monoclonal antibody obtained by oxidation were more immunogenic than those obtained by shaking or pH shift. The reason for those differences remains poorly understood. One of the possible explanations is the different biodistribution of aggregated protein, as distinct stress methods lead to formation of aggregates with different characteristic (size, number of aggregates, possible denaturation of protein, reversibility). Determination of the changes in the biodistribution of monomeric and aggregated protein might help to understand why some protein aggregates are more immunogenic than others.