Abstract

Cancelled due to ill Health - Identification of Novel Neo-Epitopes on Antibodies Generated through Chemical Degradation: Relevance for Potency and Immunogenicity

Christian Schoneich, Professor, University of Kansas

Chemical degradation reactions represent an important problem for the preparation of stable protein formulations, and increasing evidence is becoming available that specifically oxidative protein modifications may contribute to the immunogenicity of various protein pharmaceuticals. Oxidative modifications of proteins may lead to accelerated aggregation and the formation of neo-epitopes. However, to date it is unknown which oxidative modifications or combinations thereof may lead to immunogenicity. The mechanisms of protein oxidation are complex, where, depending on the nature of the oxidants, all 20 essential amino acids are targets for oxidation. Hence, a large manifold of potential products can be expected, especially for large proteins such as antibodies. Therefore, we have initiated an exhaustive characterization of oxidative and light-induced modifications of pharmaceutical proteins, generated in various formulations during long-term storage as well as accelerated stability and stress testing. Several of these modifications were then identified in immunogenic protein samples. This lecture will summarize selected examples of novel and unusual oxidation reactions of pharmaceutical peptides and proteins, including antibodies, and the influence of primary, secondary and tertiary structure, as well as glycosylation and antibody-drug conjugation, on these oxidation reactions will be discussed.