Immune responses directed against protein therapeutics can directly impact drug pharmacology, safety and efficacy. While many factors contribute to protein immunogenicity, T cell-dependent responses play a critical role. Tools to predict and reduce T cell responses to protein therapeutics present benefits at every stage of drug development. We provide evidence for two different approaches to mitigate therapeutic protein immunogenicity: epitope modification and antigen-specific tolerance induction. Following a systematic process of in silico epitope mapping applied to either Factor VIII or botulinum toxin, rational epitope modification resulted in reduced immunogenicity. In vitro and in vivo validation of computational predictions and iterative in silico modification of immunogenic epitopes were experimentally validated for selected modified sequences. Tolerance induction is achieved by co-delivery or by chemical or recombinant linkage of regulatory T cell epitopes (Tregitopes) to therapeutic proteins. We have demonstrated that Tregitope incorporation leads to lower immune responses against target epitopes identified in insulin, Factor VIII and botulinum toxin. Analysis, prediction, and modification of T cell-mediated immunogenicity of therapeutic proteins expands the available strategies for mitigating therapeutic protein immunogenicity, enables quality by design for drugs in development and improvement of licensed biologics to create biobetters.
- Copyright © 2013 by The American Association of Immunologists, Inc.