You are currently viewing the abstract.
View Full TextLog in to view the full text
AAAS login provides access to Science for AAAS members, and access to other journals in the Science family to users who have purchased individual subscriptions.
Register for free to read this article
As a service to the community, this article is available for free. Existing users log in.
More options
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.
Blocking blood loss
People with hemophilia—a chronic genetic bleeding disorder—manage their disease with blood-clotting protein replacement therapy. But in some patients, these protein drugs—factor VIII (FVIII) and factor IX (FIX)—can spur production of antibodies that block the factors’ functions and thwart successful management of disease. Now, Lamberth and colleagues devise a way to predict a protein’s immunogenicity during drug development.
New, or neo, antigens can form during the engineering of a protein analog, and this can affect the immunogenicity of a protein drug. For example, a clinical trial testing a recombinant FVIIa (rFVIIa) analog in hemophilia patients had to be discontinued in phase 3 because of the development of anti-rFVIIa antibodies. The authors used a computational approach coupled with wet-lab experiments to show that anti-rFVIIa antibodies were likely elicited by neo-epitopes in the engineered rFVIIa protein analog. Patients with certain human leucocyte antigen (HLA) types produced anti-drug antibodies, which implies a neo-epitope–driven immune response and a possible screening procedure for recombinant therapeutic proteins.
Abstract
Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors. We used computational and experimental methods to demonstrate that the observed ADAs could have been elicited by neoepitopes in the engineered protein. The human leukocyte antigen type of the patients who developed ADAs is consistent with this hypothesis of a neoepitope-driven immune response, a finding that might have implications for the preclinical screening of therapeutic protein analogs.
- Copyright © 2017, American Association for the Advancement of Science
