Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice

• Type of Material: Article
• Authors: Taran S. Lundgren, Emory University; Gabriela Denning, Express Therapeut Inc; Sean Stowell, Emory University; H Trent Spencer, Emory University; Christopher Doering, Emory University
• Language: English
• Date: 2022-04-26
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by The American Society of Hematology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2021006359
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 6
• Issue: 8
• Start Page: 2628
• End Page: 2645
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health/National Heart, Lung and Blood Institute Centers for the Investigation of the Factor VIII Immune Response in Patients with Hemophilia A (grant U54 HL141981 to C.B.D., H.T.S., and S.R.S.) and Hemophilia of Georgia (to C.B.D. and H.T.S.).
• Keywords: PROTEIN; TRANSGENE; IMMUNE-RESPONSES; Science & Technology; FVIII; Life Sciences & Biomedicine; PHARMACODYNAMICS; Hematology; DELIVERY; VECTORS; EXPRESSION; CELL; PHENOTYPIC CORRECTION
• Research Categories: Chemistry, Pharmaceutical; Biology, Cell; Health Sciences, Immunology

Abstract

Advances in the development of novel treatment options for hemophilia A are prevalent. However, the anti–factor VIII (FVIII) neutralizing antibody (inhibitor) response to existing FVIII products remains a major treatment challenge. Although some novel products are designed to function in the presence of inhibitors, they do not specific address the immunogenicity risk or mechanistic causes of inhibitor development, which remain unclear. Furthermore, most preclinical studies supporting clinical gene therapy programs have reported immunogenicity signals in animal models, especially at higher vector doses and sometimes using multiple vector designs. In these settings, immunogenicity risk factor determination, comparative immunogenicity of competing vector designs, and the potential for obtaining meaningful prognostic data remain relatively unexplored. Additionally, there remains the opportunity to investigate clinical gene therapy as an alternative to standard immune tolerance induction therapy. The current study was designed to address these issues through longitudinal dose-response evaluation of 4 adeno-associated viral (AAV) vector candidates encoding 2 different FVIII transgenes in a murine model of hemophilia A. Plasma FVIII activity and anti-FVIII antibody data were used to generate a pharmacokinetic model that (1) identifies initial AAV-FVIII product expression kinetics as the dominant risk factor for inhibitor development, (2) predicts a therapeutic window where immune tolerance is achieved, and (3) demonstrates evidence of gene therapy–based immune tolerance induction. Although there are known limitations to the predictive value of preclinical immunogenicity testing, these studies can uncover or support the development of design principles that can guide the development of safe and effective genetic medicines.