School of Medicine Publications and Presentations
Document Type
Article
Publication Date
5-2019
Abstract
The immunogenicity of protein therapeutics is an important safety and efficacy concern during drug development and regulation. Strategies to identify individuals and subpopulations at risk for an undesirable immune response represent an important unmet need. The major histocompatibility complex (MHC)–associated peptide proteomics (MAPPs) assay directly identifies the presence of peptides derived from a specific protein therapeutic on a donor’s MHC class II (MHC-II) proteins. We applied this technique to address several questions related to the use of factor VIII (FVIII) replacement therapy in the treatment of hemophilia A (HA). Although .12 FVIII therapeutics are marketed, most fall into 3 categories: (i) human plasma-derived FVIII (pdFVIII), (ii) full-length (FL)–recombinant FVIII (rFVIII; FL-rFVIII), and (iii) B-domain–deleted rFVIII. Here, we investigated whether there are differences between the FVIII peptides found on the MHC-II proteins of the same individual when incubated with these 3 classes. Based on several observational studies and a prospective, randomized, clinical trial showing that the originally approved rFVIII products may be more immunogenic than the pdFVIII products containing von Willebrand factor (VWF) in molar excess, it has been hypothesized that the pdFVIII molecules yield/ present fewer peptides (ie, potential T-cell epitopes). We have experimentally tested this hypothesis and found that dendritic cells from HA patients and healthy donors present fewer FVIII peptides when administered pdFVIII vs FL-rFVIII, despite both containing the same molar VWF excess. Our results support the hypothesis that synthesis of pdFVIII under physiological conditions could result in reduced heterogeneity and/or subtle differences in structure/conformation which, in turn, may result in reduced FVIII proteolytic processing relative to FL-rFVIII.
Recommended Citation
Wojciech Jankowski, Yara Park, Joseph McGill, Eugene Maraskovsky, Marco Hofmann, Vincent P. Diego, Bernadette W. Luu, Tom E. Howard, Roberta Kellerman, Nigel S. Key, Zuben E. Sauna; Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products. Blood Adv 2019; 3 (9): 1429–1440. doi: https://doi.org/10.1182/bloodadvances.2018030452
First Page
1429
Last Page
1440
Publication Title
Blood Advances
DOI
10.1182/ bloodadvances.2018030452
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
Original published version available at https://doi.org/10.1182/bloodadvances.2018030452