The Role of HLA-Class-II (HLAcII) Molecules in Determining the Immunogenicity Potential of Therapeutic Factor VIII Proteins (TFVIIIs) in Hemophilia a (HA): Assessing the Gate Keepe

• Activity Number: 355 - Contributed Poster Presentations: Biopharmaceutical Section
• Type: Contributed
• Date/Time: Tuesday, July 30, 2019 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Henry Mead*
• Companies: Walden University
• Keywords: Log-Linear Model analysis ; Multi-way Contingency Tables; In silico; Immunogenicity

Abstract

Regular infusions of therapeutic FVIII protein (tFVIII) are the standard-of-care for arresting and preventing bleeding in HA patients.In about 25% of severe HA patients, neutralizing anti-tFVIII-antibodies develop from an immune response to exogenous tFVIII. We propose that under the Gate Keeper hypothesis a key determinant in inhibitor development is due to complexes between HLAcII-molecules on dendritic cells (DCs)and tFVIII-derived peptides. To study this process, we performed DC-protein processing and presentation assays (DC-PPPAs).The principal data from DC-PPPAs are LC-MS/MS-based tFVIII-derived peptide counts associated with the DP-, DQ-, and DR-isomers of HLAcII-molecules.We used a log-linear model of DP-, DQ-, and DR- allotypes, tFVIII, and allotype-by-tFVIII interactions to analyze the peptide-count data.Under the statistical null of the Gate Keeper hypothesis we expect that for a given collection of HLAcII-allotypes the various allotype-by-tFVIII interactions will be no different. Log-linear model analyses of multi-way contingency tables were prepared. This permits a model of expected cell counts as a log-linear function. Within-allotype RRs were determined.