Abstract Number: PB0220
Meeting: ISTH 2020 Congress
Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors
Background: Accurately understanding the immunogenic potential (IP) of different tFVIIIs can inform development of improved biotherapeutics.
Aims: Analyze the HLAcII/tFVIII-derived-peptides presented by DCs from 26 unrelated-donors in three independent protein-processing/presentation assays (PPPAs) performed in two laboratories.
Methods: We analyzed “counts” of HLAcII-bound/tFVIII-derived-peptides from distinct tFVIIIsthe dependent variableusing a log-linear mixed model. Donors and DC-PPPAs were modeled as random effects to account for non-independent sampling and heterogeneity. HLAcII allele-groups (AGs), FVIII domains (FDs) and tFVIIIs were modeled as independent predictors. Eight tFVIIIs were examined: plasma-derived (pd) FVIII with von Willebrand Factor (VWF), “pdFVIII[+]pdVWF”; B-domain-deleted (BDD)-recombinant (r) FVIII, “BDD-rFVIII”; BDD-rFVIII with rVWF, “BDD-rFVIII[+]rVWF”; B-domain-truncated (BDT)-rFVIII, “BDT-rFVIII”; BDT-rFVIII with pdVWF, “BDT-rFVIII[+]pdVWF”; full-length (FL)-rFVIII, “FL-rFVIIIA” (‘A’ based on experiment with the highest tFVIII concentrations); and FL-rFVIIIA with pdVWF, “FL-rFVIIIA[+]pdVWF”. DR-bound/tFVIII-derived-peptides were analyzed based on which of the: 1) six FDs (A1, A2, B, A3, C1, and C2) they were derived; and 2) five DRB1-AGs identified (*01, *03, *04, *11, and *15) most likely encoded the β-chain of the pertinent HLAcII molecules. We implemented two versions of the model, “Model_1”which accounted for the different tFVIII concentrations across DC-PPPAs by scaling tFVIII-peptide counts against the experiment with the highest concentrationand “Model_2”, which analyzed unscaled tFVIII-peptide counts.
Results: Figures 1 and 2 show the effects of different tFVIIIs, DRB1-AGs, and FDs for Model_1 and Model_2, respectively, using the risk ratios (RRs) and 95%-confidence-interval lower and upper bounds (LB and UB), reported as RR (95%_LB, 95%_UB). In Model_1, RRs are overestimated for BDD-rFVIII and BDD-rFVIII[+]rVWF, likely indicating improper scaling.
Conclusions: Consistent with the literature, we showed that (i) BDT-rFVIII[+]pdVWF has the lowest IPassuming tFVIII-derived-peptide counts are proportional to IPand (ii) DR15 presents more tFVIII-derived-peptides than HLAcII-molecules of other DR-serogroups except DR4. Model_2 showed the expected FD-effect with A3 yielding more peptides than the A1-, C1-, and C2-domains.
[Figure 1. Risk ratios and 95% confidence intervals for Model 1.]
[Figure 2. Risk ratios and 95% confidence intervals for Model 2.]
To cite this abstract in AMA style:
Diego VP, Luu BW, Hofmann M, Almeida M, Gaytan MA, Mead H, Powell JS, Rajalingam R, Peralta JM, Kumar S, Curran JE, Escobar MA, Williams-Blangero S, Maraskovsky E, Blangero J, Howard TE. Combined Analysis of Dendritic Cell (DC) HLA-class-II (HLAcII) Peptidomic Profiling Data Derived from Different Therapeutic Factor VIII Proteins (tFVIIIs) in Independent Experiments/Laboratories [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/combined-analysis-of-dendritic-cell-dc-hla-class-ii-hlacii-peptidomic-profiling-data-derived-from-different-therapeutic-factor-viii-proteins-tfviiis-in-independent-experiments-laboratories/. Accessed March 21, 2024.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/combined-analysis-of-dendritic-cell-dc-hla-class-ii-hlacii-peptidomic-profiling-data-derived-from-different-therapeutic-factor-viii-proteins-tfviiis-in-independent-experiments-laboratories/