Abstract Number: OC 03.1
Meeting: ISTH 2020 Congress
Background: High-throughput quantitative immunomics data is growing rapidly. Next generation sequencing (NGS) analysis of combinatorial phage display libraries, Mimotope Variation Analysis (MVA) has the potential to characterize the immune response profile of patients at the omic level.
Aims: To dissect the inhibitory response against early replacement therapy (first 50 EDs) in previously untreated patients (PUPs) with severe haemophilia A receiving either plasma-derived (pdFVIII) or recombinant factor VIII (rFVIII).
Methods: MVA was performed on plasma samples collected before (T0) and after (EOS) FVIII infusion collected from 80 PUPs within the SIPPET study cohort. EOS samples were also analyzed in a competition MVA (Block) experiment resulting in therapy-specific immune response depletion.
To address dataset size and complexity (sequence diversity=34*106) a custom denoising pipeline was developed by exploiting the Hammock software. Differential analysis of the resulting mimotopes was performed by Wilcoxon test. Overall cluster abundance was studied by PERMANOVA.
Results: Explorative correlation analysis showed that the relationship between EOS and Block samples was strongly reduced in patients treated with pdFVIII than in patients treated with rFVIII (p< 0.001) suggesting a broader immune response toward the plasma-derived therapy.
In patients treated with rFVIII, differential analysis revealed 23 clusters associated with inhibitor development. Importantly, one was significant also at T0 (AUC=0.8, adj p=0.01). In patients treated with pdFVIII, we found 203 clusters associated with inhibitor development. The abundance of these clusters in both groups was different in T0 compared with EOS (p=0.001), supporting their mimicry of therapy-specific antigens.
Conclusions: Our results show a differential immune response in patients treated with pdFVIII or rFVIII during the first 50EDs. Even if further analyses are required to understand their biological meaning, we found different therapy-specific antigens associated to inhibitor development and one of those showed also a prognostic value.
To cite this abstract in AMA style:Baselli G, Palla R, Valsecchi C, Palm K, Miri S, Peyvandi F, SIPPET Study Group . Immune Profiling of Previously Untreated Patients with Severe Haemophilia A by High-throughput Mimotope Variation Analysis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/immune-profiling-of-previously-untreated-patients-with-severe-haemophilia-a-by-high-throughput-mimotope-variation-analysis/. Accessed September 24, 2021.
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