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The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

ABSTRACT: Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.

SUBMITTER: Reipert BM

PROVIDER: S-EPMC7686884 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Reipert B M BM Gangadharan B B Hofbauer C J CJ Berg V V Schweiger H H Bowen J J Blatny J J Fijnvandraat K K Mullins E S ES Klintman J J Male C C McGuinn C C Meeks S L SL Radulescu V C VC Ragni M V MV Recht M M Shapiro A D AD Staber J M JM Yaish H M HM Santagostino E E Brown D L DL

Blood advances 20201101 22

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate compreh ...[more]

PMID: 33232473

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Project description:Essentials Platelet-specific FVIII gene therapy is effective in hemophilia A mice even with inhibitors. The impact of platelet adherence via VWF/GPIb? binding on platelet gene therapy was investigated. GPIb? does not significantly affect platelet gene therapy of hemophilia A with inhibitors. Platelet gene therapy induces immune tolerance in hemophilia A mice with pre-existing immunity. SUMMARY: Background We have previously demonstrated that von Willebrand factor (VWF) is essential in platelet-specific FVIII (2bF8) gene therapy of hemophilia A (HA) with inhibitory antibodies (inhibitors). At the site of injury, platelet adherence is initiated by VWF binding to the platelet GPIb complex. Objective To investigate the impact of GPIb? on platelet gene therapy of HA with inhibitors. Methods Platelet-FVIII expression was introduced by 2bF8 lentivirus (2bF8LV) transduction of hematopoietic stem cells (HSCs) from GPIb?null (Ibnull ) mice or rhF8-primed FVIIInull (F8null ) mice followed by transplantation into lethally irradiated rhF8-primed F8null recipients. Animals were analyzed by flow cytometry, FVIII assays and the tail bleeding test. Results After transplantation, 99% of platelets were derived from donors. The macrothrombocytopenia phenotype was maintained in F8null mice that received 2bF8LV-transduced Ibnull HSCs (2bF8-Ibnull /F8null ). The platelet-FVIII expression level in 2bF8-Ibnull /F8null recipients was similar to that obtained from F8null mice that received 2bF8LV-transduced F8null HSCs (2bF8-F8null /F8null ). The tail bleeding test showed that the remaining hemoglobin level in the 2bF8-Ibnull /F8null group was significantly higher than in the F8null control group, but there was no significant difference between the 2bF8-Ibnull /F8null and 2bF8-F8null /F8null groups. The half-life of inhibitor disappearance time was comparable between the 2bF8-Ibnull /F8null and 2bF8-F8null /F8null groups. The rhF8 re-challenge did not elicit a memory immune response once inhibitor titers dropped to undetectable levels after 2bF8 gene therapy. Conclusion GPIb? does not significantly impact platelet gene therapy of HA with inhibitors. 2bF8 gene therapy restores hemostasis and promotes immune tolerance in HA mice with pre-existing immunity.

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The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

Publications

The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development.

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