# Characterization of the Functional Repertoire and Ontogeny of FVIII Humoral Response Across Species: Project 1

> **NIH NIH U54** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $352,168

## Abstract

Project 1 - Abstract
The formation of Factor VIII (FVIII) inhibitor is a main complication of the treatment of
hemophilia A (HA) and it is associated with increased morbidity and mortality. The overall goal
of this project is to gain insights into why FVIII is immunogenic by understanding how FVIII is
targeted by the humoral immune system. We hypothesize that the FVIII-specific humoral
immune response is composed of a diverse and dynamic antibody repertoire. We assembled a
group of investigators from a variety of complementary scientific background that together will
overcome major gaps in knowledge on FVIII immunogenicity and B cells. We will employ
innovative and state-of-art technologies to broad our current understanding of the underlying
mechanism of inhibitor formation to FVIII. We propose the following aims: Aim 1: Define the
clonal repertoire and epitope specificity of circulating anti-FVIII antibodies in patients
with HA. Taking a novel immunomics approach, we will, for the first time, characterize in
detail the FVIII epitopes recognized by FVIII-specific antibodies as well as clonal
relationships of the related B cells in HA patients with inhibitors. Aim 2: Define the FVIII
antibody repertoire and its dynamics in canine HA inhibitor models. Utilizing antigen
phage display for the first time in canine disease models, we will longitudinally characterize
the FVIII-driven humoral immune response, which will provide insight into the intrinsic
immunogenicity of FVIII. Results from this work will be compared to data from Aim 1 to
further validate the HA dog model. Aim 3: Investigate the role of B cell survival cytokines
in inhibitor formation, epitope diversity and eradication. Emerging evidence implicates B
cell survival cytokines, including BLyS, in immune-mediated diseases. Our preliminary data
suggests that BLyS may have a role in FVIII inhibitors. Herein, we will comprehensively
evaluate the contribution of BLyS to FVIII immunogenicity through a series of studies in human
and murine HA models. Together these studies will provide insights on the humoral immune
system in FVIII immunogenicity, including establishing a framework for novel therapeutic
approaches and testing the validity of small and large preclinical models.

## Key facts

- **NIH application ID:** 9949781
- **Project number:** 5U54HL142012-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Valder R. Arruda
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,168
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949781

## Citation

> US National Institutes of Health, RePORTER application 9949781, Characterization of the Functional Repertoire and Ontogeny of FVIII Humoral Response Across Species: Project 1 (5U54HL142012-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9949781. Licensed CC0.

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