# Evaluation of a High-Affinity and BTLA-specific HVEM Protein Agonist in vivo

> **NIH NIH R21** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $243,750

## Abstract

Project Summary
There have been many recent successes in the treatment of autoimmune and inflammatory diseases
including the development of antibodies and biologic proteins that block the pathogenic functions of
inflammatory cytokines such as TNF and IL-17. However, it remains a challenge to achieve sustained
responses with these anti-inflammatory therapeutics. We and others have attempted to achieve this
goal through the development of inhibitory receptor agonists that limit the activation of pathogenic
lymphocytes, and that potentially alter the long-term differentiation of autoreactive cells. The BTLA
inhibitory receptor has proven to be an important regulatory receptor in lymphocytes that we have
shown can be triggered using agonist antibodies and biologic proteins. We have previously developed
a human BTLA-specific agonist protein through site-directed mutagenesis of the BTLA ligand (HVEM)
that does not bind other cellular factors, and that shows greater affinity and inhibitory activity in
lymphocytes in vitro. In vivo analysis of this protein is limited due to species restriction of the human
HVEM protein. Here, we have proposed to test this protein using a xenogenic humanized GVHD model
in which human PBMC from normal donors are transferred in to Nod-scid IL2Rγ-/- hosts. This model
has proven to be a robust system to evaluate human immune responses in vivo. We will confirm activity
of our engineered protein in human cells, and determine the efficacy of this protein in the humanized
GVHD model. Additionally we will further evaluate the molecular and cellular determinants that are
required for this protein to achieve optimal efficacy. Completion of the aims in this proposal represent
an important step in the validation of this protein as a potential human anti-inflammatory therapeutic,
and will allow us to pursue further clinical development. Additionally this proposal will provide further
insight into how the BTLA inhibitory receptor functions to regulate human immune responses in vivo.

## Key facts

- **NIH application ID:** 10070571
- **Project number:** 5R21AI149237-02
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Carl F Ware
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $243,750
- **Award type:** 5
- **Project period:** 2019-12-12 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070571

## Citation

> US National Institutes of Health, RePORTER application 10070571, Evaluation of a High-Affinity and BTLA-specific HVEM Protein Agonist in vivo (5R21AI149237-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10070571. Licensed CC0.

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