# Targeting novel DAMP mediated signaling pathways to mitigate GVHD

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $379,528

## Abstract

ABSTRACT
Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative therapy for leukemia through the
potent immune-therapeutic effect called the graft vs leukemia effect (GVL). However, utilization of allogeneic HSCT has
been severely limited by its most significant complication, namely graft vs host disease (GVHD). Efforts to meaningfully
separate GVHD from GVL in humans have been largely unsuccessful. An important concept in immunology is that
cellular injuries cause releases of danger-associated molecular patterns (DAMPs), which are major causes of inflammation
after HSCT. While several molecules and pathways that stimulate inflammation are increasingly appreciated, the role of
pathways that are inhibitory or regulate responses to DAMPs have largely been underappreciated and not been targeted in
clinical inflammatory or immune-pathologies. We have recently demonstrated promoting negative responses to DAMPs
after experimental allo-HSCT by enhancing CD24-SiglecG interaction (Toubai et al, Blood, 2015) reduced experimental
GVHD. But the key cellular and molecular pathways remain to be deciphered. Preliminary preclinical data experimental
also demonstrate that enhancing this pathway with a novel CD24Fc fusion protein reduced experimental GVHD.
Importantly, since then we have developed clinical grade CD24Fc fusion protein that shows safety in healthy human
volunteers. These key preliminary data form the foundation for our central hypothesis that CD24Fc will reduce the
severity of GVHD without affecting GVL. Thus, in this proposal we will build on these exciting preliminary data to bring
together basic and clincial studies. We aim to translate basic observations into a hypothesis driven, proof of concept, first
in human trial with CD24Fc protein and meld it with further dissection of the immune-biological mechanisms of the
CD24-Siglec axis in negative regulation of allo-immunity. If successful, our proposal will lead to the development of a
novel therapeutic strategy while simultaneously providing biological insights into GVHD. The specific aims (SA) of the
proposal are:
SA 1: Elucidate the cellular and molecular mechanisms of CD24-Siglec mediated regulation of GVHD
In this SA we will test the hypothesis that binding of CD24Fc to the inhibitory Siglec-G receptors on both donor T cells
and host APCs is critical for regulating DAMP mediated inflammation and aggravation of GVHD.
SA 2: To perform a large, first in human clinical trial to determine whether administration of CD24Fc fusion
protein to recipients of unrelated donor allogeneic HSCT following myeloablative condition will mitigate GVHD.
We will explore the hypothesis that administration of CD24Fc fusion protein will be safe and reduce severe GVHD in a
multicenter Phase IIa/b clinical trial.

## Key facts

- **NIH application ID:** 9982255
- **Project number:** 5R01CA217156-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** PAVAN REDDY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $379,528
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982255

## Citation

> US National Institutes of Health, RePORTER application 9982255, Targeting novel DAMP mediated signaling pathways to mitigate GVHD (5R01CA217156-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982255. Licensed CC0.

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