# Targeting integrin outside-in signaling for treating sepsis

> **NIH NIH R44** · DUPAGE MEDICAL TECHNOLOGY, INC. · 2021 · $776,915

## Abstract

In severe sepsis, systemic inflammation induced by infection leads to vascular leakage, microvascular
thrombosis, disseminated intravascular coagulation (DIC), multiple organ dysfunction, hemorrhage and
circulatory collapse, resulting in high mortality. Antibiotics and standard care regimens are helpful, but
ultimately ineffective for many patients. Despite years of intensive research, the only new drug FDA approved
for treatment of sepsis is activated protein C (APC, Xigris®), which prevents thrombosis and reduces
inflammation by inhibiting thrombin generation. However, Xigris also causes hemorrhage, which outweighed its
benefits and resulted in withdrawal from the market. Thus, there is an urgent unmet need for new life-saving
treatment of sepsis. Here, we propose to develop a new drug for sepsis treatment, which potently inhibits both
thrombosis and inflammation without causing bleeding. This innovative drug targets a novel integrin signaling
mechanism recently discovered in the lab of Xiaoping Du, co-investigator of this application (Gong et al
Science 2010, Shen et al, Nature 2013, Shen MBoC 2015, Pang Blood 2018), who showed that integrin
outside-in signaling requires direct interaction between the G protein subunit G13 and an ExE motif conserved
in the cytoplasmic domain of several integrin  subunits (including 3 in platelets and 2 in leukocytes).
Disruption of G13-integrin interaction abolishes outside-in signaling without affecting the ligand binding
function of integrins important for hemostasis. We designed a selective peptide inhibitor of the 3 G13
binding ExE motif that potently inhibited occlusive intravascular thrombosis without causing excessive bleeding
(Shen et al, Nature, 2013). Because integrin outside-in signaling is critical not only in thrombosis but also in
inflammation, we designed an ExE motif peptide, MB2mP6, that inhibits G13 interaction with 3 integrins in
platelets and also 2 integrins in leukocytes. In Phase I studies, we showed that treatment of mice with
MB2mP6 immediately after or 6 h after sepsis onset potently inhibits inflammation and thrombosis in septic
mice, significantly reducing mortality. This drug also protects lungs from vascular leakage and microthrombosis
that can lead to ARDS, a severe consequence of sepsis and a major cause of mortality of SARS-coronavirus 2
infection (COVID19) as well as influenza. Importantly, this new drug did not exacerbate hemorrhage induced
by either physical injury or inflammation. We further developed novel lipid-stabilized high-loading peptide
nanoparticles (HLPN) for efficient in vivo drug delivery. In this Phase II application, we propose to (1) Evaluate
the efficacy of MB2mP6 as an adjunct to antibiotics and standard care in treating sepsis and ARDS following
bacterial and viral infection. (2) Evaluate the safety (absence of anti-hemostatic activity) and toxicity of
MB2mP6 (3) Scale up production of a GMP-grade new drug and IND preparation and submission. This...

## Key facts

- **NIH application ID:** 10140988
- **Project number:** 2R44HL142396-02A1
- **Recipient organization:** DUPAGE MEDICAL TECHNOLOGY, INC.
- **Principal Investigator:** Randal A Skidgel
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $776,915
- **Award type:** 2
- **Project period:** 2018-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140988

## Citation

> US National Institutes of Health, RePORTER application 10140988, Targeting integrin outside-in signaling for treating sepsis (2R44HL142396-02A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10140988. Licensed CC0.

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