# Fgl-2 targeted therapy for reversing multi-modality immune suppression

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $366,000

## Abstract

Our goal of this application is to test the hypothesis that blocking the newly identified immune suppressive
regulator fibrinogen-like protein 2 (Fgl2) in GBM will comprehensively reverse tumor-mediated immune
suppression thereby allowing immunological clearance of gliomas within the central nervous system. We have
discovered that Fgl2 is highly expressed in GBM tissues(recently published by JNCI). Patients with GBM
tumors that have high levels of Fgl2 expression have a statistically shorter overall survival time relative to those
with low expression levels. As further proof of concept, Fgl2-engineered GBM tumors progressed rapidly with
neurological sequela and death when compared to the reporter gene-GFP-engineered GBM cells in syngeneic
mice. Our data shows that Fgl2 is a key immune suppressive hub that correlates with immune checkpoint
family expression (PD-L1, PD-1, and CTLA-4), immune suppressive cytokines (TGF-β), and glioma-infiltrating,
of immunosuppressive immune populations such as myeloid-derived suppressor cells (MDSCs), Tregs and M2
macrophages. One underlying mechanism for this observation is Fgl2 induced CD39 and CD73 in T cells. The
CD39 protein converts ATP to ADP and AMP, which is then converted to adenosine by CD73. Adenosine is an
immunosuppressive metabolite that then suppresses T lymphocyte activation and effector function.
Furthermore, the CD39/CD73 complex enhances the conversion of M1 into tumor-promoting M2 to promote
tumor growth. Based on these data, we have created a first generation antibody that blocks Fgl2 immune
suppressive activity and increases median survival in murine models with established intracerebral gliomas.
To test our central hypothesis for this application, the following aims are proposed: Aim 1: Determine the
association of Fgl2 expression with immune suppression in human GBM and investigate the mechanism of
CD39/CD73 expression in different types of immune cells in GBM; Aim 2: Select the most therapeutically
efficacious cross-species Fgl2 mAb that promotes antitumor immune response.
 Impact: This study will yield a therapeutic candidate – a Fgl2 blocking antibody that may reverse tumor-
mediated immune suppression and the number of immune suppressive cells in GBM. Considering that Fgl2
can be detected in almost all GBMs, with most having very high levels, such a candidate therapeutic will be
important. This study will also further mechanistically elucidate how Fgl2 regulates immune suppressive gene
expression in immune suppressive cells and within effector immune populations. Finally, this study will show
whether detection of Fgl2 in circulating GBM tumor cells (CTC) using our newly invented universal CTC
capture technology (PCT/US2014/020615) will correlate with the level of GBM tumor Fgl2 expression as a
biomarker for guiding blocking therapy in the future. This type of assay would also be highly significant as a
longitudinal liquid biopsy for gene expression analysis that could be used in the con...

## Key facts

- **NIH application ID:** 9966906
- **Project number:** 5R01CA203493-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Amy Beth Heimberger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966906

## Citation

> US National Institutes of Health, RePORTER application 9966906, Fgl-2 targeted therapy for reversing multi-modality immune suppression (5R01CA203493-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966906. Licensed CC0.

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