# Therapeutic targeting of multiple glioblastoma phagocytosis checkpoints using a novel bispecific antibody

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $435,054

## Abstract

PROJECT SUMMARY
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. The
disease is universally fatal with current standard treatment being ineffective and debilitating. Cancer
immunotherapy has demonstrated remarkable clinical success against multiple aggressive cancers and
growing evidence suggests that boosting the body’s immune system can help eliminate highly aggressive and
advanced tumors, including those resistant to conventional therapies. Its effectiveness against GBM, however,
remains unclear, with multiple clinical trials exploring cancer immunotherapy regimens for GBM failed to
demonstrate significant improvement in patient outcomes. Our group and others have recently discovered that
GBM cells overexpress innate checkpoint CD47 to evade detection and clearance by professional antigen
presenting cells (APCs). The expression level of CD47 was also found to correlate with survival in GBM
patients. However, multiple studies showed that blockade of CD47 provided modest survival benefit
in preclinical models of human cancers and additional phagocytosis checkpoints such as the β2 microglobulin
(B2m) subunit of MHC-I molecule have been identified to promote tumor immune evasion. Disruption of B2m
interaction with its phagocyte receptor leukocyte Ig-like receptor B1 (LILRB1) promotes phagocytosis of a
diverse collection of tumor cells that were resistant to CD47 blockade. Yet, when anti-CD47 and anti-B2m
antibodies were administered independently, we did not observe improved GBM phagocytosis. Therefore,
based on these findings, we hypothesize that simultaneous blockade of phagocytosis checkpoints CD47 and
B2m will activate innate immune responses against GBM, leading to a potent and durable adaptive antitumor
immunity. To this end, we developed a novel bispecific antibody (CD47-B2m) that readily crosses the blood
brain barrier (BBB). Aim 1 of the proposal will mechanistically examine whether CD47-B2m can promote
antigen-specific antitumor T cell responses by APCs through induced GBM cell phagocytosis. In Aim 2, we will
investigate if innate immune sensing pathways are critical in bridging innate and adaptive antitumor immunity
in the setting of phagocytosis checkpoint blockade by CD47-B2m. Finally, in Aim 3, we will evaluate the use of
CD47-B2m as a novel immunotherapeutic for GBM in clinically relevant murine models of GBM as a
monotherapy or in combination with radiation. We will also investigate potential molecular mechanisms that
predict treatment responses. If successful, our study will provide important preclinical data supporting further
investigation of a completely novel immunotherapeutic agent against GBM. Additionally, the results generated
here will highlight the importance of bridging innate and adaptive immunity to produce the most optimal
antitumor immune responses. The concept of targeting multiple phagocytosis checkpoints can be applied to
potentially all human cancers, and if successfu...

## Key facts

- **NIH application ID:** 10428596
- **Project number:** 5R01NS117828-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Wen Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $435,054
- **Award type:** 5
- **Project period:** 2021-06-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428596

## Citation

> US National Institutes of Health, RePORTER application 10428596, Therapeutic targeting of multiple glioblastoma phagocytosis checkpoints using a novel bispecific antibody (5R01NS117828-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428596. Licensed CC0.

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