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Tumor Rapid Fire Abstract

Tumor

CD97 (ADGRE5) – A Targetable Vulnerability in Glioblastoma

Sunday, May 5, 2024
1:43 PM – 1:45 PM CT
Location:  S405a
Disclosure(s):
Hayley Donaldson, MS: No financial relationships to disclose
Karenna J. Groff, BS, MEng: No financial relationships to disclose
Introduction: Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Several adhesion G protein-coupled receptors (aGPCRs) have recently been shown to play critical roles in GBM viability and proliferation. These cell-surface receptors are potentially appealing therapeutic targets. CD97, in particular, has been shown to drive cellular proliferation, brain invasion, and glycolytic metabolism in GBM and, importantly, is highly expressed in GBM as compared to normal brain tissue. Our study aims to establish a compelling basis for the development of biologics targeting CD97 to treat GBM.

Methods: We generated an in-house antibody-drug conjugate (ADC) through the in vitro selection of a synthetic human antibody library. This antibody was linked to a cytotoxic agent (MMAF) to create an anti-CD97 ADC. LD50 was determined via WST-8 viability assays in multiple GBM patient-derived cell-lines. Orthotopic GBM xenografts in immunodeficient NSG murine models were monitored for growth using IVIS imaging after intratumoral administration of either the ADC or unconjugated antibody as control.

Results: Using WST-8 assays, we observed significantly lower LD50 values for the ADC in both patient-derived and U87 GBM cell cultures (1.8-4.7 nM) as compared to control cell cultures (neural stem cells, HEK293T cells, and normal human astrocytes, 26.3-77.1 nM). Similar findings were obtained with Hoechst 33342 staining, which showed dose-dependent effects of the anti-CD97 ADC in GBM cultures compared to control cell cultures (2-way ANOVA F2,8=12.13, p< 0.01). After implantation of GBM xenografts, a single intratumoral injection of anti-CD97 ADC significantly delayed tumor growth and prolonged overall survival of host mice (60 vs. 35 days, HR 0.299, p=0.005).

Conclusion : CD97 is a novel potential therapeutic target. The results of this preclinical pilot study indicate that an ADC targeting CD97 reduces tumor growth both in vitro and in vivo, suggesting that anti-CD97 biologics merit further consideration in the treatment of GBM.