cd97-targeting Antibody-drug Conjugate Delays Tumor Growth and Prolongs Survival in a Preclinical Glioblastoma Model

Introduction: Glioblastoma (GBM) is the most common and fatal primary brain tumor in adults. Several adhesion G protein-coupled receptors (aGPCRs) have been shown to play a critical role in GBM biology. CD97 (ADGRE5), an aGPCR, drives tumor growth via effects on GBM stem cell self-renewal and metabolism. Importantly, CD97 demonstrates a therapeutically favorable expression pattern: it is highly expressed in GBM compared to healthy brain, where it is absent.

Methods: We developed a synthetic humanized antibody against human CD97 and conjugated the antibody to pyrrolobenzodiazepine (PBD), an antitumor antibiotic that cross-links DNA resulting in cell death. To test this antibody-drug conjugate (ADC), we generated in vitro ADC dose-response curves using a WST8 assay in U87 and patient-derived GBM cells. We performed in vivo analysis of intratumoral administration of ADC using patient-derived GBM culture (PDGC) xenografts orthotopically implanted in immunodeficient NSG mice. We evaluated survival and monitored PDGC xenograft growth using an IVIS Lumina XR.

Results: We observed a lower lethal dose (LD50) in ADC-treated GBM cells (0.6788 nM), as compared to control RSV-ADC-treated cells (19.964 nM). In vivo administration of the ADC significantly reduced tumor growth and prolonged survival of host mice (n=7-8 mice/group; 2-way ANOVA F1,50=16.97, p< 0.001; logrank Mantel-Cox test, p< 0.01). Repeated ADC dosing further prolonged survival (logrank Mantel-Cox test, p< 0.0001).

Conclusion : Collectively, these data demonstrate that the CD97-targeting ADC delays tumor growth and prolongs survival in a preclinical GBM model, making it a promising candidate for future clinical trials.