Development of an Active Chimeric IL13Rα2 ADC for Diffuse Intrinsic Pontine Glioma.
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INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brain tumor with a critical unmet need due to the lack of approved, curative interventions available. The interweaving of malignant cells with normal tissue makes surgical extraction essentially impossible, and radiation provides only transient benefit. The recent ONC201 FDA approval, however, suggests DIPG therapy is tractable. Having identified overexpression of IL13Rα2 in DIPG tumor tissue versus normal brain tissue, we investigated binding of commercially available IL13Rα2 monoclonal antibodies. The top candidate antibody was used to generate a chimeric antibody, to which we conjugated deruxtecan to create a preclinical therapeutic candidate. METHODS: We validated the novel antibody-drug conjugate (ADC) in vitro, demonstrating dose-dependent, IL13Rα2 expression-dependent cell death. We further validated the novel ADC ex ovo in quail xenograft models of DIPG and in vivo in a mouse xenograft model. RESULTS: The ADC showed tumor reduction in the ex ovo quail embryo model for both IL13Rα2-high and IL13Rα2-low DIPG cell models. A proof-of-concept in vivo mouse xenograft experiment demonstrated a reduction in tumor volume beyond antibody treatment alone. DISCUSSION: The work here represents an important milestone in preclinical development of a novel deruxtecan-based ADC agent for an intractable pediatric brain cancer, concurrent with other ADC agents demonstrating real-world clinical efficacy and gaining approvals in multiple disease indications.