Design considerations of an IL13R[alpha]2 antibody-drug conjugate for diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13R[alpha]2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13R[alpha]2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13R[alpha]2 signaling in progression and invasion of DIPG and viability of IL13R[alpha]2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13R[alpha]2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13R[alpha]2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13R[alpha]2 antibody-drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13R[alpha]2 expression, supporting the potential use of targeting IL13R[alpha]2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13R[alpha]2 ADC for DIPG. Keywords: Diffuse intrinsic pontine glioma, Antibody-drug conjugates, Immunotherapy, IL13R[alpha]2, Pediatric cancer