EXTH-129. Evaluating GD2-targeting antibody-drug conjugates for DIPG using human organoid-based preclinical platforms

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Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor with no approved targeted therapies and a median survival of less than 12 months. The frequent presence of H3K27M mutations in DIPG is associated with elevated expression of GD2, a clinically actionable surface antigen. While GD2-directed CAR-T cell therapies show early promise, their clinical translation is hindered by logistical delays, antigen heterogeneity, and neurotoxicity. Antibody-drug conjugates (ADCs) offer a more controllable, off-the-shelf therapeutic approach that could overcome these limitations, yet their potential in DIPG remains unexplored. To evaluate the efficacy, resistance, and safety of GD2-targeting ADCs, we employed two complementary human-derived organoid platforms. First, DIPG models were generated using NanoGlio, a high-throughput nanoliter-volume droplet 3D organoid system. Second, we established a co-culture model with DIPG NanoGlio and iPSC-derived brain organoids to assess neurotoxicity. We tested M3554, a first-in-class clinical-stage anti-GD2 ADC conjugated to exatecan, a topoisomerase I inhibitor, in these models. We successfully generated NanoGlio derived from 10 DIPG models reflecting the key genetic alterations typically identified in DIPG, including mutations in H3.3 (H3F3A) or H3.1 (HIST1H3B), and mutations in ACVR1, PPM1D, and TP53. We assessed the expression of GD2 by flow cytometry and 3D-Fluorescence Antibody Cell Tracking (3D-FACT) and observed heterogenous GD2 expression among the DIPG models tested. We observed differential responses among the lines: most GD2+ lines responded to M3554 at significantly lower doses than GD2-low lines. Additionally, we observed partial resistance in some GD2+ lines to both M3554 and its payload exatecan, suggesting that those lines may have intrinsic resistance to the ADC. Future work will assess the efficacy and neurotoxicity of M3554 using our DIPG-brain co-culture model. Successful completion of this study will provide critical preclinical evidence supporting the assessment and use of GD2-targeting ADCs in DIPG treatment.

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