PATH-59. SYSTEMATIC CHARACTERIZATION OF ANTIBODY-DRUG CONJUGATE TARGETS IN CENTRAL NERVOUS SYSTEM TUMORS

Abstract

Abstract BACKGROUND Antibody-drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid cancers, including those expressing ERBB2/HER2, TACSTD2/TROP2, NECTIN4, folate receptor 1 (FOLR1), and tissue factor (CD142/TF). Recently, a next-generation ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level ADC target expression may be sufficient for treatment responsiveness, and CNS tumors may be responsive to next-generation ADC. However, ADC target expression is poorly characterized in most CNS tumors. METHODS To systematically characterize ADC target expression in CNS tumors, we analyzed publicly available RNA-sequencing and proteomic data from the Children’s Brain Tumor Network (n=188 tumors) and GEO RNA-expression datasets (n=356 tumors) to evaluate expression of 14 potential ADC targets that are FDA-approved or under clinical investigation in solid cancers. We also used immunohistochemistry to score the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma (GBM), oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (n=575 total tumors). RESULTS Multi-modal pan-CNS analysis showed consistent subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas (n=44) strongly expressed HER2 (36/44; 81% of cases by IHC), while meningiomas weakly-moderately expressed HER2 in most tumors (201/234; 86%). ACP (n=15) and PCP (n=3) strongly expressed B7-H3 (100% of cases), with TROP2 and HER2 expression in whorled ACP epithelium (100% of cases). AT/RT strongly expressed CLDN6 (8/9; 89%). GBM showed little subtype-specific marker expression, suggesting a need for further target development. CONCLUSIONS CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be fruitful.