Systematic characterization of antibody-drug conjugate targets in central nervous system tumors

Neuro Oncol. 2024 Mar 4;26(3):458-472. doi: 10.1093/neuonc/noad205.


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 and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an 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 expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors.

Methods: We analyzed publicly available RNA-sequencing and proteomic data from the children's brain tumor network (N = 188 tumors) and gene-expression-omnibus RNA-expression datasets (N = 356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N = 575).

Results: Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma 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 warranted.

Keywords: craniopharyngioma; ependymoma; glioma; immunoconjugates; meningioma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • B7 Antigens
  • Breast Neoplasms* / drug therapy
  • Central Nervous System Neoplasms* / drug therapy
  • Cerebellar Neoplasms* / drug therapy
  • Child
  • Claudins / therapeutic use
  • Female
  • Glioblastoma* / drug therapy
  • Humans
  • Immunoconjugates* / therapeutic use
  • Proteomics
  • RNA / therapeutic use
  • Rhabdoid Tumor* / drug therapy


  • Immunoconjugates
  • RNA
  • CLDN18 protein, human
  • Claudins
  • CD276 protein, human
  • B7 Antigens