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Updated: Jul 12, 2025
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Systematic characterization of antibody-drug conjugate targets in central nervous system tumors
Shannon Coy1,2,3, Jong Suk Lee1,2, Sabrina J Chan1,2,4
1Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
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.
Insights
Antibody-drug conjugates (ADCs) show promise for central nervous system (CNS) tumors, with many expressing targets like HER3, B7-H3, and NECTIN4. Further clinical trials of ADCs in CNS cancers are warranted.
Area of Science:
- Neuro-oncology
- Pharmacology
- Molecular Biology
Background:
- Antibody-drug conjugates (ADCs) leverage targeted delivery of cytotoxic drugs to antigen-expressing cancer cells.
- Several ADCs are approved for various malignancies, targeting antigens like HER2, TROP2, and NECTIN4.
- Recent success of an HER2-targeting ADC in metastatic breast cancer suggests low target expression may suffice for efficacy, but CNS tumor target expression is largely uncharacterized.
Purpose of the Study:
- To comprehensively evaluate the expression of potential antibody-drug conjugate (ADC) targets across diverse central nervous system (CNS) tumor subtypes.
- To determine if established ADC targets are present on CNS tumors at levels potentially amenable to targeted therapy.
Main Methods:
- Analysis of publicly available RNA-sequencing and proteomic data from 188 and 356 CNS tumors, respectively.
- Evaluation of 14 potential ADC targets using RNA-expression datasets.
- Immunohistochemical assessment of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein expression in 575 CNS tumors spanning multiple subtypes.
Main Results:
- Subtype-specific expression patterns of ADC target proteins were observed across CNS tumors.
- HER3, B7-H3, and NECTIN4 were broadly expressed across most tumor types.
- Specific strong expression of HER2 in ependymomas, HER2 (weak-moderate) in meningiomas, B7-H3 in craniopharyngiomas, CLDN6 in AT/RT, and TROP2 in specific regions of ACP were noted.
- Glioblastoma exhibited limited subtype-specific marker expression, indicating a need for novel target discovery.
Conclusions:
- Central nervous system tumors display heterogeneous but subtype-specific expression of ADC targets.
- The presence of targets like HER3, B7-H3, NECTIN4, and HER2 suggests that antibody-drug conjugates (ADCs) could be a viable therapeutic strategy for various CNS tumors.
- Clinical trials investigating ADCs for CNS malignancies are warranted based on these target expression profiles.
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