The Chimeric Antigen Receptor T Cell Target Claudin 6 Is a Marker for Early Organ-Specific Epithelial Progenitors and Is Expressed in Some Pediatric Solid Tumor EntitiesSeidmann, Wingerter, Oliver Metzig
et alCancers (Basel) (2025) 17 (6)
Abstract: Background/Objectives: The oncofetal membrane protein Claudin 6 (CLDN6) is an attractive target for T cell-based therapies. There is a lack of detailed analyses on the age-dependent expression of CLDN6 in normal tissues is lacking, which limits the expansion of CLDN6 CAR-T cell clinical trials to pediatric populations. Methods: We analyzed CLDN6 expression in extracranial solid tumors and normal tissues of children using RNA-sequencing data from over 500 pediatric solid tumor samples, qRT-PCR and immunohistochemistry (IHC) in more than 100 fresh-frozen tumor samples and, approximately, 250 formalin-fixed paraffin-embedded (FFPE) samples. We examined normal tissue expression via qRT-PCR in 32 different infant tissues and via IHC in roughly 290 tissues from donors across four age groups, as well as in fetal autopsy samples. Results: In fetal tissues, we detected CLDN6 expression primarily in the epithelial cells of several organs, including the skin, lungs, kidneys, intestinal tract, and pancreas, but not in undifferentiated blastemal cells. Postnatally, we found CLDN6-positive epithelial progenitors only during the first few weeks of life. In older-age groups, isolated clusters of CLDN6-positive progenitors were present, but in scarce quantities. In tumor tissues, we found strong and homogeneous CLDN6 expression in desmoplastic small round cell tumors and germ cell tumors. Wilms tumors demonstrated heterogeneous CLDN6 expression, notably absent in the blastemal component. Conclusions: These findings highlight an organ-specific presence of CLDN6-positive epithelial precursors that largely disappear in terminally differentiated epithelia within weeks after birth. Therefore, our data support CLDN6 as a viable therapeutic target in pediatric patients and justify their inclusion in basket studies for anti-CLDN6-based therapies.
A mini-overview of antibody-drug conjugates in platinum-resistant ovarian cancer: A preclinical and clinical perspectiveZhao, Yuan, Li
et alInt J Biol Macromol (2025) 304 (Pt 2), 140767
Abstract: Ovarian cancer is one of the most lethal gynaecologic cancers in China. Although platinum-based chemotherapy, PARP inhibitors and bevacizumab have prolonged long term survival and increased the overall response rate for platinum-sensitive ovarian cancer (PSOC), the treatment options for platinum-resistant ovarian cancer (PROC) are still limited. Antibody-drug conjugates (ADCs) represent a novel form of precision medicine, covalently linking specific monoclonal antibodies with potent cytotoxic payloads. Since mirvetuximab soravtansine (MIRV) received approval by the US Food and Drug Administration (FDA) as the first ADC for PROC in 2022, the development of novel ADCs for various targets in PROC has accelerated. In this review, we summarise the recent evidence and future prospects of ADCs targeting Folate Receptor alpha (FRα), mesothelin, cadherin-6, NaPi2b, human epidermal growth factor receptor 2 (HER2), dipeptidase 3 (DPEP3), B7-H4 (VTCN1), claudin-6 (CLDN6) and trophoblast antigen protein 2 (TROP2), in order to enhance our understanding of the clinical applications of ADCs and offer new insights for clinical practice and further research.Copyright © 2025. Published by Elsevier B.V.
177Lu-Labeled Anticlaudin 6 Monoclonal Antibody for Targeted Therapy in Esophageal CancerDu, Hao, Lin
et alJ Nucl Med (2025) 66 (3), 377-384
Abstract: Advanced or metastatic esophageal cancer (EC) is associated with poor prognosis, necessitating new and effective treatment methods. We assess whether claudin 6 (CLDN6) is a useful target for the imaging and radiopharmaceutical therapy of EC using a novel pair of radioactive nuclides, 89Zr and 177Lu. Methods: CLDN6 messenger RNA expression was evaluated in 2 EC datasets (n = 436) and through a retrospective analysis of 109 patients with EC. We then used an anti-CLDN6 monoclonal antibody (IMAB027) labeled with 89Zr and 177Lu ([89Zr]Zr-DFO-IMAB027 and [177Lu]Lu-DOTA-IMAB027) for PET imaging and therapy, respectively. Imaging and biodistribution analyses were performed using the TE-1-CLDN6 xenograft model. Finally, the therapeutic potential of [177Lu]Lu-DOTA-IMAB027 was evaluated in both the TE-1-CLDN6 and the CLDN6-PDX (patient-derived xenograft) models. Results: CLDN6 messenger RNA expression was elevated in EC compared with healthy esophageal tissues. The CLDN6 expression rate was 0 in healthy esophageal tissue but was 79.8% in EC tissue. The [89Zr]Zr-DFO-IMAB027 showed the ability to effectively image EC xenografts with high CLDN6 expression. In the TE-1-CLDN6 model, there was a significant difference in tumor volume between the 11.1-MBq [177Lu]Lu-DOTA-IMAB027 treatment group and the control group (P < 0.001). The tumor growth inhibition rate in the 11.1-MBq [177Lu]Lu-DOTA-IMAB027 group was 101.74%. In the PDX model, significant differences in tumor volume were observed among all [177Lu]Lu-DOTA-IMAB027 treatment groups and the control group (P < 0.05). Specifically, the tumor growth inhibition rate of the 11.1-MBq [177Lu]Lu-DOTA-IMAB027 group was 79.04%, whereas that of the 3.7-MBq group was 77.20%. However, the difference in efficacy between the high-dose and low-dose groups was not statistically significant (P > 0.05). Conclusion: The differential expression of CLDN6 between tumors and the normal esophagus shows its potential as a diagnostic and therapeutic target for EC. The radiotracer [89Zr]Zr-DFO-IMAB027 showed high contrast when visualizing CLDN6-expressing xenografts for PET imaging, and [177Lu]Lu-DOTA-IMAB027 induced rapid tumor regression in both the TE-1-CLDN6 and the CLDN6-PDX models. This research has implications for improving the radioligand diagnosis and treatment of EC.© 2025 by the Society of Nuclear Medicine and Molecular Imaging.
Clinicopathological Significance of Claudin-6 Immunoreactivity in Low-grade, Early-stage Endometrioid Endometrial CarcinomaLee, Kim
In Vivo (2025) 39 (1), 367-374
Abstract: Dysregulation of claudin 6 (CLDN6) expression has been widely documented in various malignancies. CLDN6 is aberrantly expressed in many types of human carcinomas; however, its clinical significance in endometrial carcinoma has seldom been investigated. This study aimed to examine the immunohistochemical expression status of CLDN6 in low-grade, early-stage endometrioid endometrial carcinoma (LGES-EEC) and to assess its clinicopathological significance.We performed immunostaining for CLDN6 in 118 tissue samples from LGES-EECs. Protein expression levels were interpreted using a semi-quantitative histoscore method. All statistical analyses were performed.CLDN6 was primarily localized along the membranes of the tumor cells. We considered histoscore ≥10 (the staining proportion ≥5% and intensity ≥2) as positive immunoreactivity for CLDN6. Twenty-six of the 118 patients (22.0%) showed CLDN6 positivity. Positive CLDN6 expression was significantly associated with deeper myometrial invasion (p=0.001), higher initial stage (p=0.015), and substantial lymphovascular space invasion (p=0.018).Aberrant CLDN6 expression is involved in tumor progression in LGES-EECs. In addition, targeting CLDN6 may offer clinical utility in patients with endometrial carcinoma.Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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