CLDN6 expression

Our data demonstrate that SAIL66, designed to engage CLDN6, CD3, and CD137, has the potential to enhance antitumor activity and provide a potent therapeutic option for patients with ovarian and other solid tumors expressing CLDN6. Clinical trials are currently underway to evaluate the safety and efficacy of SAIL66.

Claudin-6 mAbs or chimeric antigen receptor-T cells therapies are currently being clinically investigated for Claudin-6 overexpressing tumors. In conclusion, targeting Claudin proteins offers a novel clinical opportunity for the treatment of patients with advanced liver fibrosis and HCC.

More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.

Besides, CLDN6 overexpression inhibited tumor growth in vivo. In conclusion, CLDN6 inhibited NSCLC cell proliferation through inactivating aerobic glycolysis via the RIP1/ASK1/JNK axis.

We characterized the expression of CLDN6 across the different cohorts of OSCC samples and further investigated the relationship within the tumor immune microenvironment coupled to genes related to the prognosis of OSCC. A better understanding of the TME and gene expression profiling of OSCC tumors and the effect of smoking will allow us to tailor the treatment of patients to continue to improve outcomes.

Meanwhile, CLDN6 promoted the growth of bladder cancer and enhanced the carcinogenic effect by inducing polarization of M2 macrophages. In total, CLDN6 is an independent risk factor in MMRS to predict the prognosis of bladder cancer.

P1, N=145, Recruiting, BioNTech Cell & Gene Therapies GmbH | Phase classification: P1/2 --> P1 | Trial completion date: Sep 2037 --> Jan 2040 | Trial primary completion date: Aug 2024 --> Jan 2027

P1, N=200, Recruiting, Second Affiliated Hospital of Guangzhou Medical University | Phase classification: P1/2 --> P1 | N=40 --> 200

P1/2, N=114, Recruiting, BioNTech Cell & Gene Therapies GmbH

Through the PDZ-binding motif (PBM), CLDN6 bound to ZO-1 to interact with PTEN, and regulate AKT/MDM2 pathway. Collectively, our data enriched the theoretical basis for CLDN6 as a potential biomarker for diagnosis, therapy and prognosis of CRC.

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.

P1, N=98, Recruiting, Amgen | Active, not recruiting --> Recruiting | Trial completion date: Jun 2027 --> Feb 2028 | Trial primary completion date: Dec 2025 --> Apr 2026

Sequential Chromatin Immunoprecipitation (ChIP) experiments confirmed that YY1 and CREB interact in the 1279-1421 region. Our results suggest that CLDN6 expression is regulated by the binding of YY1 and CREB in the 901-1421 enhancer, in which a non-described interaction of YY1 with CREB was established in the 1279-1421 region.

P1/2, N=114, Recruiting, BioNTech Cell & Gene Therapies GmbH | Trial completion date: Sep 2036 --> Sep 2037 | Trial primary completion date: Aug 2023 --> Aug 2024

19 patients with platinum-resistant/refractory ovarian cancer were evaluated across 8 dose levels (0.2 to 2.4 mg/kg IV every 3 weeks, 21 day cycles) (data cutoff 01APR2023). Most pts had ≥ 3 prior treatment lines in the metastatic setting. The most common treatment-related adverse events were Gr1 peripheral neuropathy (n=3), Gr1/2 fatigue (n=2), and Gr1 nausea (n=2).

High expression of CLDN6 mRNA is associated with the dysregulation of distinct biological pathways regulating cell growth, proliferation, and cell-matrix interactions. Clinically, the expression of CLDN6 protein is a valuable adverse prognostic marker in EAC and GAC.

Contrarily, upon overexpression of CDLN6, the aforementioned experimental results were reversed. CLDN6 knockdown results in the inhibition of HCC cells' infiltration and migration and promotes apoptosis via downregulation of the JAK2/STAT3 signaling pathway.

Conclusions In participants with heavily-pretreated CLDN6-expressing ovarian cancer, the novel TORL-1-23 ADC has a favorable safety/tolerability profile and encouraging antitumor activity in a phase 1 dose finding study. Further evaluation in ovarian cancer and other CLDN6+ cancers is warranted.

We report the development of a novel antibody-drug conjugate, CLDN6-23-ADC, that selectively targets CLDN6, a potential onco-fetal-antigen which is highly expressed in ovarian and endometrial cancers. CLDN6-23-ADC exhibits robust tumor regressions in mouse models of human ovarian and endometrial cancers and is currently undergoing Phase I study.

P1, N=98, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting

We intend to submit efficacy, safety and CAR T-cell pharmacokinetics data from 5 cohorts treated with 1x106, 1x107 or 1x108 CLDN6 CAR-T cells ± CARVac with a data cut-off of March 14th, 2023 from ≥17 treated patients as a late-breaking abstract. Clinical trial information: NCT04503278.

TORL-1-23 has a favorable safety/tolerability profile and PK characteristics with preliminary antitumor activity in pts with heavily-pretreated CLDN6-expressing ovarian and testicular cancers. Doses above the historic MTD for MMAE containing ADCs may be explored given the safety/tolerability and PK data observed up to 2.4 mg/kg. Dose finding is ongoing to identify the MTD and optimal doses for subsequent development.

The data provide a new insight into the inhibitory effects of CLDN6-mediated autophagy on breast cancer metastasis, and revealed the new mechanism of CLDN6 regulating autophagy through WIP-dependent actin cytoskeleton. Our findings enrich the theoretical basis for CLDN6 as a potential biomarker for breast cancer diagnosis and therapy.

P1, N=98, Recruiting, Amgen | Not yet recruiting --> Recruiting

P1, N=98, Not yet recruiting, Amgen | Trial completion date: Nov 2027 --> Feb 2027 | Trial primary completion date: May 2026 --> Aug 2025

We propose that CLDN6 participates in the development of GTD and may become a new therapeutic target for CC.

P1, N=98, Not yet recruiting, Amgen | Trial completion date: Jun 2027 --> Nov 2027 | Trial primary completion date: Dec 2025 --> May 2026

Functional enrichment of DEGs linked HNF-4α and HNF-1α genes as highly expressed in Cldn6 gastric cancer. (4) Our results suggest that APOA2 and MAGEA9b could be considered as prognostic markers for Cldn6 gastric cancers.

P1/2, N=96, Recruiting, BioNTech Cell & Gene Therapies GmbH | Trial primary completion date: Sep 2022 --> Aug 2023

The 5‑year disease‑specific survival rate of cases with CLDN6‑high/CLDN9‑high, CLDN6‑high/CLDN9‑low and CLDN6‑low/CLDN9‑high status was 30.0, 37.5 and 72.7%, respectively, whereas that of CLDN6‑low/CLDN9‑low was 89.8% (P=0.004). In conclusion, aberrant CLDN9 expression is a predictor of poor prognosis for endometrial cancer and may be utilized in combination with CLDN6 to achieve higher sensitivity.

The pro-tumorigenic effect of claudin-6 in gastric cancer could be associated to dedifferentiation of epithelial cells and an increase in di novo cancer stem cell genesis.

Patient-derived xenograft models were also created through intracranial injection of multiple ATRT patient cell lines, and ongoing work will evaluate locoregional administration of CLDN6-directed CAR T cells in orthotopic xenograft models to test in vivo efficacy. This work highlights the potential for targeting CLDN6 via CAR T cell therapy in patients with ATRT as a novel therapeutic strategy for these devastating tumors.

In chRCC CLDN6 expression is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC further studies with larger cohorts are warranted.

CLDN6 expression seems ubiquitous in all elements of GCT and is worthy of investigation as a diagnostic biomarker and therapeutic target. (Clinical trial information: NCT03760081).

No abstract available

In conclusion, CLDN6 suppressed ERK/Sp1/cyclin D1 and ERK/IL-8 signaling to inhibit proliferation, migration and invasion in breast cancer cells. The mechanism may provide experimental evidence for the treatment of breast cancer targeting CLDN6.

P1, N=98, Not yet recruiting, Amgen | Trial completion date: May 2026 --> Jun 2027 | Initiation date: May 2022 --> Oct 2022 | Trial primary completion date: Jul 2024 --> Dec 2025

Only 13% patients had stable claudin-6 and decreased ER, whose prognosis might relate to the response of NAC. NAC might induce cycling intracanceral hypoxia to promote the phenotype drift in local advanced LAC, and the changes in ER and claudin-6 after NAC would determine the long-term prognosis.

This is different to some other cancers, such as breast and cervical carcinoma suggesting that claudin 6 probably induces other cellular pathways in neoplastic lung cells than in those tumors. In lung cancer, adenocarcinomas were most abundantly positive indicating a higher linkage of claudin 6 to glandular differentiation.

In addition, we demonstrated that CLDN6 may inhibit the migration and invasion abilities by activating the TYK2/STAT3 pathway. Therefore, our data indicated that CLDN6 acted as a tumor suppressor and had the potential to be regarded as a biomarker for the progression of colon cancer.