CLDN6 as a Target for Monoclonal Antibody Therapy of Ovarian and Endometrial Cancer

Aug 23, 2025

Abstract

Claudin-6 (CLDN6) is a tight junction protein that is largely excluded from the majority of adult tissues but re-expressed in several malignancies, such as ovarian and endometrial cancer. This differential expression has prompted interest in CLDN6 as a cancer-specific therapeutic target. Monoclonal antibody (mAb) therapies are an appealing modality to target this exploit with the aim of delivering cytotoxic payloads, engaging immune effector functions, or directly inhibiting tumor growth. This review covers CLDN6 molecular biology, its expression in normal and tumor tissues, and its function in tumor development. We discuss preclinical and clinical development of monoclonal antibodies and antibody-drug conjugates against CLDN6, with an emphasis on ovarian and endometrial carcinomas. We also explore newer concepts such as bispecific antibodies and mRNA-encoded antibody therapy. Finally, we address antibody specificity concerns, mechanisms of resistance, and patient selection, with future perspectives on this new therapeutic strategy.

Introduction

Ovarian and endometrial cancers are among the major cancer killers of women worldwide. HGSOC, the most deadly ovarian cancer subtype, is typically diagnosed at the advanced stage and is resistant to current immunotherapies. Endometrial cancer, although typically diagnosed earlier, contains aggressive subtypes such as serous and clear cell types that are unresponsive to standard therapy. Both of these cancers exhibit extensive molecular heterogeneity, and treatment planning and prognosis are difficult.

In the quest for more precise and efficient therapies, molecular targets with selective expression by tumor cells are highly desirable. In this regard, CLDN6 has emerged as a promising oncofetal antigen.Inactive in most healthy adult tissues, it is re-expressed in some malignant tumors. The restricted expression in normal tissues reduces the risk of off-target toxicity, which is a frequent problem in antibody-based therapies[1].

Monoclonal antibody engineering developments in recent years have enabled the development of extremely specific molecules capable of targeting CLDN6 and carrying therapeutic payloads. These have ranged from antibody-drug conjugates (ADCs), bispecific antibodies, to even mRNA-based antibody platforms. With several agents against CLDN6 moving into clinical trials, this article recapitulates the scientific rationale, state of the art, and dilemmas of targeting CLDN6 in ovarian and endometrial cancers. The biology of CLDN6

Claudins constitute a family of 27 tight junction integral membrane proteins that regulate paracellular permeability in epithelial and endothelial cells. CLDN6 is a 23-kDa tetraspan transmembrane protein encoded by a gene localized to chromosome 16p13.3. CLDN6 is expressed at high levels in the kidney, lung, and liver during embryonic development. Expression of CLDN6 declines drastically after birth and is barely detectable in normal adult tissues.

Structurally, CLDN6 contains four transmembrane domains and two extracellular loops that participate in homophilic and heterophilic interactions with other claudins. These loops are accessible to antibodies and are, as such, excellent targets for monoclonal antibody binding. CLDN6 also participates in signaling cascades that regulate cell adhesion, polarity, and proliferation.

When aberrantly re-expressed in tumors, CLDN6 can disrupt normal tight junction integrity, promoting epithelial-mesenchymal transition (EMT), invasion, and metastasis. CLDN6 can also activate oncogenic pathways like PI3K/AKT and Wnt/β-catenin signaling, thereby promoting tumor growth. Its twin role—as both a marker and functional contributor to malignancy—enhances its prospects as a therapeutic target.

CLDN6 Expression in Ovarian and Endometrial Cancers

A number of transcriptomic and immunohistochemical studies have confirmed CLDN6 overexpression in gynecologic malignancies, most frequently in serous and endometrioid types. In ovarian cancer, CLDN6 is seen in approximately 30–45% of high-grade serous carcinomas. Importantly, CLDN6 expression is often preserved in metastatic and recurrent tumors, making it accessible to long-term therapeutic targeting.

Endometrial cancers, especially the serous subtype, also exhibit expression of CLDN6, though at slightly lower frequencies (~10–15%). TCGA tumor samples reveal that CLDN6-positive tumors belong to poor prognosis-associated molecular subtypes, suggesting that CLDN6 is not just a therapeutic target but also a potential prognostic biomarker.

In contrast, CLDN6 expression is almost absent in normal adult tissues, including ovary and endometrium. This differential expression forms the rationale for its therapeutic targeting. The presence of structurally similar claudins—e.g., CLDN3, CLDN4, and CLDN9, however, poses a challenge to antibody specificity and requires stringent engineering to avoid cross-reactivity.

Figure 1. Schematic presentation and molecular diagram of CLDN6. The left shows the structure diagram of CLDN6. It contains four transmembrane domains, two extracellular ECL loops (ECL1 and ECL2), one amino-terminal, and one carboxy-terminal. The right shows the chemical structure of CLDN6 predicted by the AlphaFold[2]

Monoclonal Antibodies Against CLDN6

Several strategies have been explored to exploit CLDN6 for antibody-based therapies. These include conventional monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies.

Among the earliest therapeutic candidates was IMAB027, a humanized IgG1 directed against the extracellular domain of CLDN6. Preclinical findings showed its ability to induce antibody-dependent cellular cytotoxicity (ADCC) in CLDN6-positive tumor cells. Clinical findings have been sparse to date, and optimization has shifted to payload-bearing constructs.

Antibody-drug conjugates (ADCs) represent a more advanced strategy. These molecules consist of a monoclonal antibody linked to a very potent cytotoxin by a cleavable linker. Upon binding of the ADC to CLDN6, the ADC is internalized by the tumor cell and the cytotoxin is freed, inducing cell death. CLDN6-23-ADC (also called TORL-1-23) conjugates an antibody targeting CLDN6 with monomethyl auristatin E (MMAE), a microtubule-disrupting agent. In preclinical models, this ADC exhibited potent anti-tumor activity and durable regressions in CLDN6-positive ovarian and endometrial xenografts[3].

More recently, bispecific antibodies such as CTIM-76 have been developed. These molecules bind to CLDN6 on tumor cells and CD3 on T-cells and redirect cytotoxic lymphocytes to the tumor. Early data suggest these agents can circumvent immune evasion and elicit robust anti-tumor responses, even in tumors with low baseline immune infiltration.

A new frontier encompasses mRNA-encoded bispecific antibodies. BioNTech's BNT142 encodes an mRNA-translated CLDN6/CD3 bispecific in vivo. The platform allows for flexible dosing and breaks manufacturing constraints of traditional biologics[4].

Preclinical and Clinical Evidence

Multiple preclinical studies have validated the activity of CLDN6-targeting antibodies in models of ovarian and endometrial cancer. In mouse xenografts, CLDN6-23-ADC induced complete regressions with tolerable safety. Combination with DNA-damaging treatments such as cisplatin or PARP inhibitors was even more effective, with indications of synergistic activity.

CTIM-76 bispecific antibodies also demonstrated strong tumor regression in vivo. Importantly, engineering >500-fold selectivity for CLDN6 over homologous claudins reduced off-target toxicity in normal tissues[5].

Early clinical data are promising. In a phase I trial (NCT05262530), TORL-1-23 had a 32% objective response rate in CLDN6-positive tumors, including ovarian and endometrial carcinomas. Responses were durable and were observed even in patients who were refractory to prior therapy. CTIM-76 is in dose-escalation trials to assess safety and determine optimal dosing.

Although long-term outcomes remain uncertain, these studies affirm the clinical feasibility of CLDN6-targeted therapies. The homogeneous expression of CLDN6 in metastatic foci also holds the prospect of use in advanced or recurrent cases[6].

Challenges and Future Directions

Despite encouraging progress, several challenges must be addressed to optimize CLDN6-targeting therapies. Specificity remains a key concern. CLDN6 shares sequence homology with other claudins, particularly CLDN9. Antibody cross-reactivity could result in unintended toxicity, underscoring the need for high-fidelity engineering and robust validation in normal tissue panels.

Another challenge is the heterogeneity of CLDN6 expression among tumors and even within tumors themselves. There is a need to have strong diagnostic assays, e.g., immunohistochemistry (IHC) or RNA in situ hybridization, for patient selection. Biomarker-driven enrollment will ensure that only those patients with sufficient CLDN6 expression will receive these targeted agents.

Resistance mechanisms, though not yet fully elucidated, may involve loss of antigen presentation, impaired internalization, or activation of compensatory pathways. Combination with immune checkpoint blockade, DNA-damaging agents, or anti-angiogenic therapy can potentially overcome resistance and increase the durability of response.

Future studies will also explore CLDN6 as a chimeric antigen receptor (CAR) T-cell therapy target. Preliminary reports suggest that CLDN6-CAR T-cells exhibit potent cytotoxicity in vitro and in vivo, which is another potential modality for this antigen targeting.

Figure 2.The evolution of CAR-T cell therapy[7]

Conclusion

CLDN6 has emerged as a highly appealing therapeutic target in ovarian and endometrial cancer due to its tumor-restricted expression and involvement in oncogenesis. CLDN6-targeting monoclonal antibodies and antibody-drug conjugates have shown strong preclinical activity and early clinical signs of efficacy. As antibody technologies further evolve, and companion diagnostics become more refined, CLDN6-targeting agents can be anticipated to enter the standard arsenal against these challenging gynecologic cancers in the near future.

References

McDermott, S. J., et al. (2023). Preclinical efficacy of the antibody-drug-conjugate CLDN6–23-ADC for the treatment of CLDN6-positive cancers. Clinical Cancer Research, 29(11), 2131–2142.
Qu, H., Jin, Q., & Quan, C. (2021). CLDN6: From Traditional Barrier Function to Emerging Roles in Cancers. International Journal of Molecular Sciences, 22(24), 13416.
Miller, D. S., et al. (2023). First-in-human phase I study of a novel Claudin-6 (CLDN6) targeted antibody-drug conjugate, TORL-1–23, in patients with advanced solid tumors. Annals of Oncology, 34(Suppl 2), S756.
BioNTech SE. (2025). BNT142: An mRNA-encoded bispecific antibody targeting CLDN6/CD3 demonstrates first-in-human activity in solid tumors. OncoDaily.
Feldman, P. J., et al. (2024). Phase I, two-part, multicenter first-in-human (FIH) study of TORL-1–23, a CLDN6-targeting ADC, in patients with advanced solid tumors. Annals of Oncology, 35(Suppl 2), S721.
Wang, H., et al. (2021). Association of CLDN6 and CLDN10 with immune microenvironment in ovarian cancer. Frontiers in Genetics, 12, 595436.
Kisha K. Patel, Mito Tariveranmoshabad, Siddhant Kadu, Nour Shobaki, Carl June, From concept to cure: The evolution of CAR-T cell therapy, Molecular Therapy, Volume 33, Issue 5, 2025, Pages 2123-2140, ISSN 1525-0016