Antibody-Drug Conjugates in Ovarian Cancer
- Fay
- Nov 25
- 6 min read
Introduction
Ovarian cancer is a highly aggressive gynecological malignancy that is often diagnosed at an advanced stage. Although surgery combined with chemotherapy remains the primary treatment approach, many patients experience recurrence after therapy and gradually lose response to chemotherapy. This explains why ovarian cancer mortality rates remain persistently high, with current five-year survival rates still below 35%.
In recent years, scientists have continuously explored novel targeted therapies, such as anti-angiogenic drugs that block tumor blood supply and PARP inhibitors specifically designed for patients with BRCA gene mutations. While these emerging treatments offer hope to some patients, drug resistance, recurrence, and side effects remain formidable obstacles.
Against this backdrop, a groundbreaking therapeutic approach—antibody-drug conjugates (ADCs)—has emerged. Its mechanism resembles “precision-guided bombs”: antibodies identify specific markers on cancer cell surfaces, delivering drugs directly to the target without the widespread damage to healthy cells caused by traditional chemotherapy. It is precisely this dual capability of “targeting + killing” that has generated high expectations for ADCs, which are now being researched for application in ovarian cancer treatment.
ADC targets in ovarian cancer
In recent years, numerous clinical trials have demonstrated that ADCs exhibit manageable toxicity and favorable clinical efficacy in ovarian cancer patients. Currently, multiple ADCs targeting different tumor-associated markers have been developed, including folate receptor alpha (FRα), troponin 2 (TROP-2), mesothelin (MSLN), sodium-dependent phosphotransferase 2B (NaPi2b), human epidermal growth factor receptor 2 (HER2), dipeptidyl peptidase 3 (DPEP3), and tissue factor (TF). These ADCs enhance therapeutic efficacy and reduce damage to healthy tissues by specifically targeting tumor cells and delivering cytotoxic drugs directly to tumor sites.
Folate Receptor Alpha (FRα) and Associated ADCs
Folate receptor alpha, encoded by the FOLR1 gene, is a glycoprotein that transports folate into cells. Folate is essential for cell proliferation and DNA synthesis, and FRα is highly expressed in many ovarian cancers—approximately 76% of high-grade serous ovarian cancer patients exhibit FRα expression. Its stable expression makes it an ideal candidate for targeted therapy.
Representative FRα-targeting ADCs include Mirvetuximab Soravtansine (MIRV), Luveltamab Tazevibulin (STRO-002 or Luvelta), and Farletuzumab Ecteribulin (MORAb-202). MIRV combines an anti-FRα antibody with the microtubule inhibitor DM4, inhibiting tumor cell cycle progression and inducing a bystander effect in vivo. Clinical trials demonstrate that MIRV achieves response rates of 26% to 42% in patients with recurrent platinum-resistant ovarian cancer, significantly improving survival with manageable toxicity. STRO-002 and MORAb-202 similarly exhibit efficacy against FRα-high tumors, with their therapeutic potential to be further validated through additional Phase II/III clinical trials.
Trophoblast Surface Antigen 2 (TROP-2) and Sacituzumab Govitecan
TROP-2 is a transmembrane glycoprotein involved in cell cycle signaling. Its high expression in most ovarian cancers and low expression in normal tissues make it a potential therapeutic target.
Sacituzumab Govitecan (SG) is an ADC targeting TROP-2, consisting of an antibody conjugated to the topoisomerase inhibitor SN-38. Preclinical studies demonstrated significant antitumor activity against chemotherapy-resistant ovarian cancers. However, early clinical trials observed notable toxicity, necessitating future dose optimization to balance efficacy and safety.
Mesothelin (MSLN) and Atezolizumab Latancin (AR)
Mesothelin, a membrane glycoprotein involved in tumor differentiation, is highly expressed in approximately 70% of ovarian cancer patients. ADCs targeting MSLN, such as Atezolizumab Latancin (AR), achieve tumor-specific killing by conjugating antibodies with the microtubule inhibitor DM4. Clinical studies indicate AR achieves an objective response rate of approximately 28% in recurrent ovarian cancer patients, though efficacy may be enhanced when combined with chemotherapy. Research is also exploring combination therapy strategies with bevacizumab.
Human Epidermal Growth Factor Receptor 2 (HER2) and Trastuzumab Deruxtecan (T-DXd)
HER2 is a cell surface protein critical for regulating cell growth and division. Its overexpression correlates with ovarian cancer aggressiveness and poor prognosis. T-DXd is an HER2-targeted ADC that conjugates an antibody with the topoisomerase I inhibitor DXd, enabling specific killing of HER2-positive tumor cells. Clinical trials demonstrate that T-DXd achieves response rates of 45% to 63% in HER2-overexpressing ovarian cancer patients, prolonging both progression-free survival and overall survival.
Sodium-Dependent Phosphate Transporter 2B (NaPi2b) and Related ADCs
NaPi2b participates in phosphate transmembrane transport and is highly expressed in solid tumors such as ovarian cancer. Representative ADCs include Lifastuzumab Vedotin (LIFA) and UpRi (XMT-1536). LIFA demonstrated approximately 46% response rates in ovarian cancer patients with high NaPi2b expression, but long-term responses remained limited, leading to discontinuation of studies. XMT-1536 delivers MMAF via a high-load platform, demonstrating a 32% response rate in Phase I trials and is undergoing further clinical validation.
Dipeptidyl Peptidase 3 (DPEP3) and Tamrintamab Pamozilin (SC-003)
DPEP3 exhibits low expression in most normal tissues but is upregulated in ovarian cancer tumours, presenting a potential therapeutic target. SC-003 is an antibody-drug conjugate (ADC) targeting DPEP3, exerting its antitumour effect through conjugation with the PBD dimer. Early clinical studies indicate limited activity as a monotherapy with a response rate of approximately 4%, yet it provides valuable insights for exploring novel ADCs.
Tissue Factor (TF) and Tislotamab Vedotin (TV)
Tissue factor is highly expressed in various solid tumours, including some ovarian cancer patients. Tizotumab vedotin (TV) is an ADC targeting TF, achieving tumour killing through MMAE conjugation. Preliminary clinical trials indicate TV demonstrates manageable safety and preliminary antitumour activity in recurrent or metastatic cancers. Further clinical validation is required to confirm its efficacy in ovarian cancer treatment.
Challenges in ADC Therapy for Ovarian Cancer
ADCs offer exciting potential in treating ovarian cancer, but their use comes with several challenges. One major issue is managing toxicity. ADCs can sometimes harm healthy tissues due to off-target effects, especially when their drug payload is very potent. The stability of the linker connecting the antibody and the drug is another critical factor, as unstable linkers may release the drug too early, increasing side effects. For example, in a clinical trial of Mirvetuximab Soravtansine (MIRV), some patients experienced reversible eye-related issues such as blurred vision or corneal changes. Similarly, trials of Lifastuzumab Vedotin (LIFA) in ovarian cancer patients reported fatigue, nausea, appetite loss, vomiting, and nerve damage, with some cases of severe lung toxicity. Sacituzumab Govitecan (SG) trials were even halted due to adverse effects like severe diarrhea, neutropenia, and, in rare cases, treatment-related death. These examples show why optimizing dosing to balance safety and effectiveness is critical.
Another challenge is tumor heterogeneity. Cancer cells within the same tumor can vary in the amount of target proteins they express, limiting how effectively ADCs can target all tumor cells. In ovarian tumors, markers like FOLR1, MSLN, and HER2 show variable expression, affecting overall treatment success. Clinical trials also often have limited diversity, enrolling only certain patient groups based on prior treatments or disease characteristics. This restricts understanding of how ADCs work in broader populations, including different racial or ethnic groups. Designing more inclusive trials is essential to ensure findings apply widely.
The resistance mechanism is also a challenge. Cancer cells can develop resistance to ADCs through multiple mechanisms. They may reduce or alter the target protein, impair internalization, or block drug release inside the cell. Changes in the tumor microenvironment, enhanced drug metabolism, or activation of DNA repair pathways can further limit ADC effectiveness. Without detailed genomic markers to predict response, it is challenging to anticipate which patients will benefit most. Small trial sizes and limited patient data make it difficult to fully evaluate an ADC’s performance, as seen in studies of Anetumab Ravtansine, Tamrintamab Pamozirine (SC-003), Tisotumab Vedotin (TV), and Trastuzumab Deruxtecan (T-DXd).
In addition, the production of ADCs is complex and expensive, which limits availability and contributes to small trial sizes. Immune reactions triggered by components like dendritic cells can also affect safety and efficacy, further complicating their clinical use.
Despite these challenges, recent advances show promise. Combining ADCs with other treatments—such as immunotherapy, traditional chemotherapy, or PARP inhibitors—can improve effectiveness and reduce resistance. Early trials suggest that such combination therapies can work synergistically to increase overall survival while minimizing toxicity. New ADC designs with alternative drug payloads, including immune modulators or DNA-targeting agents, may help overcome resistance and reduce off-target effects. Improvements in linker technology to control drug release and maintain stability in circulation are also critical to enhancing safety.
Conclusion
Antibody-drug conjugates hold great promise for ovarian cancer therapy, but challenges like toxicity, tumor heterogeneity, resistance, and complex production must be addressed. Ongoing research into combination therapies, novel payloads, and improved delivery methods is crucial to maximizing their potential and bringing safer, more effective treatments to patients.
Source
Assessed and Endorsed by the MedReport Medical Review Board
