ADCs are complexes comprising an antibody, a cytotoxic payload and a connecting linker. They specifically recognize tumor cell surface antigens, induce endocytosis and release cytotoxic drugs into tumor cells, ultimately leading to the death of tumor cells (6,11). The connection of cytotoxic drugs with antibodies was first realized in the 1950s (12). Researchers conducted clinical trials on the mouse immunoglobulin G (IgG)-based ADCs in the 1980s (13). Following a long and slow development, the field has become active again in the last decade, with ADCs entering the global market at a much faster pace. Usually, ADCs are administered intravenously. Then, the antibodies of ADCs bind to the antigen on cancer cells, penetrate the cells via receptor-mediated endocytosis to form endosomes and fuse with lysosomes. The cytotoxic payload detaches from the antibody and diffuses into the cell in the presence of various lysosome enzymes, resulting in tumor cell death by disrupting DNA structures or inhibiting microtubule polymerization (8,14,15). In addition, the payload can penetrate the extracellular matrix and surrounding cells, resulting in a bystander effect (16). Fig. 1 shows a schematic representation of the structure and mechanism of action of conventional ADCs.

The most commonly used antibody backbone in ADCs is IgG. The antibody-binding antigen should be highly expressed on the surface of tumor cell membranes with minimal expression on normal tissues (17,18) to enhance the effectiveness of the drug by delivering it to specific targets, protect the non-target tissues from the damage caused by chemotherapy, and reduce the systemic toxicity. FRα, human epidermal growth factor receptor 2 (HER2), trophoblast cell surface antigen-2 (TROP2), mesothelin, sodium-dependent phosphate transporter 2b (NaPi2b) and CDH6 are usually overexpressed in epithelial ovarian cancer, making them the most commonly used conjugated antigens (19).

The covalent binding of antigen-targeting antibodies to cytotoxic payloads requires connecting linkers (20). Linkers have two main functions; the primary one is maintaining stability in the bloodstream, keeping the cytotoxic payload attached to the antibody when it moves through the plasma; the other aspect is to efficiently release the payload into the tumor (8). The linkers should keep this attachment stable and unchanged in the bloodstream, with the drug being released only after antigen-antibody binding (21). Linkers are cleavable or non-cleavable depending on their chemical characteristics. Cleavable linkers are chemically unstable structures that can deliver drugs extracellularly and induce the killing of nearby tumor cells (22,23). The non-cleavable linker releases the drug solely when the antibody undergoes internalization and degradation within the lysosomes of the target cells. However, the cytotoxic payloads are released after the apoptosis of tumor cells, which may also result in the non-specific killing of surrounding tumor cells (24).

The cytotoxic payloads in ADCs now encompass a range of DNA-targeting agents, microtubule-binding proteins and some topoisomerase 1 inhibitors. The agents targeting microtubules are the most frequently used payloads, targeting the medenosine and periwinkle alkaloid sites. They interfere with the kinetics of microtubule protein polymerization and maintain the cell cycle in the G₂/M phase, leading to cell death (25,26). Not all tumor types are sensitive to a given type of payload and, therefore, diversifying payloads is critical to expanding the indications of ADCs.

Alternative strategies based on the use of ADCs are highly effective in treating cancer. The use of ADCs in clinical oncology has increased with the advent of novel technologies and the discovery of new targets (9,27). To date, 15 ADCs have received marketing approval from the FDA, and hundreds more are undergoing preclinical and clinical evaluation (28). Besides hematological tumors, ADCs have been approved for use in breast, gastric, lung, uroepithelial, cervical, ovarian and head-and-neck squamous cell carcinomas. Several previous studies have described the ADC drugs approved for oncology treatment (29–31).

Solid tumors offer a broad opportunity for ADC development. The treatment choices for advanced or metastatic recurrent solid tumors are limited, and current immunotherapies rarely cure the disease (9). Therefore, ADCs have immense potential and unique advantages in a wide range of solid tumors.

HER2 is another promising target that can enhance cell proliferation, differentiation and migration and inhibit apoptosis (50). HER2 is upregulated in a range of solid tumors, including breast, gastric and gynecological tumors (51). However, HER2-targeted therapies are not yet approved for use in diseases other than breast, lung, gastric and colorectal cancers (52). Trastuzumab deruxtecan (T-DXd) targets HER2 and contains a topoisomerase I inhibitor payload (53). T-DXd is approved for treating HER2-expressing breast and gastric cancers and HER2-mutated non-small-cell lung cancer (50). Preclinical studies demonstrated the antitumor activity of T-DXd against primary and metastatic ovarian tumors overexpressing HER2 (54). A global multicenter phase II study (NCT04482309) was conducted to evaluate the efficacy and safety of T-DXd in patients with HER2-expressing solid tumors across seven cohorts, including three major gynecological tumors. T-DXd treatment exhibited robust clinical efficacy, conferring sustained clinical benefits for patients with HER2-expressing solid tumors (55). Among all studied tumor types, the highest ORR was observed in the three major gynecological tumor cohorts, with an ORR of 57.5% for endometrial cancer, 50.0% for cervical cancer and 45.0% for ovarian cancer. Among the ovarian cancer cohort, 35.0% of the patients had previously received five or more lines of treatment and the median overall survival time was 13.2 months; by contrast, the median overall survival time for patients with high HER2 expression (IHC 3+) increased to 20.0 months (55). These findings indicate that T-DXd is a promising drug for HER2-expressing recurrent PROC (56).

TROP2 is another tumor target highly expressed in ovarian cancer. This is a type I cell surface glycoprotein first discovered in human trophoblasts (57). It is upregulated in a variety of malignant tumors and plays an important role in tumor development, invasion and metastasis (58). Datopotamab deruxtecan (Dato-DXd; DS-1062a), an effective topoisomerase I inhibitor, is an ADC that targets TROP2. Dato-DXd specifically binds to TROP2, transports it intracellularly to lysosomes and releases DXd. In preclinical experiments, Dato-DXd induced DNA damage and apoptosis of tumor cells in vitro and displayed antitumor activity in vivo in xenograft tumors with high TROP2 expression (59). When mixed with TROP2 (IHC 3+) tumor cells, Dato-DXd showed a significant bystander-killing effect on tumor cells with low TROP2 expression, thus prolonging the survival time of epithelial ovarian cancer xenograft models and reducing toxicity (60). Most clinical trials are conducted on breast cancer. A phase II clinical trial (NCT05489211) is currently evaluating Dato-DXd for treating advanced/metastatic solid tumors, including ovarian cancer (61). The efficacy of Dato-DXd in ovarian cancer expressing TROP2 deserves continued attention.

Mesothelin represents a promising potential target for ovarian cancer. High expression of mesothelin is associated with chemotherapeutic resistance and poor prognosis in epithelial ovarian cancer (62). Anetumab ravtansine exhibits a high degree of affinity for mesothelin, using the microtubule inhibitor DM4 as a payload. It has displayed high antitumor activity and good tolerability as a monotherapy in the preclinical models of ovarian cancer (63). A phase I study (NCT02751918) determined the antitumor activity, safety and pharmacokinetics of anetumab ravtansine in PROC-expressing mesothelin. The result showed an ORR of 27.7%, DOR of 7.6 months and PFS of 5.0 months (64). This result suggests that targeting mesothelin is an effective and well-tolerated treatment option in patients with PROC. The development of other combination therapy regimens for anetumab ravtansine (65) and other ADCs targeting mesothelin (BMS-986148) (66) has also provided preliminary evidence of clinical activity and tolerable adverse reactions and toxicity in ovarian cancer.

NaPi2b is another promising target for ADC, which is expressed in 95% of ovarian cancers (67). Lifastuzumab vedotin (LIFA) targeting NaPi2b displayed activity and acceptable safety in phase I studies (68,69). A phase II study compared the efficacy of LIFA and polyethylene glycol liposome doxorubicin in patients with PROC. The results showed that LIFA was well-tolerated, and ORR increased (34 vs. 15%; P=0.03) (70). Moreover, XMT-1536 and TUB-040 are other ADCs targeting NaPi2b. Currently, the safety and efficacy of these drugs in PROC are under evaluation in clinical trials (NCT06517485, NCT03319628, NCT06517433 and NCT06303505).

New ADCs for ovarian cancer are constantly being developed. Raludotatug deruxtecan (R-DXd) targets cadherin 6 (CDH6) and was effective and safe in a preclinical study using PDX tumor models of serous ovarian cancer expressing CDH6 (71). B7-H4-directed ADC, using a pyrrolobenzodiazepine-dimer payload, displayed antitumor activity in a PARP inhibitor and platinum-resistant PDX model of high-grade serous ovarian cancer (72).

The findings of several newly completed clinical trials examining the use of ADCs in ovarian cancer (NCT06517485 and NCT06517433) are yet to be published. Table I lists the clinical trials investigating ADC monotherapy for ovarian cancer that deserve continued attention in the future.

A prevalent issue in solid tumors is inadequate blood flow and hypoxia within the vasculature (76). Using drugs such as anti-vascular endothelial growth factor antibodies (e.g., bevacizumab) can modulate angiogenesis and vascular porosity, thereby altering the tumor vascular system. Bevacizumab, the first targeted drug indicated for ovarian cancer, has been approved for use in combination with chemotherapy (77). Administering bevacizumab in combination with platinum-based chemotherapy after disease progression still improved PFS (78). ADCs have also shown safety and efficacy in combination with bevacizumab, particularly in PROC. Preclinical studies demonstrated that MIRV combined with bevacizumab resulted in rapid destruction of the tumor microvascular system and extensive areas of necrosis (73,74). Moreover, it was highly effective in a PDX model of PROC, causing significant regression and complete remission (73). Anetumab ravtansine combined with bevacizumab also demonstrated enhanced antitumor efficacy (74). These results emphasized the superior biological activity of the combination and further advanced the combination into clinical trials.

In clinical trials, the combination of MIRV and bevacizumab demonstrated efficacy and was well-tolerated in patients with PROC (79). In another cohort from the same study (NCT02606305), 94 patients with PROC treated with MIRV and bevacizumab had an ORR of 44%, an median duration of remission (mDOR) of 9.7 months, and an median progression-free survival (mPFS) of 8.2 months (80). Furthermore, incorporating MIRV into dual therapy with platinum and bevacizumab demonstrated enhanced efficacy and safety profiles in platinum-sensitive ovarian cancer (81). All these results point to the importance of ADCs combined with bevacizumab. Currently, a number of ongoing trials are investigating several additional combinations of different ADCs with bevacizumab (NCT05445778, NCT05200364 and NCT03587311).

Other than directly inducing cancer cell death using cytotoxic payloads, ADC also has antitumor immune activity (8,82,83). The related mechanisms, including Fc-mediated effector function, immune cell death, dendritic cell maturation, enhancement of T-cell infiltration and enhancement of immune memory, among others, have been the subject of discussion (84–87). ADCs have been shown to possess considerable immunomodulatory capacity in animal models (88). Combination of ADCs with immunotherapy in refractory tumors is a promising strategy for clinical treatment; its improved antitumor effects have been initially demonstrated in many preclinical studies and early clinical trials.

Immune checkpoint inhibitors (ICIs) combined with ADCs have synergistic effects in triple-negative breast cancer (89); the rationale behind this combination is that ADCs activate the immune system, whereas ICIs remove the brakes, allowing the immune system to regain its ability to recognize and kill tumor cells (90). Durvalumab combined with T-DXd (NCT03742102) exhibited an ORR of 100% and was found to be safe in a small group of patients with low expression of HER2. The interim results of T-DXd alone and combined with patulizumab (NCT04538742) showed ORRs of 77.3 and 82.0% and 12-month PFSs of 77.3 and 89.4%, respectively, demonstrating promising efficacy and controllable safety. The clinical benefits of ADCs combined with immunotherapy have been observed in clinical trials on both uroepithelial cancer (NCT03288545 and NCT04264936) and lung cancer (NCT02099058), besides breast cancer (91). MIRV combined with other agents, including pembrolizumab, was evaluated in FRα-positive PROC. Preliminary data showed good tolerability and therapeutic activity, with an ORR of 43%, mDOR of 6.9 months, and mPFS of 5.2 months for MIRV combined with pembrolizumab (NCT02606305). The synergistic effect of ADCs and immunotherapy can overcome treatment resistance, displaying encouraging efficacy and safety in tumor treatment. However, large, randomized phase III clinical trials are needed to test their efficacy against conventional therapy.

Table II lists the ongoing clinical trials on ADC combination therapy for ovarian cancer.

ADC has fewer side effects compared with conventional chemotherapy due to its ability to target tumor cells. The toxicity of ADCs arises primarily from the payload and secondarily from linker and bystander effects (92).

A common treatment-related adverse event (TRAE) associated with MIRV is ocular toxicity. A systematic review and meta-analysis showed that the most common TRAEs in patients treated with MIRV were blurred vision (all grades, 45%; grade III, 2%; no grade IV), nausea (all grades, 42%; grade III, 1%; no grade IV) and diarrhea (all grades, 42%; grade III, 2%; no grade IV) (93). In a previously mentioned phase II trial of MIRV (NCT04296890), the most common TRAEs were blurred vision (all grades, 41%; grade III, 6%; no grade IV), keratoconus (all grades, 29%; grade III, 8%; grade IV, 1%) and nausea (all grades, 29%; no grade III or grade IV) (43). Further, ocular events requiring dose reductions occurred in 12 patients (11%). One patient required discontinuation of therapy.

T-DXd is associated with interstitial lung disease (ILD)/pneumonia due to the expression of HER2 in lung epithelial cells (94). It is mainly localized to alveolar macrophages; the incidence and severity of ILD/pneumonia depend on the T-DXd dose and frequency of administration, suggesting that this ILD/pneumonia may be caused by cytotoxic lung injury (95). It is mild in most cases and can be effectively treated, but may be fatal in some cases (96). Respiratory disease (pneumonia) has been the most common cause of treatment-related mortalities in all types of ADC therapy (97). Other TRAEs include nausea and diarrhea, which are effectively controlled using antiemetic and antidiarrheal medications.

Toxicity management includes implementing supportive measures, suspension of treatment, dosage adjustments, or permanent discontinuation of therapy. Most ocular adverse events are mild and reversible; they improve or subside upon discontinuation or therapy improvement (98). Scheduling regular eye examinations to monitor early signs and symptoms, detecting ocular adverse effects in an early stage and prompting pharmacological intervention, promoting the prophylactic use of corticosteroids and lubricating eye drops, adjusting ADC dosage when needed, and maintaining clear communication with the ophthalmologist can help relieve symptoms before the vision is affected, ultimately helping the patient to continue treatment (98,99).

New guidelines for T-DXd-associated ILD/pneumonia toxicity have been published. A multidisciplinary team and timely management with steroids are recommended (100). Careful monitoring by a multidisciplinary team facilitates early detection [e.g., grade I (100)] of ILD/pneumonia, leading to timely discontinuation of medication and initiation of steroids, which prevents the development of fatal ILD/pneumonia.

ADC resistance can be caused by various mechanisms, including change in antigen expression, failure of ADC transportation, failure of ADC internalization, change in tumor sensitivity, exocytosis of ADC payload and activation of signaling pathways (101–103). Some of these mechanisms are not fully understood.

First, alterations occur in target antigen expression, including target downregulation, loss or mutations in target genes. Some tumor cells may evade ADC recognition and binding by reducing or completely losing target expression. Mutations in the target gene may also alter the structure and function of the target, thus affecting the binding affinity of the ADC to the target (101,102).

Second, the abnormal expression or defective function of endocytosis-related proteins, such as cell surface grid proteins, in some tumor cells can lead to the inability of ADC to enter the cell effectively during the internalization and processing of ADC. ADCs that enter the cell are usually transported to the lysosome for degradation, releasing cytotoxic drugs to play a role. If tumor cells enhance the stability of lysosomes or change the microenvironment of lysosomes, ADCs cannot release drugs in lysosomes, resulting in drug resistance (103,104).

Furthermore, a resistance mechanism related to drug metabolism and clearance involves high expression of drug efflux pumps (e.g., drug transporter proteins such as multidrug resistance protein 1 and multidrug resistance-associated protein 1), which can pump ADCs or their released cytotoxic drugs out of the cell, decreasing the drug concentration in the cell, thus leading to drug resistance (104). In breast cancer, acquired resistance to ADC developed in two different cancer cells after months of drug treatment, primarily due to increased expression of the drug efflux protein ABCC1 or decreased expression of HER2 antigen (105).

Finally, the alterations in multiple signaling pathways in tumor cells are also closely related to ADC resistance. For example, the activation of the PI3K/Akt/mTOR signaling pathway can promote the proliferation, survival and metabolism of tumor cells, making them resistant to the cytotoxic effects of ADCs. The abnormal activation of the JAK/STAT signaling pathway may also lead to the development of ADC resistance in tumor cells (106). Alterations in some signaling pathways involved in regulating the cell cycle and apoptosis (such as aberrant activation of STAT3) can also lead to the development of ADC resistance (106).

The selection of potential biomarkers for ADC drug development is also challenging. Normal tissues and cells may also partially express ADC targets, and therefore ADC payloads may have serious side effects on these normal cells (15). The biomarker should preferably be present only on tumor cells or tumor tissue and not expressed in normal cells and tissues. Uniform criteria to determine the expression level that accurately predicts ADC efficacy are lacking. For example, in the case of gosatuzumab, the TROP-2 ADC drug, although TROP-2 expression is associated with efficacy, the exact threshold of expression needs to be further defined with more sufficient evidence. In addition, the biomarker expression of different cells within the same tumor may vary or the biomarker expression levels of the same types of tumors originating from different patients may be different due to the existence of intra-tumor and inter-tumor heterogeneity. All of these increase the difficulty in finding universal biomarkers (107), making the selection of specific targets highly challenging. Moreover, the tumor cells lacking a specific target can proliferate rapidly in the presence of ADCs, leading to a new round of recurrence and drug resistance (108), again demonstrating the importance of finding tumor-specific targets.

Current clinical trials are mostly limited to the efficacy of ADC monotherapy. The information on the safety and toxicity of monotherapy and the efficacy of combination therapy is still in the preliminary stages. First, like-for-like comparisons of newer ADC drugs with standard-of-care or other comparable ADC drugs in clinical trials are scarce, limiting their status and superiority in their class and creating difficulties in dosing choices for clinicians and patients. Second, the maximum tolerated dose is usually derived from safety data in phase I trials. However, the cumulative toxicity of a drug may not be apparent until after multiple courses of therapy, which needs further investigation. In addition, the complexity of the design of sequencing, dosage and duration of combination therapy, as well as the lack of established theoretical and practical guidance, makes the design and implementation of clinical trials more difficult.

A number of other novel approaches to tumor treatment are currently available, which include tumor cell therapy, chimeric antigen receptor T-cell therapy (109), T-cell receptor engineered T-cell therapy (110), tumor-infiltrating lymphocyte therapy (111), ICI therapies, therapies using gene editing techniques such as CRISPR-Cas9 (112) and oncolytic virotherapy (113). ADCs have shown good efficacy in treating various hematological malignancies and solid tumors, with relatively good safety, controllable adverse effects and fewer serious adverse effects such as cytokine release syndrome (114). The precise delivery mechanism, excellent therapeutic effect and safety of ADC indicate its great developmental potential in the field of tumor therapy and wide recognition in the tumor therapy market.

However, the development of ADCs faces several practical challenges in clinical practice. First, comprehensive patient stratification from both clinical and molecular characteristics is needed for specific clinical applications. Besides determining the molecular typing of the patient's tumor cells to select sensitive ADC drugs, the patient's general conditions, such as age, physical status and comorbidities, and other tumor-related characteristics, such as tumor site, size, stage and metastasis, need to be comprehensively considered. For example, the tolerability of ADC therapy may need to be more carefully evaluated in patients with advanced stage and poor physical status. Further, patient tumor samples can be comprehensively analyzed using multi-omics technologies, such as genomics, transcriptomics, proteomics and metabolomics, to mine highly specific and sensitive biomarker combinations for individualized and precise treatment. Second, as ADCs are expensive, a study suggested a reduction in total drug acquisition costs by at least 50% to make it a cost-effective strategy (115). The present study recommends using advanced computer simulation and artificial intelligence techniques to improve drug design and screening efficiency, optimize research and development processes, and enhance production by increasing coupling efficiency and product purity, ultimately reducing research and development and manufacturing costs.