The global medical community has been battling cancer as a significant challenge for many years. Traditional cancer treatments, including surgery, radiotherapy, and chemotherapy, provide some control over tumor development and spread. However, these treatment approaches frequently produce intense side effects and fail to effectively control advanced or resistant cancer types. Recent biotechnology advances have led to the development of antibody-drug conjugates (ADCs) as cutting-edge targeted cancer treatments that show great promise. This article examines Trop-2 ADCs by exploring their exceptional benefits for cancer treatment alongside current research developments and potential future advancements.

ADC Therapy

ADCs function as a groundbreaking cancer therapy that merges monoclonal antibodies' targeting capabilities with the strong cell-killing power of chemotherapy drugs. ADCs deliver therapeutic agents to cancer cell surfaces through chemical linkers that attach drugs to antibodies while minimizing normal cell damage and killing cancer cells precisely. Targeted therapies improve treatment effectiveness while substantially decreasing common chemotherapy side effects, including nausea, vomiting, hair loss, and bone marrow suppression. ADCs present unique benefits when compared to conventional chemotherapy medications. The targeting ability of these drugs enables them to attack tumor cells selectively while minimizing normal tissue damage. ADCs show improved therapeutic outcomes over standard chemotherapy by delivering better results with reduced dosages. Additionally, ADCs show reduced toxicity levels, which results in better patient tolerance. ADCs exhibit significant benefits which establish them as a powerful option in cancer therapy.

Fig. 1. Antibody-drug conjugates.

ADC Structure

ADC therapeutic effectiveness depends on their structural design. ADCs are composed of three main elements, which include the antibody as well as the linker and the payload that contains a cytotoxic drug. Detailed explanations about these components and their specific functions in ADCs are presented in the following sections:

• ADC Antibody

The antibody is the core component of ADCs, providing targeting specificity. An ideal antibody must have high affinity and specificity, ensuring accurate recognition and binding to specific antigens on the surface of cancer cells. In Trop-2 ADCs, the antibody is specifically designed to bind to Trop-2, an antigen overexpressed in various tumor cells. Through precise antibody design, ADCs can efficiently deliver drugs to tumor cells, achieving targeted therapy. The selection and optimization of antibodies are key steps in ADC development. Researchers use multiple techniques to screen and refine antibodies to ensure high affinity and specificity. For example, phage display technology is commonly employed to identify high-affinity monoclonal antibodies. Additionally, genetic engineering techniques can be used to optimize antibody sequences and structures, further enhancing their stability and targeting efficiency.

• ADC Linker

The linker is the chemical bond that connects the antibody to the cytotoxic drug in ADCs. The stability of the linker is crucial, as it must remain intact during circulation in the bloodstream to prevent premature drug release while enabling efficient drug release upon reaching the tumor cells. Linkers are generally categorized into two types: cleavable and non-cleavable linkers.

• Cleavable linkers: These linkers release the drug in specific cellular environments. For example, some cleavable linkers break down in the acidic lysosomal environment, releasing the cytotoxic drug. The advantage of cleavable linkers is that they minimize drug release in circulation, reducing side effects. However, their potential instability may lead to premature drug release in the bloodstream.
• Non-cleavable linkers: These linkers are more stable and typically require proteolytic mechanisms to release the drug. Their key advantage is high stability, preventing drug leakage during circulation. However, their drug release efficiency may be relatively lower, necessitating sufficient intracellular protease activity in tumor cells for effective drug activation.

The choice of linker requires a comprehensive evaluation of drug stability, release efficiency, and potential side effects. Researchers conduct extensive experimental validation to select the most suitable linker.

• ADC Payload

The cytotoxic drug is the core functional component of ADCs, responsible for killing cancer cells. These drugs are highly toxic but are restricted within tumor cells when delivered via ADCs, reducing harm to normal cells. Common cytotoxic agents include microtubule inhibitors and DNA-damaging agents. Microtubule inhibitors interfere with microtubule structures in cancer cells, preventing cell division and inducing cell death. For example, paclitaxel is a widely used microtubule inhibitor that stabilizes microtubule structures, preventing mitotic progression. DNA-damaging agents disrupt the DNA of cancer cells, leading to cell death. For instance, carboplatin is a commonly used DNA-damaging agent that binds to DNA, forming cross-links that inhibit DNA replication and transcription. In Trop-2 ADCs, selecting an appropriate cytotoxic drug is crucial for therapeutic efficacy. Researchers must consider tumor cell characteristics and drug release mechanisms to choose highly potent and selective cytotoxic agents. Additionally, drug release mechanisms must be carefully designed to ensure efficient drug activation within tumor cells while minimizing damage to normal cells.

ADC Target

The target is a unique marker on the surface of cancer cells. ADCs achieve highly efficient and low-toxicity therapeutic effects by binding to these targets and precisely delivering the drug into cancer cells. An ideal ADC target should possess several key characteristics: First, the target antigen should be highly expressed specifically in tumor cells, effectively distinguishing tumor cells from normal cells and reducing damage to normal tissues. Second, the target antigen should be easily recognized and bound by ADCs and be able to facilitate the internalization of the cytotoxic drug into the cell. Finally, the stability of target antigen expression is also crucial to ensure the sustained effectiveness of ADC therapy. Currently, widely studied targets in the ADC field include:

Trop-2 Antibody Drug Conjugate

Trop-2 (Trophoblast cell-surface antigen 2) is an antigen overexpressed on the surface of various tumor cells. It was initially discovered in trophoblast cells, and subsequent studies have found that Trop-2 is highly expressed in multiple solid tumors, such as breast cancer, lung cancer, and colorectal cancer. Research indicates that Trop-2 overexpression is closely associated with tumor invasiveness, metastatic potential, and poor prognosis. Therefore, Trop-2 is considered an ideal tumor therapeutic target. By designing specific antibodies to bind Trop-2, ADCs can precisely deliver cytotoxic drugs to Trop-2-positive tumor cells, achieving efficient tumor treatment.

The development of Trop-2 ADCs can be traced back to the late 20th century. Early research primarily focused on the biological function of the Trop-2 protein and its expression in tumors. As understanding of Trop-2 deepened, researchers began exploring its potential as a drug target. In recent years, with advancements in biotechnology, the development of Trop-2 ADCs has made significant progress. For example, Immunomedics developed the Trop-2 ADC drug Sacituzumab Govitecan (brand name Trodelvy), which has demonstrated promising efficacy in multiple cancer clinical trials and received FDA approval.

Trop-2 ADC Approved

Trop-2-targeting ADCs have shown great potential in the treatment of various cancers. Sacituzumab govitecan has received multiple approvals for different indications, while Datopotamab deruxtecan is approaching approval for lung cancer treatment and has already been approved for breast cancer in certain regions. These approvals highlight the significance of Trop-2 as a tumor treatment target.

• Trop-2 ADC in Breast Cancer

Sacituzumab govitecan (Trodelvy) is the first approved Trop-2-targeting ADC. In 2020, the FDA granted accelerated approval to Sacituzumab govitecan for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior therapies for metastatic disease. This approval was based on the ASCENT trial, which demonstrated that Sacituzumab govitecan significantly improved progression-free survival (PFS) and objective response rate (ORR) compared to single-agent chemotherapy.

In April 2021, the FDA converted this accelerated approval into full approval for the treatment of mTNBC patients who had received two or more systemic therapies, including at least one for metastatic disease. Additionally, in April 2021, the FDA granted accelerated approval to Sacituzumab govitecan for the treatment of locally advanced or metastatic urothelial carcinoma in patients who had previously received platinum-based chemotherapy and a PD-L1 inhibitor. In February 2023, the FDA approved Sacituzumab govitecan for the treatment of hormone receptor-positive, HER2-negative breast cancer patients who had undergone endocrine therapy and at least two other systemic therapies.

• Trop-2 ADC in Lung Cancer

Datopotamab deruxtecan (Dato-DXd) is another Trop-2-targeting ADC that has shown promising results in clinical trials. In December 2024, the FDA granted breakthrough therapy designation to Datopotamab deruxtecan for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFR-mutated) non-small cell lung cancer (NSCLC) who had experienced disease progression after treatment with an EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy. This designation was based on data from the Phase 2 TROPION-Lung05 trial and was supported by findings from the Phase 3 TROPION-Lung01 trial.

In January 2025, the FDA accepted the Biologics License Application (BLA) for Datopotamab deruxtecan for the treatment of adult patients with locally advanced or metastatic non-squamous NSCLC who had received prior systemic therapy. This BLA was based on the results of the Phase 3 TROPION-Lung01 trial, in which Datopotamab deruxtecan demonstrated significantly improved progression-free survival (PFS) compared to the current standard therapy, docetaxel. Additionally, Datopotamab deruxtecan has been approved in Japan and the United States for the treatment of adult patients with unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer who had received prior endocrine therapy and chemotherapy. This approval was based on the results of the TROPION-Breast01 trial.

Trop-2 ADC Clinical Trials

Currently, multiple clinical trials of Trop-2 ADCs are underway worldwide. These trials cover various cancer types and treatment stages, aiming to further evaluate the safety, efficacy, and optimal treatment strategies of Trop-2 ADCs. For instance, some trials are exploring the application of Trop-2 ADCs in the treatment of early-stage breast cancer in hopes of achieving better therapeutic outcomes at the early stages of the disease.

• Triple-Negative Breast Cancer

On September 27, 2024, at the Chinese Society of Clinical Oncology (CSCO) conference, Academician Xu Binghe from the Cancer Hospital of the Chinese Academy of Medical Sciences delivered an oral presentation on the results of the Phase III OptiTROP-Breast01 study, which evaluated Sac-TMT in patients with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC). In this study, the median progression-free survival (PFS) assessed by an independent blinded central review (BICR) was 6.7 months in the Sac-TMT group compared to 2.5 months in the chemotherapy group, representing a 68% reduction in the risk of disease progression or death in the Sac-TMT group. In the subgroup of patients with a Trop-2 H-score >200, the median PFS was 8.3 months for the Sac-TMT group and 2.3 months for the chemotherapy group. The median overall survival (OS) in the Sac-TMT group was not yet reached, while it was 9.4 months in the chemotherapy group, with Sac-TMT reducing the risk of death by 47%. The safety profile of Sac-TMT was manageable, indicating that Sac-TMT could serve as a new and effective treatment option for patients with metastatic TNBC.

• Non-Small Cell Lung Cancer

In October 2024, Kelun-Biotech announced that its Trop-2 ADC drug, Sac-TMT, had received acceptance from China's National Medical Products Administration (NMPA) for a New Drug Application (NDA) for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. This application was based on positive results from the pivotal Phase III OptiTROP-Lung04 study, a multicenter, randomized, registrational Phase III clinical trial designed to evaluate the efficacy and safety of Sac-TMT monotherapy compared with pemetrexed plus platinum-based chemotherapy in patients with locally advanced or metastatic NSCLC who had disease progression following treatment with EGFR tyrosine kinase inhibitors (TKIs). In a pre-specified interim analysis, Sac-TMT monotherapy demonstrated a statistically and clinically significant improvement in PFS, the primary endpoint, compared to pemetrexed plus platinum-based chemotherapy, with no unexpected safety signals identified.

• Breast Cancer

In the Phase I TROPION-PanTUMOR01 study (NCT03401385), Dato-DXd was administered to patients with advanced solid tumors who had undergone standard treatment to determine its safety and efficacy. For patients with advanced/metastatic TNBC and HR+/HER2- breast cancer, Dato-DXd was given at a dose of 6 mg/kg every three weeks, with all patients having received at least two prior lines of therapy. Results showed that the objective response rate (ORR) was 26.8% for the HR+/HER2- breast cancer cohort and 31.8% for the TNBC cohort, while the ORR for the topo I-naïve TNBC subgroup was 40.0%. The median PFS was 8.3 months for the HR+/HER2- breast cancer cohort, 4.4 months for the TNBC cohort, and 7.3 months for the topo I-naïve TNBC subgroup. The median OS was not yet reached for the HR+/HER2- breast cancer cohort, while it was 13.5 months for the TNBC cohort and 14.3 months for the topo I-naïve TNBC subgroup. Additionally, the Phase III TROPION-Breast01 study also yielded positive results, with patients in the Dato-DXd group showing a significant improvement in PFS and a trend toward OS benefit, further supporting Dato-DXd as a new treatment option for advanced HR+/HER2- breast cancer.

In Conclusion

As an emerging targeted cancer therapy, Trop-2 ADCs have demonstrated significant potential in treating various types of cancer. Their precise targeting, remarkable therapeutic efficacy, and relatively manageable side effects make them a promising direction for future cancer treatment. With continuous advancements in technology and deeper clinical research, Trop-2 ADCs are expected to be widely applied to more cancer types, offering greater hope to cancer patients. In the future, Trop-2 ADCs are anticipated to play a crucial role in personalized medicine. Through genetic testing and biomarker analysis, physicians can tailor individualized treatment regimens based on the tumor characteristics of each patient. For instance, patients with high Trop-2 expression and specific genetic mutations may receive the most suitable Trop-2 ADC drugs and treatment strategies, thereby improving therapeutic outcomes.

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