When the dual-antibody ADC drug iza-bren presented an astonishing “objective response rate of 100%” at the 2025 World Lung Cancer Conference, this category of drugs, known as “biological missiles,” completely rewrote the narrative logic of tumor treatment. From the first approved drug, trastuzumab, to the domestically developed dual-antibody ADCs, ADC drugs have established a foothold in the treatment of over a dozen tumors due to their unique design. However, beneath the halo of precise efficacy, the full picture of their clinical application and future direction still requires in-depth interpretation.
1. What are ADC Drugs: A “Trinity” Precision Strike System
ADC drugs, or Antibody-Drug Conjugates, are a new type of tumor treatment drug formed by the precise coupling of monoclonal antibodies with cytotoxic drugs through a chemical linker. Their core advantage stems from the “guidance-warhead-safety” trinity molecular architecture.
Antibodies: The “Biological GPS” for Tumor Recognition: As the “navigation system” of the drug, monoclonal antibodies accurately identify specific antigens on the surface of tumor cells (such as HER2, CD30, TROP2, etc.). These antigens act like the “unique address plates” of cancer cells, guiding ADC drugs to accumulate in tumor tissues, resulting in drug concentrations at the tumor site that are 10-100 times higher than traditional chemotherapy.
Cytotoxic Drugs: The “Warhead” with High Killing Efficiency: The small molecule toxins (such as monomethyl auristatin E, camptothecin derivatives, etc.) carried by ADCs are 100-1000 times more potent than conventional chemotherapy, requiring only 1-2 molecules to enter a cell to induce apoptosis, and they have lower immunogenicity after chemical modification.
Linkers: The Safe and Controllable “Safety Pin”: Responsible for the dual role of “stable transport-targeted release,” linkers maintain stability in the bloodstream to prevent premature leakage of toxins that could damage normal cells. Upon reaching tumor cells, they precisely release toxins through mechanisms such as pH sensitivity and enzymatic cleavage. The commonly used valine-citrulline linker achieves targeted release through lysosomal enzyme cleavage.
The mechanism of action can be divided into five steps: antibody recognition and binding to tumor antigens → tumor cell endocytosis of the ADC-antigen complex → fusion of endosomes with lysosomes → linker cleavage and toxin release → toxins damaging tumor cell DNA or microtubules to induce apoptosis. Some toxins can also kill adjacent cancer cells that do not express the target through the “bystander effect.”
2. Clinical Advantages: From “Carpet Bombing” to “Precision Sniping” Transition
Compared to traditional chemotherapy and simple targeted therapy, ADC drugs have achieved a revolution in treatment logic, with core advantages reflected in three dimensions:
1. Higher Precision and More Controllable Toxicity: Traditional chemotherapy is akin to “carpet bombing,” damaging normal tissues while killing cancer cells. In contrast, ADC drugs concentrate their toxic effects on tumor cells through antigen targeting, significantly reducing harm to healthy tissues. For example, trastuzumab emtansine used for breast cancer has much lower cardiac toxicity than traditional chemotherapy.
2. Breaking Through Resistance Dilemmas: For tumors resistant to targeted drugs, the “bystander effect” of ADC drugs can expand the killing range, making them particularly suitable for heterogeneous solid tumors. For instance, trastuzumab deruxtecan is effective not only for HER2-positive breast cancer but also for HER2-low expressing breast cancer, covering about half of breast cancer patients.
3. Unlocking “Undruggable” Targets: For membrane protein targets that are difficult for traditional targeted drugs to act upon, ADC drugs can achieve effective killing while ensuring targeting by adjusting the “drug-antibody ratio” (linking 2-8 toxin molecules to each antibody).
3. Applicable Tumors: A Broad Layout Covering Hematological and Solid Tumors
Currently, 15 ADC drugs have been launched globally, with 10 approved domestically, covering over a dozen tumor indications and forming a pattern that balances hematological and solid tumors:
Hematological Tumors: The CD30-targeting drug brentuximab vedotin is a typical representative, treating Hodgkin lymphoma by targeting the CD30 antigen. Its anti-cancer activity stems from the internalization and release of toxins after ADC binds to CD30, inducing cell cycle arrest and apoptosis. Additionally, ADC drugs targeting CD22, BCMA, etc., have also been approved for use in leukemia and multiple myeloma treatments.
Solid Tumors: In the field of breast cancer, HER2-targeting ADC drugs have become important treatment options for HER2-positive and low-expressing patients. In lung cancer, trastuzumab deruxtecan (HER2-targeting) and sacituzumab govitecan (TROP2-targeting) have been approved, with the dual-antibody ADC drug iza-bren demonstrating a 100% objective response rate in EGFR-mutant lung cancer. In gastrointestinal tumors such as gastric cancer and colorectal cancer, Claudin 18.2-targeting ADC drugs have also made breakthrough progress.
4. Usage Method: Individualized Administration Based on Target Detection
The use of ADC drugs must follow the principle of “testing first-individualized administration,” with the core process including target detection, treatment plan formulation, and efficacy monitoring:
1. Prerequisites Before Medication: Target detection: ADC drugs are only effective for patients with positive target expression. Before administration, it is necessary to confirm whether the tumor expresses specific antigens through tissue or liquid biopsy. For example, to use brentuximab vedotin, it is essential to confirm that the tumor expresses CD30, and for HER2-targeting ADCs, HER2 expression status must be tested to avoid blind medication.
2. Administration Method and Dosage: Currently approved ADC drugs are all injectable (mostly lyophilized powders that need to be reconstituted), administered via intravenous infusion. Dosage is usually calculated based on the patient’s body surface area or weight. For instance, each vial of brentuximab vedotin contains 50 mg, with a reconstituted concentration of 5 mg per mL. The specific administration frequency and cycle should follow medical advice.
3. Monitoring During Treatment: Regular monitoring of target status, liver and kidney function, and blood routine indicators is required during treatment. Some drugs require special monitoring; for example, HER2-targeting ADCs need regular echocardiograms to assess cardiac toxicity.
5. Adverse Reactions and Patient Responses: The Art of Balancing Efficacy and Safety
The adverse reactions of ADC drugs exhibit characteristics of both antibodies and cytotoxic drugs, overall being milder than traditional chemotherapy, but still requiring close attention:
Main Adverse Reactions:
1. Bone marrow suppression: One of the most common adverse reactions, manifested as neutropenia, anemia, and thrombocytopenia. Drugs like brentuximab vedotin and sacituzumab govitecan are particularly notable, and patients may need to receive white blood cell-stimulating injections to improve neutrophil levels.
2. Target-related toxicity: Related to the antibody component, such as HER2-targeting ADCs potentially causing cardiac toxicity, necessitating regular monitoring of heart function. Some drugs may lead to immune-related reactions such as rashes and diarrhea.
3. Special severe toxicities: A few drugs carry rare but fatal risks, such as brentuximab vedotin potentially causing JC virus infection leading to progressive multifocal leukoencephalopathy (PML), which, although rare, requires vigilance.
4. Other common reactions: Including gastrointestinal symptoms such as nausea and vomiting, as well as liver and kidney function impairment, which need to be monitored before and after treatment.
Patient Responses: Most patients tolerate ADC drugs better than traditional chemotherapy, with significantly lower rates of adverse reactions that affect quality of life, such as hair loss and severe vomiting. However, individual responses vary: some patients may experience fatigue and increased susceptibility to infections due to mild bone marrow suppression, but can continue treatment after symptomatic management; a few patients may need to pause medication due to cardiac toxicity or severe infections. Overall, under standardized management, about 80% of patients can complete the planned treatment cycle.
6. Treatment Effects and Long-term Prognosis: Breakthroughs that Rewrite Survival Patterns
ADC drugs have demonstrated outstanding efficacy in multiple clinical studies, especially bringing new hope to advanced or resistant patients:
Recent Efficacy: In advanced lung cancer with EGFR mutations, the phase II study of iza-bren combined with osimertinib showed an objective response rate of 100% and a disease control rate of 100%. In HER2-mutant lung cancer patients treated with trastuzumab deruxtecan, the objective response rate reached 58.3%, with a disease control rate exceeding 90%. For recurrent refractory small cell lung cancer, the objective response rate of YL201 (targeting B7H3) reached 63.9%, with a disease control rate of 91.7%.
Long-term Prognosis Improvement: ADC drugs not only enhance response rates but also extend patient survival times. Some advanced breast cancer patients have seen survival extended by over a year after using ADC drugs; in EGFR-resistant lung cancer patients treated with dual-antibody ADCs, the average tumor control time reached 12.5 months, the longest among similar drugs; in Hodgkin lymphoma, brentuximab vedotin has enabled some patients to achieve long-term remission.
7. Future Development Directions: Technological Integration and Strategic Upgrades
Despite the breakthrough progress of ADC drugs, challenges such as target limitations, resistance, and toxicity management remain. Future development will focus on four major directions:
1. Target and Structural Innovation: Expanding from classic targets like HER2 and CD30 to new targets like B7H3, while developing dual-antibody ADCs (such as EGFR/HER3 dual-antibody ADCs) and multi-target ADCs to achieve dual effects of “targeted killing + immune activation,” thereby expanding the beneficiary population.
2. Combination Therapy to Overcome Resistance: Combining ADC drugs with immune checkpoint inhibitors and small molecule targeted drugs to break tumor resistance mechanisms. For example, combining ADCs with PD-1 monoclonal antibodies can enhance efficacy through “targeted killing + immune activation,” with related clinical trials already underway in various solid tumors.
3. Technological Empowerment for Precision R&D: Utilizing artificial intelligence and bioinformatics to predict target efficacy, optimize linker and toxin design, enhance drug stability and targeting, and shorten R&D cycles.
4. Optimizing Individualized Treatment: Formulating medication plans based on patients’ tumor antigen expression levels and genetic mutation characteristics, while establishing standardized antigen detection systems to clarify detection standards for different mutation types, ensuring precise selection of beneficiary populations.
From the launch of the first ADC drug to the dual-antibody ADC achieving “100% response,” ADC drugs have completed a transition from concept to clinical application over more than a decade. They are not only a reflection of the development of precision medicine but also carry the hope of advancing cancer treatment from “prolonging survival” to “possibility of cure.” With continuous technological breakthroughs and the accumulation of clinical experience, this “smart missile” will ultimately play a core role in the treatment of more cancer patients, writing a new chapter in precision cancer therapy.