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Editor’s Note: With their unique mechanisms of action and powerful efficacy, Antibody-Drug Conjugates (ADCs) have become indispensable treatment methods for various solid tumors and hematological cancers, such as breast cancer. The core component that determines the efficacy of ADCs is undoubtedly the payload. Different payloads exhibit significant differences in their mechanisms of action and potency, and the selection of potent and multi-mechanism novel payloads has become a key reason for the success of new-generation ADC drugs like Trastuzumab Deruxtecan (T-DXd). This article will review the characteristics of approved ADCs and some payloads used in ADCs that have entered Phase III clinical trials, as well as introduce some potential innovative payloads, providing insight into the development trends of ADC payloads.
Thanks to the unique biological distribution and metabolic characteristics of ADCs, payloads can be precisely delivered to cancer cells and exert lethal effects after being internalized by these cells. Although studies show that only about 2% of ADCs effectively reach tumor targets after intravenous injection[1], the payloads can still maintain significant efficacy at such low concentrations, highlighting their powerful effectiveness. Additionally, an ideal ADC payload should possess excellent physiological stability, with specific requirements including low molecular weight and high water solubility, and even after ADCs degrade into payload-linker complexes, the payload must be capable of resisting the acidic environment within lysosomes.
Currently, the payloads approved for ADC use mainly fall into five categories: Topoisomerase I (TOP1) inhibitors, microtubule inhibitors, DNA damaging agents, photosensitizers, and bacterial toxins. Among these, TOP1 inhibitors are represented by DXd and SN-38, microtubule inhibitor payloads include Auristatin derivatives (such as MMAE, MMAF) and Maytansinoid derivatives, DNA damaging agents include Calicheamicin derivatives and PBD molecules, and there is one type each of photosensitizer and bacterial toxin. The types of payloads selected for investigational ADCs not only cover the aforementioned categories but are also undergoing in-depth expansion and extension. For instance, DXd and its derivatives among TOP1 inhibitors have been selected as payloads for over 45.8% of ADCs currently in Phase III clinical trials, making them trendsetters. Other investigational payloads include microtubule inhibitor SC209 molecules and DNA damaging seco-DUBA molecules, which will be reviewed one by one below.
TOP1 Inhibitors
TOP1 inhibitor payloads primarily induce apoptosis in cancer cells by interfering with DNA replication and transcription processes. Although their cytotoxicity is slightly lower than that of DNA damaging agents, through sophisticated linker design, they can achieve improvements in drug-antibody ratio (DAR) and stability, effectively enhancing the bystander effect, making them very promising ADC payloads.
The representative TOP1 inhibitor payloads are SN-38 and DXd. The former is the active metabolite of Irinotecan, with antitumor activity 1000 times higher than that of Irinotecan itself. The approved drug Gemtuzumab Ozogamicin for breast cancer uses SN-38 as its payload. DXd, a derivative of Exatecan, has over ten times the antitumor activity of SN-38, along with good water solubility, a short half-life, and the bystander effect.
Trastuzumab Deruxtecan (T-DXd), which shows good efficacy in both HER2 low-expressing and HER2-positive breast cancer patients, uses DXd as its payload. With the innovative GGFG peptide linker, the drug-antibody ratio (DAR) reaches 7.8, and the DXd payload not only induces apoptosis in cancer cells after internalization but also kills other cancer cells through a significant bystander effect.
High-quality evidence from Phase III clinical studies has fully demonstrated the significant efficacy of T-DXd using a powerful payload.
For instance, in the DESTINY-Breast 03 study involving HER2-positive metastatic breast cancer patients who had previously received Trastuzumab and taxane treatments, the median progression-free survival (mPFS, assessed by blinded independent central review) for the T-DXd treatment group was 28.8 months, significantly better than the 6.8 months for the T-DM1 control group (HR 0.33; 95% CI: 0.26-0.43; P<0.0001)[2], and the 36-month overall survival (OS) rate for the T-DXd group was 67.6%, also higher than the 55.7% for the T-DM1 group (HR 0.73; 95% CI: 0.56-0.94)[3]. These outstanding efficacy data have made T-DXd the new standard for second-line treatment of HER2-positive metastatic breast cancer.
The DESTINY-Breast 04 study targeting HER2 low-expressing metastatic breast cancer also showed that T-DXd treatment significantly prolonged mPFS and mOS compared to standard chemotherapy. The DESTINY-Breast series of studies continues to extend and expand, and T-DXd has strong potential to continue transforming the treatment landscape for breast cancer.
The success of T-DXd has made DXd and its derivatives one of the frequently selected payloads for subsequent investigational ADCs, with at least four ADCs in Phase III studies using DXd. Recently, the SHR-A1811, which has been approved for lung cancer indications in China, uses the DXd derivative payload SHR9265, which enhances membrane permeability and cytotoxicity by introducing a cyclopropyl structure. Other approved or investigational ADCs using TOP1 inhibitor payloads include Adizutecan (ABBV-400) and KL610023 (Lukankasomab).
Microtubule Inhibitors
Microtubules, as key components of the cancer cell cytoskeleton, play an indispensable role in the rapid proliferation of cancer cells. The currently used microtubule inhibitor payloads in ADCs mainly include Auristatin and Maytansine drugs.
Among Auristatin drugs, MMAE and MMAF are widely used ADC payloads. They effectively inhibit the polymerization of microtubules or promote their depolymerization by targeting the colchicine binding site on tubulin, thereby disrupting microtubule dynamics, ultimately leading to cell cycle arrest and inducing apoptosis in cancer cells. The difference between the two is that MMAE has high membrane permeability and can produce a significant bystander effect, while MMAF is more hydrophilic and less likely to aggregate, resulting in relatively lower systemic toxicity.
Approved ADCs using Auristatin as a payload include those using MMAE such as Brentuximab Vedotin, Polatuzumab Vedotin, Inotuzumab Ozogamicin, and Tisotumab Vedotin (the domestic application has been accepted), as well as those using MMAF such as Belantamab Mafodotin (the domestic application has been accepted). ADCs currently in Phase III studies include Zilovertamab Vedotin and FS-1502.
Maytansine drugs primarily inhibit the dynamic changes of microtubules by binding to the ends of tubulin, causing cancer cells to stall in the G2/M phase and inducing apoptosis. DM1 and DM4 (Ravtansine) are typical representatives of this type of payload. Approved ADCs using Maytansine payloads include Trastuzumab Emtansine (T-DM1) and Sunitinib (using DM4 as a payload), while ADCs in Phase III studies include Tusamitamab Ravtansine (using DM4 as a payload).
DNA Damaging Agents
DNA damaging agents effectively kill cancer cells by inhibiting DNA synthesis or directly damaging DNA structure (e.g., inducing double-strand breaks, alkylation, or cross-linking). Compared to microtubule inhibitors, ADCs using DNA damaging agents as payloads typically exhibit stronger cytotoxicity (at equivalent payload doses) and can effectively target cancer cells with lower antigen expression levels, thereby improving treatment precision. Commonly used DNA damaging agent payloads include Calicheamicin, PBD, and DUBA:
1) Calicheamicin, a natural enediyne antibiotic, induces apoptosis in cancer cells by binding to the minor groove of DNA, leading to double-strand breaks. Approved ADCs using it include Gemtuzumab Ozogamicin and Moxetumomab Pasudotox.
2) PBD also tightly binds to the grooves of the DNA double helix, but its mechanism for inducing apoptosis involves forming interstrand cross-links, thereby inhibiting transcription factor binding. The cross-links do not distort the DNA structure, helping to evade DNA repair mechanisms and enhance cytotoxicity. Additionally, ADCs using PBD as a payload have shorter half-lives, which can reduce off-target toxicity. However, due to numerous challenges[4], only Polatuzumab Vedotin has been approved using PBD as a payload.
3) DUBA, short for Duobamycin hydroxybenzamide-azaindole, is a highly effective DNA damaging agent. Most ADCs use its prodrug seco-DUBA as a payload to allow its modifiable hydroxyl group to efficiently couple with monoclonal antibodies. The trastuzumab duocarmazine currently in Phase III studies uses seco-DUBA as a payload.
Bacterial Toxins
Bacterial toxins produced by pathogens can also be used to kill host cells. For example, the PEA toxin produced by the opportunistic pathogen Pseudomonas aeruginosa is considered its strongest toxin, which induces apoptosis in host cells by inhibiting protein synthesis. The approved drug Moxetumomab Pasudotox for treating hairy cell leukemia uses a truncated form of PEA as its payload, PE38.
Photosensitizers
Photosensitizers are key components of photodynamic therapy (PDT) and can be activated by light to produce singlet oxygen that kills cancer cells. However, factors such as the hypoxic environment inside cancer cells and limited light penetration depth often restrict the efficacy of PDT. Generally, red light and near-infrared (NIR) light with wavelengths between 650–1100 nanometers, which have good deep penetration and minimal tissue damage, are used to activate photosensitizer payloads. For instance, the cetuximab sarotalocan approved in Japan uses the NIR photosensitizer IRDye® 700DX as a payload for treating head and neck squamous cell carcinoma (HNSCC)[5].
Potential Innovative Payloads
Immunostimulatory small molecules: ADCs can also precisely deliver immunostimulatory small molecules to the tumor microenvironment for local release, significantly reducing systemic toxicity while activating antitumor immune responses. Currently studied payloads mainly include Toll-like receptor 7/8/9 (TLR7/8/9) agonists and STING agonists, among which the STING agonist XMT-2056[6] has entered Phase I clinical trials and has received orphan drug designation from the FDA for gastric cancer treatment.
RNA inhibitors: RNA inhibitors can effectively eliminate dividing and dormant cancer cells, potentially overcoming drug resistance and tumor recurrence caused by dormant cancer cells. Suitable RNA inhibitors for ADC payloads include RNA polymerase II inhibitors and RNA splicing inhibitors. The RNA polymerase II inhibitor Amatoxins used as a payload in HDP-101 (targeting BCMA) has entered Phase II studies.
Other novel payloads: Other payloads used in investigational ADCs include Bcl-xL inhibitors (to reduce systemic platelet toxicity), proteasome inhibitors (such as Carmaphycin), and NAMPT inhibitors, each with different mechanisms of action and generally high cytotoxicity. Using ADCs as drug delivery vehicles can enhance treatment precision and improve safety.
Conclusion and Outlook
Currently approved and investigational ADC payloads are all cytotoxic payloads. Although their mechanisms of action vary, they generally need to possess high cytotoxicity (IC50<1 nM), low immunogenicity, and good plasma stability. Based on the comprehensive results of clinical studies and the design and development trends of investigational ADCs, TOP1 inhibitor payloads represented by DXd are rapidly developing. For instance, T-DXd has shown significantly improved efficacy compared to existing ADCs using microtubule inhibitor payloads, not only achieving remarkable results in breast cancer treatment but also expected to expand its application range in different solid tumors, making it a leader among the new generation of ADCs. In the future, various new payloads that are efficient, low-toxicity, and capable of overcoming drug resistance are expected to lead the development of the next generation of ADCs, pushing cancer treatment into a new era of precision, efficiency, and personalization.
References
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[1] Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93. Published 2022 Mar 22. doi:10.1038/s41392-022-00947-7
[2] Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5
[3] Cortés J, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med. 2024;30(8):2208-2215. doi:10.1038/s41591-024-03021-7
[4] Wang R, Hu B, Pan Z, et al. Antibody-Drug Conjugates (ADCs): current and future biopharmaceuticals. J Hematol Oncol. 2025;18(1):51. Published 2025 Apr 30. doi:10.1186/s13045-025-01704-3
[5] Okamoto I. Photoimmunotherapy for head and neck cancer: A systematic review. Auris Nasus Larynx. 2025;52(2):186-194. doi:10.1016/j.anl.2025.01.005
[6] Bukhalid RA, Duvall JR, Lancaster K, et al. XMT-2056, a HER2-Directed STING Agonist Antibody-Drug Conjugate, Induces Innate Antitumor Immune Responses by Acting on Cancer Cells and Tumor-Resident Immune Cells. Clin Cancer Res. 2025;31(9):1766-1782. doi:10.1158/1078-0432.CCR-24-2449
Material Code: CN-20250811-00002
This material is for reference only for healthcare professionals and should not be distributed to non-healthcare professionals.
(Source: Editorial Department of “Oncology Outlook”)
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