If there is one area where Chinese innovative drugs have gained significant prominence in recent years, ADC (antibody-drug conjugate) is undoubtedly the answer. At this year's AACR and ASCO conferences, ADCs from Chinese pharmaceutical companies made a dense appearance, steadily entering the international spotlight with solid data.

At the 2025 AACR conference, 111 Chinese pharmaceutical companies showcased 246 innovative drugs, of which 86 were ADCs, accounting for over one-third of the total. Behind these numbers lies a new wave of technological advancement.

From Humira, which dominated the global sales rankings as the "king of drugs" for nearly nine years, to the rise of PD(L)-1 inhibitors on the charts, the journey of each generation of drugs—from successful development and peak popularity to eventual replacement—has always been an "old story" with "nothing new under the sun."

In the current increasingly competitive landscape of PD(L)-1 inhibitors, many pharmaceutical companies are eagerly anticipating the emergence of the next "king of drugs"—not just with hope but with concrete investments. Perhaps antibody-drug conjugates (ADCs) represent the next wave. Among the various emerging therapies and molecular structures, the ADC field may offer the most predictable prospects.

As of 2024, the total sales of the 17 globally approved ADC drugs have reached a scale of tens of billions of dollars. Among them, trastuzumab emtansine has maintained annual sales of over $2 billion since 2021, while Enhertu   has shown even more rapid growth, with sales surging from $500 million in 2021 to $3.48 billion in 2024. In the first half of 2025, its sales reached $2.067 billion, a year-on-year increase of 21.9%. The industry widely expects its full-year sales for 2025 to exceed $4 billion, and some investment research institutions predict its peak sales could surpass $9 billion, marking the ADC field's entry into a high-speed development and harvest period.

The emergence of domestic "blockbuster" drugs may also come from this field.

However, industry insiders note that the current state of ADC research and development has reached a stage of "equal know-how"—older linkers and cytotoxic payloads have been largely abandoned, and mature ADC technologies that have been clinically validated—such as the use of specific linker molecules/toxins, methods for achieving homogeneous conjugation, and strategies for site-specific coupling—are now widely understood by most experienced researchers.

The question then arises: Is this the starting point for the second domestic "blockbuster," or is it the beginning of a homogenized competition that is already undergoing consolidation?

The Rise and Advancement of Domestic ADCs

The concept of "drugs linked to antibodies" proposed by Nobel laureate Paul Ehrlich in 1913 served as the early inspiration for antibody-drug conjugates (ADCs). An ADC consists of three components: an antibody, a linker, and a cytotoxic payload. The specific antibody carries the cytotoxic payload to target and accumulate near relevant tumor cells based on the designed target. After internalization, the cytotoxic drug is released, effectively killing tumor cells while also exhibiting a certain bystander effect.

Such precise targeting of tumor cells has long been the dream of scientists and drug developers. However, it was only realized approximately a century later, following advancements in antibody technology, linker technology, and other related fields.

Globally, the first clinically validated ADC molecules were approved between 2011 and 2013. In China, the first ADC drug was approved in 2021 (RemeGen's disitamab vedotin, targeting HER2). Compared to PD-1 drugs, domestic pharmaceutical companies did not further shorten the gap in the ADC field.

This is partly due to the more complex structure and greater number of technical challenges associated with ADCs. After the approval of Kadcyla (trastuzumab emtansine) in 2013, there was a certain "generation gap" in the field. Lumoxiti (AstraZeneca), approved in 2018, was even withdrawn from the market in 2023. It was not until 2019 that a new generation of ADC drugs representing more advanced technology, Enhertu (trastuzumab deruxtecan, AstraZeneca/Daiichi Sankyo), entered the market. During this period, approximately one-third of clinical trials failed due to intolerable toxicity or insufficient efficacy compared to existing therapies (Exploration of the antibody-drug conjugate clinical landscape, Heather Maecker, Vidya Jonnalagadda, Sunil Bhakta—Mabs, 2023).

Another reason is related to the slower sales growth of ADC drugs compared to PD-1 drugs. Kadcyla, approved in 2013, reached sales of CHF 910 million (approximately $1.14 billion) in 2015. From 2016 to 2019, its sales remained stagnant at around $1.1–1.3 billion, only surpassing $2 billion in 2020.

Looking at the establishment of domestic ADC drug R&D companies and the initiation of ADC projects by major pharmaceutical firms, these efforts were largely concentrated around 2019–2020.

Nevertheless, domestic pharmaceutical companies have been extremely swift in expanding ADC targets. HER2, as a well-understood and validated mature target for monoclonal antibodies, naturally became the first target for ADC development.

To date, three domestic HER2-targeting ADC drugs have been approved for marketing, developed by RemeGen, Hengrui, and Kelun-Biotech, respectively.

However, after the validation of ADC technology and facing the reality of numerous "first-mover pipelines" focusing on HER2, expanding into other targets such as Trop2, c-Met, DLL3, and CLDN18.2 has become an inevitable choice for many ADC-focused pharmaceutical companies.

Taking the Trop2 target as an example, the world's first Trop2-targeting ADC drug (Trodelvy/sacituzumab govitecan, Gilead/Immunomedics) was approved in 2020. In China, the first Trop2-targeting ADC drug (sacituzumab tirumotecan, Kelun-Biotech) was approved by the National Medical Products Administration in November 2024 for the treatment of unresectable locally advanced or metastatic triple-negative breast cancer in patients who have received at least two prior lines of systemic therapy. This demonstrates a further narrowing of the gap.

In terms of expanding the indications for Trop2-targeting ADC drugs, domestic pharmaceutical companies have even outpaced their foreign counterparts:

Sacituzumab tirumotecan received approval for its second indication on March 10, 2025, for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC) patients who have failed EGFR-TKI and platinum-based chemotherapy, as well as locally advanced or metastatic EGFR mutation-positive non-squamous NSCLC patients who have progressed after EGFR-TKI therapy. According to clinical data, sacituzumab tirumotecan significantly prolonged overall survival (OS) compared to standard treatment.

In June 2025, Daiichi Sankyo's Datroway received approval from the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic EGFR-mutated NSCLC patients. This approval was granted under an accelerated pathway, and its full approval will depend on the final results of the confirmatory Phase III TROPION-Lung15 trial, expected to be released in 2026.

However, it is undeniable that the ADC field, both domestically and internationally, has become highly competitive. Once the concept of precise toxin delivery was validated in practice, it was only natural that numerous pharmaceutical companies would flock to this area. According to reports, in 2024, over 800 ADC drugs were in various stages of development globally, with 519 of them being domestic ADC projects in China. Among these 519 projects, 155 have entered clinical trials. Although the figures "800 (global) and 500+ (China)" include preclinical projects and thus represent a broader scope, the intense competition in ADC drug R&D remains an undeniable fact.

In August 2024, an article published in Nature Reviews Drug Discovery, titled "The antibody–drug conjugate landscape," provided a more objective and detailed analysis of the current state of global ADC drug development.

Image source: 深蓝观

The article compiled global ADC research and development projects from registered IND filings to Phase III clinical trials, estimating approximately 180 related pipelines currently under investigation worldwide. Breaking it down more specifically:

The targets are predominantly focused on HER2, Trop2, Claudin-18, B7-H3, among others. Monoclonal IgG1 antibodies constitute the vast majority, while bispecific ADCs are also emerging continuously.

In terms of linkers, VC peptide linkers dominate as the mainstream choice (the most commonly used peptide sequence includes Valine-Citrulline, Val-Cit). Peptide-based linkers achieve selective cleavage through proteases (such as cathepsin B) highly expressed in tumor cells. The GGFG polypeptide linker is a special case among peptide linkers, serving as an enzyme-sensitive tetrapeptide linker. A typical example is Daiichi Sankyo's Trastuzumab Deruxtecan (T-DXd). The SMCC linker, belonging to the non-cleavable linker category, demonstrates extremely high stability in plasma, with payload release relying on the complete degradation of the antibody in lysosomes after cellular internalization. The most classic example is Trastuzumab Emtansine/Kadcyla (T-DM1). The metabolites of such ADCs (e.g., Lys-SMC-DM1) often carry charges and exhibit poor cell membrane permeability, thereby lacking significant bystander effects.

Regarding mechanisms of action (MoAs), currently approved ADC payloads encompass three cytotoxic MoAs—anti-mitotic tubulin inhibitors, DNA alkylating agents, and topoisomerase 1 inhibitors.

Breaking Through "Involution": Technological Iteration and Renewal

Naturally occurring biological targets cannot be patented. Pharmaceutical companies can only seek patent protection for their specific molecular structures, amino acid sequences, or particular linker compounds. This regulatory approach not only encourages new entrants to continuously iterate and innovate in drug and technology development but also helps protect the existing research achievements of pharmaceutical companies.

Amidst the "involution" phenomenon—characterized by intense competition in popular targets and closely contested new targets—the current trend of "anti-involution" has emerged. However, strategies aimed at establishing "franchises" or "monopoly dominance" are clearly unsuitable for the field of new drug development. While large pharmaceutical companies possess advantages such as extensive sales networks, brand influence, and mature distribution channels, the adoption of drugs has always prioritized "clinical efficacy." Once a new drug demonstrates significantly superior "hard metrics" like ORR, OS, or PFS compared to existing treatments, clinical practice will inevitably favor the newer and more effective option from a patient-benefit perspective.

From this viewpoint, successful innovation in the new drug development industry can be decentralized and "distributed," rather than necessarily "centralized." It also follows that the path to "anti-involution" in this field has always been through technological iteration and renewal.

Focusing specifically on the ADC domain, many pharmaceutical companies have already begun developing "next-generation ADCs":

Bispecific ADCs and combination therapies (with PD-(L)1 inhibitors, CTLA-4 antibodies, or radiotherapy) have become standard in the second-tier pipelines of many ADC drug developers due to their clear mechanisms and pathways. More fundamental technological advancements—such as innovations in conjugation techniques (site-specific conjugation: cysteine site-specific modification, enzymatic conjugation, glycan site-specific conjugation), experimentation with novel linkers, new cytotoxic payloads, and more uniform drug-to-antibody ratios (DAR)—have also become highlights for companies to differentiate themselves at academic conferences. Ultimately, however, these innovations must be validated through "clinical outcomes."

Another frontier in ADC research involves payload release mechanisms that do not rely on endogenous enzyme-mediated cleavage. For instance, ADCs designed to activate in the tumor microenvironment (e.g., low pH or high GSH levels) via linker cleavage face the challenge of balancing efficacy and toxicity. As ADC drugs circulate systemically, they must ensure that the pH levels in other organs or tissues do not overlap with the targeted tumor microenvironment. This presents significant potential risks, given the variability in patients' internal environments.

Preclinical antibody-drug conjugates like TGW101 from TagWork, which employ exogenous chemical activators to induce payload release, may offer another promising avenue.

Additionally, integrating proteolysis-targeting chimeras (PROTACs) into ADC structures to form PROTAC-ADC complexes, along with novel conjugation technologies such as PDCs and RDCs, represents an active area of exploration.

Outlook

China's biopharmaceutical industry has rapidly risen to prominence in the global drug licensing landscape. The number of related transactions in China surged from 55 in 2015 to 213 in 2024, while the total transaction value skyrocketed from $3.1 billion to $57.1 billion during the same period, significantly outpacing global market growth.

In the specific field of antibody-drug conjugates (ADCs), transactions originating from China grew to $10 billion in 2024. Over the past decade, 19 ADC transactions from China have each exceeded $1 billion in value.

Currently, most approved indications for ADC drugs are for late-line treatments (patients who have failed or relapsed after chemotherapy/targeted therapy/immune checkpoint inhibitor therapy). Clinical trials extending ADC drugs to "first-line" treatment not only validate the achievements in drug design and R&D capabilities but also represent a crucial pathway to expanding the eligible patient population.

The ESMO 2025 Annual Meeting (European Society for Medical Oncology) confirmed the potential of ADC drugs to extend from "later-line" to "first-line" treatment: The TROPION-Breast02 (datopotamab deruxtecan/Datroway, Dato-DXd, AstraZeneca/Daiichi Sankyo) Phase III trial demonstrated for the first time that a TROP2-targeting ADC significantly reduced the risk of death in previously untreated advanced triple-negative breast cancer (TNBC) patients ineligible for immunotherapy, achieving dual benefits in overall survival (OS) and progression-free survival (PFS). This provides a new chemotherapy-free option for such patients.

The ASCENT-03 (sacituzumab govitecan/Trodelvy, Gilead/Immunomedics) Phase III trial also simultaneously met its primary endpoints for PFS and OS, reaffirming the value of TROP2-targeting ADCs in first-line TNBC treatment.

Once "first-line" treatment becomes the mainstream in clinical design and marketing applications for ADC drugs, these therapies are poised to occupy positions on the global top 10 sales rankings. Compared to cell therapies like CAR-T, ADC drugs involve standardized production processes and do not require the complex personalized steps of blood extraction, cell isolation, modification, and reinfusion. Meanwhile, the clinical efficacy of ADC drugs has already proven remarkable.

Conclusion

Biopharmaceutical research and development is an extremely rigorous science: no matter how innovative a drug design concept may seem, how exceptional the team is, or how influential the endorsements from key opinion leaders, all ultimately yield to clinical outcomes.

This is why "clinical data review" constitutes a highly specialized and critical regulatory task. Pharmaceutical companies, as participants in the field, always have an incentive to cut corners. Instances of data tampering or concealing adverse effects have occurred both in the United States and domestically. Transportation, food safety, and drug regulation and review are all heavily regulated industries. These three sectors share a commonality: once an incident occurs, the consequences are severe—fatal traffic accidents, toxic milk powder, and counterfeit drugs (ineffective drugs delay treatment, while harmful or toxic drugs directly exacerbate patients' conditions). Among these heavily regulated industries, drug regulation demands the highest level of professionalism and expertise from regulatory personnel.

It can be said that drug regulation shoulders the immense responsibility of safeguarding public health. If rigorous science yields to personal connections, the influence of key opinion leaders, or "online sentiment," then scientific rigor will be compromised, the drug R&D industry will cease to exist, and public health will ultimately be endangered in the long run.

All rational and responsible regulatory bodies and pharmaceutical companies understand the principle of "acting for the long term."

For example, in June 2025, Daiichi Sankyo’s Datroway achieved a milestone in expanding its indications for non-small cell lung cancer (NSCLC), receiving accelerated (conditional) approval from the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic NSCLC patients with EGFR mutations. This accelerated approval was based on robust clinical data. According to the disclosed results from the single-arm, open-label TROPION-Lung05 study and supporting data from the Phase III TROPION-Lung01 trial in EGFR-mutated advanced or metastatic NSCLC patients, among 114 patients treated with Datroway, the objective response rate reached 45%, with a complete response rate of 4.4% and a partial response rate of 40%. The median duration of response was 6.5 months, demonstrating the clinical value of Datroway in later-line treatment.

In contrast, Gilead’s efforts to expand indications for Trodelvy faced setbacks. In January 2024, Gilead announced that its EVOKE-01 trial in pretreated NSCLC failed to achieve its primary endpoints of overall survival (OS) and progression-free survival (PFS). This study was a key trial for Trodelvy in the NSCLC field, leading Gilead to write down the asset value of Trodelvy by $2.4 billion in April 2024. In May 2024, another Phase III trial for Trodelvy also failed: Gilead announced that the confirmatory Phase III TROPiCS-04 study in locally advanced or metastatic urothelial carcinoma did not meet its primary endpoint.

No drug remains the "king" forever. Even a drug as dominant as Humira—which topped global sales from 2012 to 2020—saw its ranking decline to fourth in 2023 and fall out of the top 10 by 2024.

This decline is related to the expiration of Humira's core patents. In 2016, Humira's core patents in the U.S. market actually expired, and Amgen launched its adalimumab biosimilar shortly after. However, AbbVie delayed the market entry of adalimumab biosimilars in the U.S. until 2023 by filing lawsuits against biosimilar developers such as Amgen, Merck, Pfizer, and Novartis.

Humira's patents in China and Europe expired in 2017 and 2018, respectively. In these markets, adalimumab biosimilars have long been available. Consequently, starting in 2018, Humira's global sales growth stagnated to single digits.

Even without the 20-year patent protection period, new treatment modalities and novel drug molecules offering better clinical efficacy and fewer side effects can still iterate and replace existing drugs. The evolution of the top 10 global drug sales rankings from 2010 to 2024 reflects a significant transformation in the pharmaceutical industry: early dominance by small-molecule cardiovascular drugs like statins has gradually been supplanted by biological targeted therapies.

As a rising star in the field, ADC drugs have secured their "entry ticket" to the next wave of innovation through outstanding clinical "test scores." However, new treatment modalities are emerging (and may already be doing so) to replace ADC drugs and become the mainstay of the field in the more distant future.

Each wave of innovation is accompanied by breakthroughs over existing therapies, improved efficacy, and manageable safety profiles, as well as competition, pursuit, failures, and eliminations.

Virtually every ambitious drug R&D company aspires to catch the next wave—ideally, a few steps ahead of its competitors. Perhaps continuous iteration and relentless evolution remain the perpetual task for every pharmaceutical company.