DACs share a similar structure and mechanism with ADCs, both consisting of an antibody, a conjugation site, a linker, and a payload. A DAC achieves the selective degradation of specific intracellular target proteins by conjugating a Targeted Protein Degrader (TPD) to an antibody.

The key difference is that ADCs typically use small-molecule toxins, whereas the core payload of a DAC is a PROTAC or molecular glue. Its mechanism of action is to induce the ubiquitination and proteasomal degradation of target proteins, rather than directly killing cells.

Generally speaking, the cell-killing potency of TPD molecules is weaker than the traditional toxins used in ADCs. To achieve therapeutic efficacy, DACs often require a higher Drug-to-Antibody Ratio (DAR). On the other hand, the higher payload loading and the larger molecular weight of protein degraders themselves impose more stringent requirements on linker technology and the in vivo stability of the antibody.

In 2017, Genentech filed the first patent related to DACs. In 2020, Genentech researchers first detailed a DAC molecule targeting the BRD4 protein in a paper, completing the first Proof of Concept (POC) in the DAC field.

Subsequently, this emerging technology entered the industry's spotlight, and the DAC sector began to heat up. Particularly in 2023, a flurry of DAC-related deals emerged. In addition to the aforementioned Hezheng Pharmaceutical, multinational corporations (MNCs) such as Pfizer and BMS chose to build their presence by in-licensing pipelines at this time.

In September 2023, Nurix Therapeutics announced a collaboration with Seagen, a pioneer in ADC therapy (since acquired by Pfizer), to co-develop an anti-cancer DAC. Under the terms, Nurix received a $60 million upfront payment and is eligible for up to approximately $3.4 billion in research, regulatory, and commercial milestones across multiple programs, plus tiered royalties on future sales.

In November of the same year, BMS in-licensed ORM-6151 from Orum Therapeutics for a total transaction value of $180 million. ORM-6151 is a GSPT1 degrader targeting CD33, which had already received FDA approval for a Phase I clinical trial in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) at the time.

Orum is a pioneer in the DAC space, with 6 pipelines currently under development, including 2 clinical-stage and 4 preclinical projects.

Beyond its deal with BMS, in July 2024, Orum announced a collaboration with Vertex. The two parties will leverage Orum's proprietary Dual-Precision Targeted Protein Degradation (TPD²) technology to co-develop up to 3 novel DAC drugs.

Vertex will pay Orum a $15 million upfront payment and obtain global exclusive rights for each target. Additionally, Orum is eligible for up to $310 million in milestone payments per program, with a potential total deal value of $945 million. If the drugs are launched in the future, Orum will also receive tiered royalties based on global net sales.

In December 2023, Merck & Co. (MSD) entered into a $610 million collaboration agreement with C4 Therapeutics (C4T), including a $10 million upfront payment and $600 million in milestones, to jointly develop DAC drugs. C4T will be responsible for developing the active ingredients of the protein degraders during the discovery phase, while Merck will lead the antibody conjugation and oversee subsequent clinical development and commercialization.

According to data from the Wisdom 芽 New Drug Intelligence Database, there are currently 37 DAC-related pipelines worldwide, the vast majority of which are in preclinical or earlier stages, with only one project in Phase I clinical trials.

This means the arena for DACs has only just opened its doors, with plenty of open track. However, navigating this seemingly vast blue ocean is far from smooth sailing.

The primary challenge in DAC development is that a successful DAC requires an extremely delicate balance between DAR, linker stability, and internalization efficiency. This is no easy feat.

In April 2025, Orum announced the termination of clinical development for ORM-5029, its DAC drug targeting HER2 as a GSPT1 degrader. The decision stemmed directly from a serious adverse event in a Phase I trial, where a patient died from liver failure. Following the incident, Orum suspended patient enrollment and, after a comprehensive evaluation, ultimately decided to terminate the program.

This setback cast a shadow over the entire DAC sector, leading to a temporary lull in BD activity in the field.

AbbVie's DAC program, ABBV-787 (targeting CD33 for AML), also advanced to Phase I clinical trials. However, for strategic reasons, AbbVie decided to put the program on hold.

To address the patent cliff brought by Humira, AbbVie has made extensive investments in the ADC space in recent years. In comparison, the competitiveness and priority of its DAC pipelines appear insufficient.

In February 2024, AbbVie completed the acquisition of ImmunoGen, gaining Elahere, an ADC drug targeting FRα. This drug has already generated substantial cash flow for AbbVie, with sales revenue of approximately $508 million in the first three quarters of 2025.

Furthermore, on May 14, 2025, the FDA granted accelerated approval to AbbVie's ABBV-399 for the treatment of adult patients with previously treated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein expression. This is AbbVie's first approved ADC targeting c-Met.

AbbVie currently has at least 7 ADC programs in its portfolio, spanning from marketed products to late-stage clinical trials, covering therapeutic areas including oncology and autoimmune diseases. Against the backdrop of a robust ADC pipeline and established advantages, diverting significant resources to the less technically mature DAC field is not its current optimal strategic choice.

To date, the only clinically active DAC pipeline remaining globally appears to be ORM-6151 (BMS-986497), in-licensed by BMS from Orum, which is currently in Phase I clinical trials for relapsed or refractory acute myeloid leukemia.

Despite these setbacks, exploration in the DAC sector has not stopped. Orum remains a key driver in the DAC space.

Simultaneously with announcing the termination of ORM-5029, Orum revealed it is advancing the development of a next-generation DAC drug, ORM-1153. Also designed on its proprietary TPD² platform and targeting GSPT1, it aims to improve selectivity and broaden the therapeutic window.

At the 2025 ASH Annual Meeting, Orum presented the latest preclinical data for ORM-1153. The results showed that in comparative studies, the drug was approximately 1,000 times more potent than the unconjugated degrader and induced dose-dependent tumor regression in a disseminated AML xenograft model, with complete and durable responses achieved in the highest dose group.

Shifting our focus from the still-unplowed "experimental field" of DACs back to the main battlefield of ADCs, we find that competition here has entered a white-hot "arms race" stage.

According to the Wisdom 芽 New Drug Intelligence Database, there are as many as 20 approved ADC drugs globally, with over 2,000 ADC candidates in development.

Frost & Sullivan predicts that the global ADC market size will grow from $7.9 billion in 2022 to $64.7 billion by 2030, representing a compound annual growth rate (CAGR) of 30%.

This is a figure enough to quicken the pulse of any participant. Almost all MNCs have integrated ADCs into their core strategies. From oncology to autoimmunity, the "battlefield" of ADCs is expanding.

ADC-related deals have also surged. A research report from Southwest Securities noted that in 2025, domestic ADC drug BD deals secured $1.63 billion in upfront payments overseas, a year-on-year increase of 676.2%, with a total transaction value of $21.13 billion, a year-on-year increase of 390.6%.

The landscape of the ADC 1.0 era has been initially defined, with AstraZeneca/Daiichi Sankyo's Enhertu (DS-8201) leading by a wide margin. According to Daiichi Sankyo's latest financial report, on a calendar-year basis, Enhertu achieved global sales of ¥655.2 billion (approximately $4.373 billion) in 2025, a nearly 25% year-on-year increase, leaving other competitors far behind. With so many followers and such a clear leader, finding the direction for the next generation of iteration has become a necessity for survival.

The current limitations of ADCs are precisely the starting point for innovation.

Traditional ADC payloads are still dominated by conventional cytotoxic agents, which can easily lead to drug resistance in tumor cells. Second, there is the limitation of targets: drugs rely on antigens that are stably and highly expressed on the cancer cell surface and are easily internalized, but targets often suffer from insufficient expression or heterogeneity, leading to poor efficacy. Finally, there is the challenge of linker stability: excessive instability causes premature toxin release in the bloodstream, triggering systemic toxicity, while excessive stability may prevent effective release inside the cell, rendering the drug ineffective.

Therefore, the next generation of ADCs needs to solve three problems: expanding payload types, breaking through target limitations, and upgrading linkers.

In terms of payload innovation, the industry is no longer satisfied with traditional tubulin inhibitors (such as MMAE/MMAF) and is beginning to explore dual-payload strategies. By loading two "warheads" with different mechanisms of action, these aim to achieve a "1+1>2" therapeutic effect and circumvent cross-resistance.

For example, Kanghong Pharmaceutical's KH815 uses a payload combining a topoisomerase I inhibitor (TOP1i) and an RNA polymerase II inhibitor (RNA POL IIi), enabling multi-faceted tumor suppression. The drug has initiated a Phase I clinical trial in Australia.

Bispecific ADCs, on the other hand, enhance the specific capture and internalization efficiency of tumor cells by enabling the antibody to recognize two different tumor targets or epitopes simultaneously.

BioRay's BL-B01D1 (targeting EGFR/HER3), the world's first bispecific ADC to complete a Phase III clinical trial, is regarded as a benchmark in this direction. CStone Pharmaceuticals' JSKN-003 (a bispecific ADC targeting HER2) has also demonstrated high response rates and favorable safety in clinical studies and has advanced to Phase III.

Some players are even attempting the stacked innovation of "bispecific, dual-payload" ADCs.

On January 29th, Innovent Biologics' IND application for IBI3028, a bispecific dual-payload ADC, was approved for the treatment of locally advanced, unresectable, or metastatic solid tumors that have failed standard therapy. While the specific target combination and toxin type of IBI3028 have not been fully disclosed, it still marks a significant step forward for the bispecific dual-toxin technical route.

The linker determines the drug's stability in the bloodstream and its ability to be precisely cleaved and released within tumor cells, making its technological upgrade equally critical.

Domestically, Elpiscience Biologics' TMALIN platform features a unique toxin-linker design that enables ADC enrichment in the tumor microenvironment, increasing the proportion of payload in the tumor and plasma concentration, while offering a high therapeutic index. During JPM 2026, Sunjing Pharma launched its SG Linker-Payload technology platform.

Through a unique highly hydrophilic design, it addresses the bottlenecks of traditional ADCs at the molecular level, such as aggregation, poor stability, and high toxicity caused by the hydrophobic nature of toxins.

If we view the technological evolution of ADCs as a grand upgrade race, then DAC represents an imaginative and radical branch. Its path forward is filled with unknowns, yet it brings entirely new possibilities.

Today, the story of ADCs has long transcended the scope of a single technology, evolving into a narrative deeply intertwined with antibody engineering, linker chemistry, cell biology, and clinical medicine. Whether it is DACs, bispecific ADCs, dual-payload ADCs, or novel linker platforms, all these diverse technical pathways point toward the same ultimate goal: the pursuit of superior efficacy and higher safety.

The tide of hype may shift, but humanity's exploration of the mysteries of life and pursuit of health remain the most fundamental and enduring driving forces pushing technology forward. This race has no final destination, only constant evolution.