DAC, ISAC, and Dual Payload ADC: Who Will Lead the Next Generation of ADC Technology Innovation?

If a few years ago, presenting a simple PowerPoint on the ADC field could impress without the need for future visions, cutting-edge technologies, or a vibrant pipeline forest, today, the ADC field requires substantial content to make an impact. This shift is attributed to advancements in industry technology and rising awareness. Data shows that from 2014 to 2024, both market size and the number of clinical pipelines in the ADC field have undergone qualitative changes, with a record 83 ADCs entering clinical trials for the first time in 2024.

Data Source: Beacon ADC

The question now is, what can still impress in the ADC field? Is it PDC or RDC? Is it cyclic peptide RDC or non-protein conjugates? Or is it the “fourth generation payload” that is expected to lead the next generation of ADC technology innovation?

In March 2025, Pfizer revealed during its ADC R&D investor event that, in addition to conventional ADC technology, it will focus on “developing next-generation payloads” as a key strategic layout, such as new Auristatin-based payloads or entirely new payloads (immune agonists + protein degradation agents + new toxins).

Data Source: Pfizer ADC Event

Historically, it seems that every transformation in the ADC field has been driven by advancements in “payloads.” So, what changes in payloads can we expect in the next ADC innovation?

The Path of Payload Upgrades

The principle of ADCs is straightforward: it combines the precise targeting of monoclonal antibodies with the powerful cytotoxicity of effective payloads to achieve highly targeted cancer treatment. Among these, the payload is a key factor determining the efficacy, safety, and treatment range of ADCs, receiving significant attention from the industry.

Since the 1950s, when ADC technology officially entered the drug development era, the effective payloads of ADCs have undergone three major transformations driven by increasingly mature technologies.

First Generation: Traditional Chemotherapeutic Agents (1950s–1990s)

Initially, the selection of ADC payloads primarily included traditional chemotherapeutic agents such as Methotrexate and Vinblastine. However, due to insufficient clinical efficacy (lack of cytotoxicity), poor targeting, and low accumulation rates in target cells, these approaches ultimately led to clinical failures.

Second Generation: Novel Highly Cytotoxic Compounds (2000s–2010s)

To address the shortcomings of the first generation’s cytotoxicity, the second generation of payloads selected novel toxic compounds such as microtubule inhibitors, which can be up to 1000 times more effective than traditional chemotherapeutic agents. However, such high cytotoxicity can lead to unacceptable side effects when used as a single agent for cancer treatment, including strong anti-proliferative activity, neurotoxicity, and gastrointestinal reactions.

When these compounds were applied to ADCs, they showed promise because rapidly dividing tumor cells are more sensitive to microtubule inhibitors, and the sufficient targeting significantly reduced damage to normal tissues. However, later developments were limited because these compounds primarily acted on dividing cells and were largely ineffective against resting tumor cells, with some drugs exhibiting dose-limiting toxicity due to the bystander effect.

Third Generation: DNA Damaging Agents and TOP1 Inhibitors (2010s–2020s)

The emergence of DNA damaging agents allowed for the possibility of targeting the entire cell cycle. These agents primarily damage DNA structures through double-strand breaks, alkylation, chimerization, and cross-linking, theoretically capable of killing both resting and dividing tumor cells. After lipophilicity optimization, their ability to kill solid tumors was significantly enhanced, with representative compounds including alkynes, topoisomerase I inhibitors, and pyrrolobenzodiazepines (PBD).

During this phase, the payload strategies of ADCs also began to differentiate:

One direction is “low DAR high toxicity,” with PBD as a typical representative. However, due to therapeutic window issues, this type of payload has limited clinical benefits.

The other direction is “high DAR low toxicity,” with camptothecin derivatives as a typical representative. The success of Enhertu and Trodelvy in this direction has made it the mainstream choice for ADC payloads today.

Overall, the technical evolution logic of the three generations of ADC payloads is very clear, transitioning from low-efficiency broad-spectrum toxicity to high-efficiency targeted killing, and then to full-cycle killing and multifunctional synergy. The iterative upgrades have always focused on improving the therapeutic window, with the core contradiction shifting from early “toxicity control” to today’s “overcoming resistance” and “adapting to complex tumor microenvironments.”

Specifically, in terms of industry, among the 15 approved ADC products, the effective payloads are mostly concentrated in the first and second generations, especially microtubule inhibitors and DNA damaging agents.

Rank	Pipeline Name	Brand Name	Original Manufacturer	Target	Payload	Approval Date
1	CMA-676	Mylotarg	Pfizer	CD33	Calicheamicin	2000.05
2	SGN-35	Adcetris	Seagen Inc; Takeda	CD30	MMAE	2011.08
3	T-DM1	Kadcyla	ImmunoGen Inc; Genentech	HER2	DMI	2013.02
4	CMC-544	Besponsa	Hercules (Suzhou) Pharmaceutical Co., Ltd; Pfizer	CD22	Calicheamicin	2017.08
5	CAT-8015	Lumoxiti	Medimmune LLC; AstraZeneca	CD22	Pseudomonas	2018.09
6	RG7596	Polivy	Roche	CD79b	MMAE	2019.07
7	ASG-22CE	Padcev	Seagen Inc; Astellas Pharma	Nectin-4	MMAE	2019.12
8	DS-8201	Enhertu	Daiichi Sankyo; AstraZeneca	HER2	Dxd	2019.12
9	GS-0132	Immunomedics Inc	Immunomedics	Trop-2	SN-38	2020.04
10	GSK-2857916	Blenrep	GlaxoSmithKline	BCMA	MMAF	2020.08
11	ASP-1929	Akalux	Rakuten Medical Inc	EGFR	IRDye700DX	2020.09
12	ADCT-402	Zynlonta	ADC Therapeutics SA	CD19	SG3199	2021.04
13	RC48	Aidixi	Rongchang Biopharmaceutical (Yantai) Co., Ltd	HER2	MMAE	2021.06
14	TIVDAK	Tivdak	Genmab A/S; Seagen Inc	Tissue factor	MMAE	2021.09
15	TAK-853	ELAHERETM	ImmunoGen Inc	Fra	DM4	2022.11

Data Source: Public Data Compilation

In the clinical phase, Beacon’s annual review and outlook on ADCs mentioned that among the 3100+ drug conjugates tracked, 1850 are traditional ADCs, 450 are targeted radiopharmaceuticals (TRP), and only 207 are antibodies conjugated with novel payloads (such as oligonucleotides, degradation agents, or dual payloads), accounting for 7%.

Data Source: Beacon ADC

This indicates a significant lack of innovation in ADC payloads, with severe product homogeneity in older technologies. The effective targets in the ADC field in 2022 and 2023 were dominated by microtubule inhibitors, while 2024 saw a sudden shift to topoisomerase inhibitors as the mainstream.

In the future, developing more ideal payloads may become one of the primary tasks in the ADC field.

Next-Generation Payloads: New ADC Payload Strategies

First, it is essential to clarify that the update and iteration of payloads will never stop. Even the currently mainstream topoisomerase inhibitors are not perfect and still have many clinical limitations, such as side effects and resistance issues.

Therefore, developing more ideal ADC payloads remains the ultimate pursuit of the ADC industry, leading to the emergence of many concepts related to fourth-generation payloads, such as protein degradation-targeting chimeric molecules (PROTACs) introducing new tumor-killing mechanisms, immune modulators utilizing the power of the immune system to target tumor cells, and dual payloads addressing the inherent heterogeneity of tumors.

Although most new payload strategies currently have limited clinical data, existing data show their potential for stronger efficacy and higher therapeutic indices (TI), while these new methods also indicate the direction for the next development of ADCs.

Targeted Protein Degradation (DAC)

The main challenge in ADC development lies in balancing efficacy and off-target toxicity. Using targeted protein degradation agents as ADC payloads differs from inhibition mechanisms; it primarily involves E3 ligases, leading to the ubiquitination and subsequent degradation of the target protein (POI).

Data Source: Yao Research Network

Moreover, since DAC combines the catalytic properties of PROTACs with the tissue specificity of ADCs, it can effectively degrade target proteins at lower doses, overcoming the targeting deficiencies of degradation agents and the toxicity limitations of high-toxicity ADCs, showing great potential in targeting new sites.

As the effectiveness and safety advantages of DAC continue to be discovered, global pharmaceutical companies are gradually entering the race for DAC drugs.

• In September 2023, Nurix Therapeutics announced a new strategic collaboration with Seagen, involving a $60 million upfront payment and $3.4 billion in milestone payments to advance a new class of drugs called antibody-drug conjugated protein degradation agents (DAC) for cancer treatment.

• In November 2023, Bristol-Myers Squibb announced an agreement to acquire the potential “first-in-class” antibody-drug conjugated protein degradation agent ORM-6151 for approximately $180 million.

• In December 2023, Merck entered into an exclusive licensing and collaboration agreement with C4T to develop antibody-drug conjugated protein degradation agents (DAC), involving a $10 million upfront payment and $600 million in milestone payments. In this collaboration, C4T is responsible for developing effective components of protein degradation agents during the discovery phase, while Merck is responsible for antibody conjugation to construct DAC and subsequent clinical and commercialization efforts.

• In February 2024, Firefly Bio, founded by Nobel Prize-winning professor Carolyn Bertozzi, announced the completion of a $94 million Series A financing to develop a protein degradation conjugated drug (DAC) platform that uses potent catalytic protein degradation agents as ADC payloads, combining the advantages of antibody-drug conjugates (ADC) and protein degradation therapies while overcoming potential challenges associated with the combination of the two modalities.

Although DAC is still in the preliminary development stage and not fully validated compared to mainstream innovative therapies, the verification of its numerous advantages has led well-known pharmaceutical companies such as Merck, BMS, and Genentech to seek winning opportunities in this field.

Data Source: BoYao DAC Article (click to view larger image)

In recent years, the development of DAC has accelerated, with numerous MNCs and biotech companies vying to take the lead in this field. However, the lack of clinical validation for PROTACs has posed significant challenges to drug development (e.g., ARV-471 clinical phase III data was unsatisfactory), indirectly affecting the DAC field. As research in foundational technology deepens, DAC development may experience a renewed acceleration.

Immune Modulators (ISAC)

In recent years, discussions about payloads have often referred to certain cytotoxic drugs or tumor-killing agents. However, with advancements in basic medical research, another effect has gradually been attempted in the ADC field: immunogenic cell death (ICD).

As immune modulators, the immune-stimulating antibody conjugates (ISACs) have unique effects compared to traditional ADCs in terms of mechanism of action, target selection, and endocytosis:

• In terms of mechanism, immune-stimulating ADCs resemble bispecific antibodies, acting as small molecules that enhance immune responses while the tumor-targeting antibodies reduce the toxicity of small molecule immune stimulators.

• In target selection, traditional ADCs must strictly limit tumor-specific antigens due to the use of toxins, while immune-stimulating ADCs can extend to more tumor-associated antigens.

• In endocytosis, traditional ADCs mediate endocytosis through target antigens to directly kill cancer cells, while immune-stimulating ADCs activate immune cells through Fc-mediated endocytosis.

In summary, traditional ADCs directly kill cancer cells, while immune-modulating ADCs activate immune cells, achieving more complex targeting strategies and offering numerous advantages over traditional ADCs:

• Antitumor responses can target various damage-associated molecular patterns (DAMPs) related to tumors.

• They can activate not only antigen-presenting cells but also other tumor-infiltrating immune cells, such as T cells.

• They can induce immune memory effects that span the entire cellular immune response, providing lasting antitumor effects and reducing the risk of recurrence.

Today, the combination of precise targeting and powerful modulation technologies opens new frontiers in cancer treatment. This direction is developing rapidly, with various new immune-modulating ADC drugs under investigation. Current research progress includes Toll-like receptor (TLR) agonists and stimulator of interferon genes (STING) molecules as effective payloads.

Currently, several biotech companies globally are involved in ISAC, attracting major MNCs such as Takeda and Novartis to enter the field. Domestic companies, including HengRui, BeiGene, Qide Pharma, JAKS, and Innovent Biologics, are also making strides in this area, with the potential to lead globally.

Category	Drug Name	Target	Indications Under Investigation (Total)	Original Manufacturer	Global Highest Phase	Update Date
Toll-like receptor (TLR) agonists	SBT-6290 (failed)	NECTIN4; TLR8	Triple-negative breast cancer; breast cancer; head and neck squamous cell carcinoma; urothelial carcinoma; non-small cell lung cancer	Silverback	Clinical Phase II	2022-01-13
BDC-1001 (failed)	HER2; TLR7; TLR8	Breast cancer; solid tumors; cancer	Bolt Biotherapeutics; BMS	Clinical Phase II	2024-05-14
TAC-001	CD22; TLR9	Solid tumors	Tallac Therapeutics	Clinical Phase II	2022-05-19
GQ-1007	HER2; TLR7; TLR8	Solid tumors	Borui Biotech; Qide Pharma	Clinical Phase I	2022-03-31
SBT-6050 (failed)	HER2; TLR8	Solid tumors	Silverback	Clinical Phase I	2020-06-29
NJH-395 (failed)	HER2; TLR7	Cancer	Novartis	Clinical Phase I	2018-09-04
IBI-3007	TACSTD2; TLR7; TLR8	Solid tumors	Innovent Biologics	Clinical Application	2024-12-19
SBT8230	ASGR1; TLR8	Chronic hepatitis B	Silverback	Preclinical	Toll-like receptor (TLR) agonists
TAC-002	SHPS-1; TLR9	Solid tumors	ALX Oncology; Tallac Therapeutics	Preclinical	Toll-like receptor (TLR) agonists
BDC-2034	CEACAM5; TLR7; TLR8	Solid tumors	Bolt Biotherapeutics	Preclinical	Toll-like receptor (TLR) agonists
BDC-4182	CLDN18; TLR7; TLR8	Tumors	Bolt Biotherapeutics	Preclinical	2024-11-12
Stimulator of Interferon Genes (STING)	TAK-500 (failed)	CCR2; STING	Solid tumors	Takeda	Clinical Phase II	2021-09-24
XMT-2056 (failed)	HER2; STING	Breast cancer; solid tumors; gastric cancer; metastatic liver cancer	Mersana Therapeutics; GlaxoSmithKline	Clinical Phase I	2023-03-13
IMD-2739	STING	Solid tumors	Affinity Biosciences	Preclinical	2023-03-01
JAB-BX400	HER2; STING	Solid tumors	JAKS	Preclinical	2022-09-06
IMGS-501	PD-L1; PD-L2; STING	Tumors	ImmunoGenesis	Preclinical	2022-01-13
XMT-2068	STING	–	Mersana Therapeutics	Preclinical	2022-01-13

Data Source: Yaozhi Data, Yaozhi Consulting Compilation

Additionally, during this rapid development phase of ISAC, several clinical ISAC drugs have failed, forcing a cooling of the research enthusiasm in this field. Fortunately, after setbacks faced by companies like Silverback, Bolt Biotherapeutics, and Novartis, domestic companies such as HengRui, BeiGene, Innovent Biologics, and Qide Pharma are still actively laying out ISAC pipelines, potentially injecting new research momentum into the industry.

Overall, ISAC development is still in a very early stage. While the concept is clear, it is challenging to overcome the dose escalation hurdle in clinical trials. Moreover, the development of TLRs, STING, and other agonists often comes with narrow therapeutic windows and systemic toxicity issues, making it more difficult to control the therapeutic window compared to ADCs.

Dual Payload ADC

Although ADCs currently show potential in various tumor diseases, tumor heterogeneity and resistance remain the biggest challenges in this field. The former can lead to persistent recurrence and metastasis of tumors, while the latter can result in aggressive tumor growth and low survival rates. Most ADC research aims to overcome these obstacles, and dual payload ADCs may be a potential solution.

Dual payload ADCs integrate two different effective payloads, combining the mechanisms of multiple cytotoxic drugs to leverage their synergistic effects, simplifying treatment regimens while potentially overcoming resistance in tumor patients who are insensitive to treatment.

In early studies in this field, Levengood and others developed a dual payload ADC that utilized a single linker to connect both monomethyl Auristatin E (MMAE) and monomethyl Auristatin F (MMAF). Subsequent experiments demonstrated that this dual payload ADC exhibited significantly higher activity in a mouse xenograft model of CD30 multidrug-resistant anaplastic large cell lymphoma (ALCL) compared to ADCs with only MMAF or MMAE.

As more related research delves into this area, numerous similar studies have achieved breakthrough progress, establishing several different payload combinations and gradually industrializing dual payload ADC technology, with multiple drugs entering clinical trials:

• DNA Damage + Repair Inhibition: Topoisomerase I inhibitors (Topo1i) induce DNA breaks, while ATR inhibitors (ATRi) or PARP inhibitors (PARPi) block damage repair.

• Cytotoxicity + Immune Activation: Cytotoxic payloads kill tumor cells and induce immunogenic death, while STING agonists activate the immune microenvironment for long-lasting antitumor responses.

Pipeline	Original Manufacturer	Target Antigen	Payload 1	Payload 2
ADC2202	Adcoris Biopharmaceutical	HER2	/	/
ADC2192	Adcoris Biopharmaceutical	TROP2	/	/
CB-120	CrossBridge Bio	TROP2	Top-i (Exatecan)	ATR inhibitor
BR113	BioRay	TROP2	Top-i inhibitor	Immune stimulator
JSKNO21	Alphamab	/	/	/
JSKN023	Alphamab	/	/	/
HMBD-802	Hummingbird Bioscience; Callio Therapeutics	HER2	Top-i	ATR inhibitor
CATB-101	Catena Biosciences	/	/	/
CATB-102	Catena Biosciences	/	/	/
NBD14	Celltrion	–	–	–
BsAD2C	Baosai Tu; Yushibo	Bispecific Antibody	/	/
TJ 102	Tuojimedic	/	/	/
/	Mersana	/	MTAs (Auristatin)	PBDS
/	Hummingbird	/	Top-i inhibitor	/
/	Sutro Biopharma	/	TLR agonist	/
/	BrickBio	/	/	/
/	Medilink	HER2	Top-i inhibitor	Eribulin
/	Qide Pharma	TROP2	Top-i	Immune stimulator
/	Qide Pharma	HER3	Top-i	EGFR Tki
/	Ohio State University	B7-H3	MTAS (MMAF)	TLR7/8
/	Araris Biotech	NaPi2b	Top-i (Exatecan)	Top-i
/	Huaou Biotech	/	/	/
/	Xilingyuan Pharmaceutical	/	/	/
/	Innovent Biologics	/	/	/
/	Innovent Biologics	/	/	/

Data Source: ApexOnco, “ADC Payloads: Past, Present & Future” and other public data compilations

On the other hand, as dual payload ADC technology enters the industrialization phase, the capital market has begun to focus on this field, with some biotech companies specializing in this area receiving financing support.

• On March 3, Callio Therapeutics announced the completion of $187 million in Series A financing, primarily to achieve clinical concept validation for its HER2-targeting dual payload ADC and a second undisclosed ADC project. Callio Therapeutics is developing next-generation multi-payload ADCs that utilize differentiated payloads and linker technologies to maximize therapeutic effects by targeting multiple payloads to tumor cells.

• On November 4, 2024, CrossBridge Bio announced the completion of a new round of financing of $10 million to advance its innovative TROP2 dual payload ADC drug CBB-120 into IND stage development. CrossBridge Bio is a preclinical-stage biotechnology company based in Houston, dedicated to developing advanced antibody-drug conjugates (ADCs) for various cancers.

Overall, dual payload ADCs represent an important iterative direction for ADC technology, with their core value lying in overcoming tumor heterogeneity and resistance through multiple mechanisms. Although they still face challenges related to technical complexity and safety, breakthroughs in foundational technologies such as linkers and antibody engineering, along with the accumulation of clinical data, are expected to position them as a crucial component of combination therapy strategies in solid tumor treatment.

Of course, in addition to DAC, ISAC, and dual payload ADCs, there are many other directions for the iteration of ADC payloads, such as ADCs using HSP90 inhibitors or translation inhibitors as effective payloads, which not only differ in their antitumor mechanisms from traditional ADCs but also possess broad-spectrum, high activity, and high selectivity characteristics.

It is foreseeable that as long as ADC drug forms remain popular, the industry’s pursuit of more ideal payloads will not cease. Although the road is long and challenging, it is worth looking forward to.

Conclusion

The ADC field has experienced rapid technological advancements and increased awareness in recent years, particularly in the innovation and development of effective payloads. From the initial traditional chemotherapeutic agents to today’s diverse payload strategies, ADC technology has undergone four significant transformations, each centered around the upgrade of “payloads.”

It is evident that the continuous iteration of ADC technology is driven by innovations in effective payloads.

From the first generation of traditional chemotherapeutic agents as payloads to the later mainstreaming of topoisomerase inhibitors, the rapid development has involved enhancements in lethality, full-cycle killing, and multifunctional synergy, with the core contradiction gradually shifting from “toxicity control” to “overcoming resistance” and “adapting to complex tumor microenvironments.”

In the face of new challenges, the ADC field is actively exploring next-generation payload strategies, where protein degradation agents (DAC) address the targeting deficiencies of degradation agents and the toxicity limitations of ADC drugs; immune modulators (ISAC) offer more complex targeting strategies and lasting antitumor effects; and dual payload ADCs combine multiple cytotoxic drug mechanisms to attempt to overcome tumor heterogeneity and resistance issues.

In summary, the ADC field is continuously emerging with various development models, and the pursuit of more ideal payloads has never ceased. In the future, with ongoing technological advancements and the accumulation of clinical data, ADCs are expected to play an increasingly important role in cancer treatment, bringing more hope and benefits to patients.

Source | BoYao (Authorized Reprint from Yaozhi Network)

Author | BoYao Content Center

Editor | Bajiao

Cooperation, Submission | Mr. Ma 18323856316 (same as WeChat)