Uncategorized Saturday, 2025/08/23
Dual Payload ADCs aim to enhance drug activity, produce synergistic effects, improve therapeutic efficacy, expand indications, and overcome resistance challenges by simultaneously attaching two payloads with different mechanisms (or different linker forms of the same payload) to a single antibody, allowing flexible modulation of the total drug-to-antibody ratio (DAR).
Currently, two dual payload ADCs have entered clinical trials for cancer treatment, with dozens of candidates in preclinical development.
The activity in this field is evident from the dynamic financing landscape: Startup Callio Therapeutics successfully raised $187 million this year to advance its dual payload ADC pipeline. The company's Chief Scientific Officer, Jerome Boyd-Kirkup, stated, "This field is undergoing rapid evolution."
Table 1. Selected Dual Payload ADCs in Development
|
Project Name |
Company |
Target(s) |
Payload Mechanism(s) |
Current Status |
|---|---|---|---|---|
|
KH815 |
Chengdu Kanghong |
TOP1 inhibitor + RNA polymerase II inhibitor |
Phase 1 |
|
|
CATB-101 |
CatenaBio |
TOP1 inhibitor + tubulin inhibitor |
Preclinical |
|
|
TJ102 |
Phrontline Biopharma |
CDH6 × FRα |
TOP1 inhibitor + tubulin inhibitor |
Preclinical |
|
JSKN021 |
Jiangsu Alphamab |
EGFR × HER3 |
TOP1 inhibitor + tubulin inhibitor |
Preclinical |
|
ARC-201 |
Araris / Taiho |
NaPi2b |
Dual TOP1 inhibitors |
IND 2026 |
|
Undisclosed |
Araris / Taiho |
Dual TOP1 inhibitors + tubulin inhibitor |
IND 2026 |
|
|
DXC018 |
Hangzhou Dac |
TOP1 inhibitor + nucleoside analogue |
Preclinical |
|
|
STRO-00X / STRO-0OY |
Sutro |
Not disclosed |
TOP1 inhibitor + DDR inhibitor OR tubulin inhibitor |
IND 2027 |
|
CLIO-8221 |
Callio Therapeutics |
TOP1 inhibitor + ATR inhibitor |
Phase 1 2026 |
|
|
CBB-120 |
Crossbridge Bio |
TOP1 inhibitor + ATR inhibitor |
IND 2026 |
|
|
Undisclosed |
Sutro / Astellas |
Not disclosed |
TOP1 inhibitor + immune agonist |
Preclinical |
|
QHL-1096 |
Affinity Biopharma |
Not disclosed |
TOP1 inhibitor + TLR7/8 immune agonist |
Preclinical |
|
BR-113 |
BioRay |
TOP1 inhibitor + immune agonist |
Preclinical |
|
|
IBI3020 |
Innovent |
Not disclosed |
Phase 1 |
|
|
ADC2192 |
Adcoris |
Not disclosed |
Preclinical |
|
|
ADC2202 |
Adcoris |
Not disclosed |
Preclinical |
|
|
AD2C-Oncology |
Acepodia |
Not disclosed |
Preclinical |
(Source: Nature Reviews Drug Discovery)
Chemotherapy Combinations First
Dr. Yonghao Zhao from the Biological Drug Research Institute of Chengdu Kanghong Pharmaceutical pointed out that existing ADC clinical data reveal its limitations: while they can significantly extend progression-free survival (PFS) in some cancer types, patients ultimately face disease progression.
Under the pressure of cytotoxic drugs, cancer cells can easily develop resistance by activating alternative signaling pathways or upregulating drug efflux pumps. Combination therapy is a classic strategy to overcome this challenge, and dual payload ADCs offer an innovative path for synergistic treatment through a single drug.
The advantage of dual payload ADCs is that tumor cells need to develop escape mutations for both inhibited pathways simultaneously, which is more challenging, potentially preventing the timely accumulation of sufficient resistance mutations.
The key question is: how to choose the paired payloads?
In current disclosed projects, topoisomerase I (TOP1) inhibitors (such as irinotecan and its derivative deruxtecan) are the preferred choice for the base payload due to their efficient DNA replication disruption mechanism.
Kanghong Pharmaceutical innovatively paired irinotecan with triptolide, an RNA polymerase II inhibitor derived from the herb Tripterygium Wilfordii, targeting transcription mechanisms. Both have nanomolar potency, which is crucial because ADC efficacy and tolerance are often limited by the weakest payload.
Considering that TROP2-targeting ADCs (such as sacituzumab govitecan and datopotamab deruxtecan) have more optimization space than mature HER2-targeting ADCs, Kanghong Pharmaceutical designed a differentiated structure: four irinotecan molecules are linked to the antibody Fab arm, and an average of 3.5 triptolide molecules are linked to the Fc region (DAR = 7.5).
The key is the differentiated linker design, allowing for timed controlled release of the payloads: the irinotecan linker is more stable, mainly cleaving after the antibody is internalized by tumor cells, achieving precise killing (the released free irinotecan also produces a bystander effect). The triptolide linker is designed to cleave in the tumor microenvironment, before internalization, rapidly clearing surrounding cancer cells and enhancing the overall bystander effect.
Preclinical studies show that the candidate KH815 exhibits significant activity in various resistant xenograft models, including those resistant to sacituzumab govitecan or datopotamab deruxtecan. Kanghong Pharmaceutical has commenced clinical trial patient recruitment for KH815.
Besides Kanghong Pharmaceutical, Innovent's CEACAM5-targeting dual payload ADC (IBI3020) has also entered clinical stages, although the specific payload combination has not been disclosed.
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Exploration of Triple Payloads
Dual payloads are not the end.
Araris is exploring ADCs with dual and even triple payloads. Their dual payload ADC targeting NaPi2b combines two TOP1 inhibitors, irinotecan and its derivative, with differentiated design to regulate the bystander effect: irinotecan plays the primary bystander role, while its low permeability derivative focuses on enhancing direct cytotoxicity within target cells.
Another triple payload ADC targeting Nectin-4 integrates two TOP1 inhibitors and the microtubule inhibitor MMAE. These two classes of payloads have been fully validated in Nectin-4 targeting applications. The immunogenic cell death (ICD) characteristic induced by MMAE also provides potential for combination with immune checkpoint inhibitors. Notably, combining TOP1 inhibitors with microtubule inhibitors (such as MMAE) is a research focus for many companies.
Linker technology is crucial to the success of such complex ADCs. Araris uses unique branched peptide linker technology, conjugating all payloads to specific glutamine sites on the antibody through a single hydrophilic linker. This design maintains ADC stability, effectively shields hydrophobic payloads, and reduces off-target uptake. Its optimized cleavage kinetics prevent instantaneous payload release post-internalization. In March 2025, Taiho Pharmaceutical, a subsidiary of Otsuka Pharmaceutical, acquired Araris for $400 million, fully recognizing the value of its linker platform.
Expanding Novel Payload Combinations
Some companies are breaking away from traditional chemotherapy payloads, exploring novel combinations with greater mechanistic synergy. Notably, the combination of drugs targeting the DNA damage repair (DDR) pathway with TOP1 inhibitors is receiving attention.
The scientific rationale is that tumor cells often gain resistance by upregulating the DDR pathway to repair DNA damage caused by TOP1 inhibitors; conversely, inhibiting DDR renders tumor cells abnormally sensitive to TOP1 inhibition. ATR, as a key regulator of DDR, emerges as a promising combination target with selective cytotoxicity to tumor cells.
Callio Therapeutics' HER2-targeting dual payload ADC CLIO-8221 (HMBD-802) embodies this strategy, with a 4+4 DAR combination of TOP1 and ATR inhibitors. High-dose experiments in non-human primates showed no unexpected synergistic toxicity. The company plans to initiate the first human trials in Q1 2026. This strategy holds promise for overcoming poor responses of HER2-low expressing tumors to existing ADCs.
CrossBridge Bio also focuses on the TOP1 and ATR combination. Through systematic free drug screening matrices, they identified the most synergistic pairing. Key in vivo experiments demonstrate their proprietary branched linker technology dual payload ADC achieved 100% response and maintained efficacy beyond 120 days in resistant models ineffective to datopotamab deruxtecan (benchmark ADC) and single payload ADC (50% response rate), showing significant advantage.
Additionally, Sutro is exploring the combination of TOP1 inhibitors with DDR inhibitors (specific targets undisclosed). Their AACR conference data indicated PARP inhibition can enhance the effect of TOP1 inhibitors.
Immunostimulation Strategy
Immunotherapy and ADCs are naturally complementary: the former has long-lasting effects but is limited by high tumor burden. The latter has strong tumor-reduction capability but faces resistance issues.
Dual payload ADCs provide the possibility of integrating cytotoxins and immune stimulators into a single molecule, aiming to create conditions for immunostimulants to activate the immune system through ADC tumor-reduction, achieving synergistic enhancement.
Despite explorations by companies such as Novartis and Tallac Therapeutics in the antibody-immune stimulator conjugate (ISAC) field, clinical breakthroughs are yet to be realized. Immunostimulatory dual payload ADCs (iADCs) represent the deepening of this concept. The collaborative project between Sutro and Astellas includes two such iADCs, one of which is undergoing preclinical toxicology studies required for IND submission.
Clinical Data Imminent
As the first dual payload ADCs enter clinical trials, human data will soon be revealed. The primary focus of phase I studies remains safety. The toxicity profiles of different payload combinations vary. For instance, both irinotecan and triptolide in Kanghong Pharmaceutical's KH815 pose risks of hematological toxicity (e.g., neutropenia), and their combined effects need close monitoring.
Moreover, response rate and durability are crucial efficacy indicators. It should be noted that the enormous variation in targets, payloads, indications, and linker designs among different dual payload ADCs means that the success or failure of a single project cannot be easily generalized to the entire field.
The diversity of linker strategies is particularly notable: Callio and CrossBridge use branched linkers; Sutro and Kanghong Pharmaceutical design independent linkers for different payloads; Araris merges the strengths of both. These designs directly affect ADC stability, cleavage kinetics, production feasibility, and ultimate fate. The interpretation of the initial clinical data should consider the specific technical route, and the results are worth anticipating.
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Reference
- Mullard, A. (2025). Dual-payload ADCs move into first oncology clinical trials. https://doi.org/10.1038/d41573-025-00121-y