Looking for the next ten-billion-dollar ADC

In the field of oncology drugs, the birth of any phenomenal blockbuster drug is always accompanied by prosperity and hidden challenges.

With DS-8201, Daiichi Sankyo has pushed ADCs to new heights on its own, and made the Topo-1 inhibitor DXd the industry standard. In the first half of 2026, its global sales reached USD 2.961 billion (compared to USD 2.289 billion in the same period last year), with a quarterly growth rate still exceeding 30%; the industry consensus on its peak sales is to steadily exceed USD 10 billion, and even reach USD 15 billion.

This is an ADC legend destined to go down in history. However, the scale of this legend also defines the scope of the hidden challenges. As DS-8201 is being moved from later-line to earlier-line treatment, DXd-related drug resistance has become increasingly prominent. Existing studies show that even if the targets of the antibodies are different, the use of similar TOP1 inhibitor payloads may lead to significant cross-resistance after sequential administration, and continuous exposure to DXd may also bring the risk of cumulative pulmonary toxicity.

The more successful DS-8201 is, the larger the space left for drug resistance may be. The greater variable lies at the platform level: when more and more ADCs begin to share similar drug resistance mechanisms, what truly determines the upper limit of next-generation ADCs may no longer be the antibodies, but which party can take the lead in building a brand-new payload system. This is also the foundation for the birth of the next USD 10 billion ADC.

01

Payload Drug Resistance Is Becoming More Specific

The entire industry is searching for the next ADC with USD 10 billion in annual sales after DS-8201. However, payload-related drug resistance has become an unavoidable clinical reality.

ADCs have multiple sources of drug resistance: target downregulation, endocytosis disorders, drug efflux, and apoptosis pathway alterations may all affect efficacy, but the most concerning one is payload-related drug resistance. Especially after TOP1 inhibitors (DXd, SN-38) and microtubule inhibitors (MMAE, DM1) became the mainstream of ADC development, relevant drug resistance has become increasingly prominent.

Two Phase II studies presented at the ESMO Breast Cancer Congress this year further revealed that toxins are the main source of ADC drug resistance.

One of them is a study exploring the activity of HER3-DXd (patritumab deruxtecan) in metastatic breast cancer under different prior ADC exposure backgrounds. The results showed that in ADC-naive patients, the ORR of HR+/HER2− and TNBC subgroups was 39.3% and 25% respectively, with median PFS of 6.8 months and 3.0 months; however, in patients who had previously received TOP1i ADC, the ORR was only about 5%, with median PFS of approximately 2.6–3.0 months, and the HER2+ population previously treated with DS-8201 had almost no response, with median PFS of only 1.4 months.

HER3 has certain potential as an ADC target, but even if the ADC target is switched from HER2 to HER3, as long as the same DXd payload is retained, significant cross-resistance may still exist. In addition, the study also observed deaths related to interstitial lung disease (ILD).

The other SATEEN study explored the combination of sacituzumab govitecan (SG) and trastuzumab in HER2+ metastatic breast cancer that had failed prior DS-8201 treatment, and was terminated early because the pre-set endpoints were not met in the interim analysis of Phase II clinical trials. Specifically, in heavily pretreated patients who received a median of 5 lines of HER2-targeted therapy, the ORR of the combination regimen was only 3.7%, only 1 out of 27 patients had confirmed PR, and the median PFS was only 2.3 months.

In this clinical trial, switching from HER2-DXd to TROP2-SN38 combined with trastuzumab still failed to restore effective antitumor activity after sequential administration.

This cross-resistance is not difficult to understand at the mechanistic level. Studies have pointed out that both DS-8201 (DXd) and SG (SN-38) rely on the TOP1-DNA cleavage complex to induce replication stress, and share drug resistance pathways such as upregulation of efflux transporters ABCG2/BCRP, replication fork stabilization, reprogramming of DNA damage response, and altered TOP1 expression. Simply replacing the antibody target and retaining a similar payload backbone may not fundamentally restore drug sensitivity.

Although ADCs have pharmacokinetic properties similar to antibodies/proteins, it is the payload that ultimately exerts tumor-killing effects. From this perspective, it is not unexpected that payloads determine drug resistance.

02

MNCs Are Accelerating Layouts

To bypass drug resistance, the industry has proposed many solutions, the most popular of which are bispecific ADCs and dual-payload ADCs.

Bispecific ADCs solve problems at the target end by binding two targets at the same time and improving endocytosis efficiency; but at the effector end, if the mounted payloads are still DXd or MMAE, once tumors evolve efflux pumps (such as P-gp/MDR1), transporter mutations or apoptosis pathway blockade, bispecific antibodies may not be able to solve toxin-level drug resistance.

Dual-payload ADCs go a step further, attempting to mount two toxins with different killing mechanisms on the same antibody. Compared with single-toxin ADCs, they can cover more patients, and may provide a better treatment option for some patients with drug resistance. However, the safety of dual toxins is more critical: if the PK/PD metabolism of the two toxins in the body cannot be synchronized, it is more likely to lead to superimposed toxicity.

Starting from the underlying logic of solving toxin resistance, novel payloads with brand-new killing mechanisms are regarded as an important development direction of next-generation ADCs, and are becoming scarce strategic assets that MNCs are competing to seize.

The most typical example is Novartis, which once claimed that "ADCs are not worth investing in". In July, Novartis acquired British biotech company Myricx Bio for USD 1.1 billion in cash upfront plus up to USD 400 million in milestone payments, for a total consideration of up to USD 1.5 billion. Its core asset is N-myristoyltransferase (NMT) inhibitors, which block the lipid modification of membrane proteins essential for tumor survival, with a mechanism of action different from DNA damage and microtubule inhibition. Preclinical data shows that NMTi payloads still exert strong efficacy in models with high DXd resistance.

Recently, Genentech, a subsidiary of Roche and a global pioneer in ADCs, reached a deal with Inkstone Bio, which also values the underlying logic of anti-TOP1i drug resistance. The two parties reached a cooperation on the development of next-generation ADCs based on Inkstone's DUPAC new payload platform: Inkstone received USD 45 million in upfront payment and over USD 1 billion in milestone payments, to generate and develop ADCs against oncology targets specified by Genentech. Inkstone will lead the discovery and early global clinical development of the cooperative projects, and Genentech will obtain exclusive global licenses after the completion of the Phase 1a clinical trial.

DUPAC covers multiple payloads with novel mechanisms such as DUP5, DUP9, and DUP10. Each payload is designed based on a unique anti-tumor mechanism, and is paired with optimized, matching linker technology. Preclinical data of ADCs based on DUP5 and DUP9 payloads have been presented at conferences including AACR 2025, AACR-NCI-EORTC 2025 and AACR 2026, including activity data in topoisomerase inhibitor-insensitive models and tolerability data in non-human primates.

Earlier in April, CrossBridge Bio was acquired by Eli Lilly. Its core candidate CBB-120 is a TROP2-targeting dual-payload ADC loaded with both a TOP1 inhibitor and an ATR inhibitor, which is expected to submit an IND application in 2026. The two mechanisms create DNA damage while cutting off the path for tumor cells to repair the damage, aiming to improve the therapeutic index, prolong efficacy, and raise the threshold of drug resistance.

MNCs are intensively deploying heavy resources in the field of non-Topo-1 payloads.

03

New Landscape of the Arms Race

Although the ADC drug resistance problem is still in the early stage of development, the global arms race for novel payloads has already kicked off.

To avoid the drug resistance traps of DXd and traditional microtubule toxins, the novel payloads currently under research are evolving along four core mechanisms of action, with the core goal of breaking through the current action framework of TOP1i and microtubule toxins.

The first path is metabolism and lipidation blockade. The most representative one is the NMT inhibitor of Myricx Bio mentioned above. The metabolic route also includes DHODH inhibitors, which inhibit the de novo pyrimidine synthesis pathway, cause cellular pyrimidine starvation, block DNA/RNA replication, and can synergize with ferroptosis to enhance efficacy.

The second path is to target new nodes of transcription and DNA damage. The representative one is α-Amanitin (an RNA polymerase II inhibitor derived from the poisonous mushroom *Amanita phalloides*) from Heidelberg Pharma — it is not effluxed by P-gp at all, can kill both rapidly dividing tumor cells and dormant tumor stem cells, and shows unique advantages in the face of Topo-1i drug resistance caused by DNA repair defects.

In addition, Topo-2i and Topo-1 have essential differences in enzyme structure and binding sites, which can effectively counteract target mutations that cause DXd resistance; the new generation of structurally modified PBD and Duocarmycin derivatives attempt to maintain the strong ability to cross-link DNA double strands while reducing the delayed toxicity of the first-generation PBD.

The third path is to jump out of direct cytotoxicity and directly target tumor driver pathways. As payloads, pan-RAS inhibitors target activated RAS in the form of ternary complex molecular glues, directly blocking downstream oncogenic signals. Multiple preclinical molecules including GFS78 from Genfion Pharma and IMD2146 from Yifei Pharma have shown potential efficacy against DXd resistance. At the same time, pan-RASi ADCs can greatly reduce the systemic exposure of pan-RAS small molecules, which is expected to improve the target-related dose-limiting toxicity of oral pan-RAS small molecules.

None of the multiple paths is the absolute standard answer, but the general direction is becoming increasingly clear.

04

Conclusion

The fact that DS-8201 is hitting USD 10 billion in peak sales is itself a precision chemotherapy revolution: ADCs, with far lower toxicity than chemotherapy, are systematically replacing chemotherapy-containing regimens, advancing from later-line treatment to first-line treatment and even adjuvant therapy. What is more profound is IO 2.0 — the paradigm of IO+ADC replacing IO+chemotherapy is becoming a new consensus.

As ADCs become the underlying infrastructure of oncology treatment, the competition for next-generation ADCs is not only about the peak sales of individual products, but also about the entry point of the entire treatment paradigm. This is the core reason why global pharmaceutical companies are scrambling to deploy next-generation ADCs.

Against this background, the importance of novel payloads is even more prominent. Referring to the fact that Daiichi Sankyo relied on the Topo-1 inhibitor platform to build today's DS-8201, and carried out a series of layouts based on this platform. For global ADC players, once a new payload platform succeeds, it will bring huge room for development.

Of course, although the direction is clear and the existing novel payloads have shown considerable potential in early clinical trials, the relevant clinical transformation is not a smooth path. The physicochemical properties of payloads, linker stability, DAR control, off-target toxicity, trade-off of the pros and cons of the bystander effect, etc., are all key bottlenecks in the clinical transformation of new-generation ADCs.

In particular, after experiencing the selective pressure of TOP1i, tumor cells will evolve complex mechanisms such as high expression of efflux pumps, abnormal lysosomes, target protein mutations, and DNA repair pathway reorganization. Novel payloads must prove in clinical practice that they can bypass the above pathways and deliver verifiable improvements in ORR and PFS.

The evolution of the pharmaceutical industry has never been sustained by replicating the myths of the past. The future winners will be those explorers who dare to step out of the old routes and rediscover solutions.

This article is from the WeChat official account "Anji Observation" (ID: anjiguancha), author: Anji Jun, authorized for release by 36Kr.