Growing 'Toxicity' Concerns Over ADCs... Korean Therapies Also Affected

TOP1 Inhibitor-Based ADCs Continue to Report Toxic Side Effects
Safety Competition Intensifies with Payload Diversification and Advanced Linker Technologies

Antibody-drug conjugates (ADCs), which have gained attention as next-generation cancer treatments, are now facing a series of controversies over toxic side effects. The burden is increasing for major domestic companies as their clinical-stage ADC candidates have adopted substances that the global academic community has flagged for toxicity risks.

According to an international joint research team published in The Lancet Regional Health – Europe on May 7, 2026, ADC cancer drugs have been continuously linked to side effects affecting the lungs, liver, and eyes. In particular, pulmonary toxicity is cited as a side effect that can lead to patient deaths. The research team explained, "First-generation ADCs that were approved and marketed early on saw toxicity rates exceeding 50% when administered at the maximum dose."

ADCs are anticancer drugs made by attaching a highly toxic substance (payload) to an antibody that targets proteins expressed on the surface of cancer cells. When the antibody binds to the cancer cell, the payload is released, killing the cancer cell. However, if the payload is released prematurely in the bloodstream or attaches to normal cells, toxic side effects occur.

Such toxic side effects have also been observed in therapies developed by major pharmaceutical companies. Enhertu (active ingredient: trastuzumab deruxtecan), widely prescribed for breast cancer and non-small cell lung cancer, is a prime example. Jointly developed by Daiichi Sankyo and AstraZeneca, Enhertu achieved blockbuster status with global sales of approximately 5 trillion won last year, but clinical trial results showed that about 15% of treated patients experienced interstitial lung disease. Post-marketing studies also confirmed the same side effect in 9.6% of patients. The academic community has designated lung toxicity as an 'identified risk' of Enhertu and recommends close monitoring during treatment.

The core cause of these toxic side effects has been identified as the concentration of specific payloads. As many companies focus on using 'TOP1 inhibitor' payloads, the risk of toxicity is accumulating. According to the journal Nature Cancer, about 60% of ADCs that entered clinical trials in 2024 adopted TOP1 inhibitor payloads.

TOP1 inhibitors are toxic drugs that block an enzyme called topoisomerase I, which is essential for cancer cell division. By preventing normal DNA replication, they kill cancer cells. Although they are somewhat less potent than other payloads, they can be attached in larger quantities to antibodies, offering the dual benefit of efficacy and safety. Since Enhertu’s successful application of a TOP1 inhibitor payload in the global market, many following companies have adopted the same class.

A significant number of ADC candidates from major domestic companies currently in clinical trials have also chosen the TOP1 inhibitor payload. For example, Celltrion’s non-small cell lung cancer candidates CT-P70, CT-P71, and CT-P73 are all being developed based on the TOP1 inhibitor payload 'PBX-7016.' Likewise, ABL Bio’s candidates ABL206 and ABL209, which are being tested in clinical trials through its US subsidiary Neoc Bio, also use TOP1 inhibitor payloads.

As the evaluation criteria in the ADC market shift from efficacy to safety, domestic ADC-specialized companies are adopting differentiated strategies to circumvent the toxicity limitations.

Sanghoon Lee, CEO of ABL Bio, announced at the American Association for Cancer Research (AACR) meeting last month, "ABL206 and ABL209 will be our last TOP1-based projects; subsequent pipelines will shift toward dual payloads." Dual payloads represent a next-generation ADC design strategy, where two drugs with different mechanisms of action are loaded onto a single antibody, thereby moving away from dependence on a single payload.

Ligachem Bio is diversifying payloads across several classes, such as MMAE, MMAF, and PBD, to reduce the risks associated with relying on a single payload. The company’s key candidate LCB84, which was licensed out to Johnson & Johnson in the US, utilizes an MMAE-class payload instead of a TOP1 inhibitor. According to the company, they have applied a linker technology called 'ConjuAll' to ensure that the payload does not leak in the bloodstream and is only released inside the tumor cell.

IntoCell is developing a payload modification technology (PMT) that chemically alters the payload itself to reduce uptake by normal cells, thereby minimizing side effects. The first clinical candidate, ITC-6146RO, uses duocarmycin—a more potent drug than TOP1 inhibitors—while the PMT technology reduces the risk of penetrating normal cells. While Ligachem Bio has enhanced safety at the linker stage, IntoCell is pursuing a strategy of modifying the payload itself.

This content was produced with the assistance of AI translation services.