© Amino Observation – Innovative Drug Group Original Production
Author | Zheng Xiao
The explosive popularity of DS-8201 has accelerated the rapid development of the ADC field. Now, this track is about to welcome a new breakthrough – the era of dual-antibody ADCs is accelerating towards us.
On November 21, according to the CDE official website, Baillie Tianheng’s EGFR/HER3 dual-antibody ADC drug BL-B01D1 has submitted a market application for the treatment of nasopharyngeal carcinoma.
BL-B01D1 is the world’s first dual-antibody ADC drug to submit a market application, and it is expected to become the first approved dual-antibody ADC drug, marking the official start of the dual-antibody ADC era.
This field is destined to become a focus of the industry. Global pharmaceutical companies are heavily investing in dual-antibody ADCs; domestically, not only Baillie Tianheng but also companies like Ying’en Biotechnology, Innovent Biologics, and Naan Biologics are actively laying out in the dual-antibody ADC field, viewing it as an important strategy for future competition.
The new era of dual-antibody ADCs is bound to be exciting.
/ 01 /
Changing the Treatment Landscape
Dual-antibody ADCs are not a simple “1+1” combination, but can profoundly change the landscape of tumor treatment.
Dual-antibody ADCs are mainly divided into two categories. The first category is dual-target ADC drugs that target two different epitopes.
For example, with the combination of EGFR and HER3 targets, these ADC drugs can simultaneously target and bind to the EGFR and HER3 on the surface of tumor cells, as exemplified by Baillie Tianheng’s BL-B01D1.
Dual-target ADCs can significantly enhance the specificity of tumor cell recognition by simultaneously blocking two tumor proliferation signaling pathways; on the other hand, they can enhance antibody internalization efficiency, allowing more drug payloads to enter tumor cells and exert cytotoxic effects.
The second category is dual-epitope ADC drugs, which are designed to target different epitopes of the same target. These drugs can bind to both poorly internalizing and well-internalizing epitopes on the target simultaneously. In simple terms, the core logic is to leverage the synergistic effect of the “efficient internalizing epitope driving the inefficient internalizing epitope” to improve the overall internalization efficiency of the drug, thereby enhancing anti-tumor activity.
The advantages of dual-antibody ADCs do not stop there. Theoretically, they may effectively overcome tumor resistance to single-target drugs.
For example, in HER2-resistant patients, many advanced breast cancer patients gradually develop resistance after first-line HER2 monoclonal antibody treatment, ultimately leading to disease progression. One reason for HER2 monoclonal antibody resistance is the loss or decreased expression of HER2 receptors on the surface of tumor cells, preventing effective binding of the monoclonal antibody.
However, dual-epitope ADCs can bind to two different epitopes of the HER2 target simultaneously – this means that even if one epitope is lost or its expression is reduced, the dual-epitope ADC can still enter cancer cells through binding to the other epitope, thereby overcoming resistance caused by abnormal expression of single-target epitopes.
Thanks to these significant advantages, more and more pharmaceutical companies are entering the dual-antibody ADC field. If BL-B01D1 is officially approved in the future, it will mark the official start of the dual-antibody ADC era.
/ 02 /
The Balance of Efficacy and Safety
Behind the excitement, the path of dual-antibody ADCs is destined to be challenging.
Innovative drug development is not a simple arithmetic problem; it involves complex and intricate mechanisms of action, and the “miracle through brute force” approach does not always hold in the field of innovative drugs.
For example, one of the early pioneers of dual-antibody ADCs, Zymeworks, faced efficacy challenges with its pipeline drug ZW49. ZW49 is a HER2 dual-antibody ADC that can bind to different epitopes of HER2.
In terms of safety, ZW49 did not exhibit severe adverse reactions, with most treatment-related adverse events (TRAEs) being grade 1 or 2. However, unfortunately, while ZW49 maintained the “sail of safety,” it failed to grasp the “sail of efficacy.”
As early as the 2023 financial report, Zymeworks revealed that due to the constantly changing clinical situation, the planned Phase II study of the HER2 dual-antibody ADC drug ZW49 would no longer be prioritized before further clarifying the research direction.
In the Q2 2024 financial report, the company chose to completely abandon the project. The reason was that after strategically evaluating the company’s emerging wholly-owned pipeline, it decided to officially terminate the clinical development of ZW49.
In addition to efficacy, another major challenge is toxicity control. The HER2 dual-epitope ADC drug MEDI4276 is a typical case: although it has shown anti-tumor activity in HER2-positive tumor models with acquired resistance to T-DM1 and in HER2 low-expressing cell lines, it also presents toxicity issues that cannot be ignored.
On one hand, a high incidence of liver damage and related adverse events has led to frequent treatment interruptions; on the other hand, its tolerable dose is limited, with a very narrow safety window.
It can be said that the balance between efficacy and safety of dual-antibody ADCs is like a delicate scale – in pursuit of better efficacy, serious side effects may accompany, leading to a narrow therapeutic window; however, if too much emphasis is placed on safety, efficacy may be sacrificed. Maintaining a delicate balance between the two is a significant challenge in the development process.
/ 03 /
Clear Direction and Twisted Path
The balance between efficacy and safety is not the only issue faced by dual-antibody ADCs. There are many obstacles in the development process of dual-antibody ADCs.
For example, there is a lack of sufficient “scaffolds” for rapidly constructing stable expressing dual-antibody ADC molecules. After all, there are few antibody scaffold molecules available for dual-antibody construction, and the targets are very concentrated, with only a few targets such as HER2, HER3, EGFR, and MUC1.
Additionally, from a production perspective, the production of dual-antibodies is already challenging due to mismatches leading to low efficiency, and now, with the added complexity of ADCs, the difficulty and challenges in the production process are further increased.
It can be anticipated that the development path of dual-antibody ADCs will not be easy. However, on the other hand, the only issues that need to be resolved in the development of dual-antibody ADCs are specific problems encountered in the process of innovative drug development.
Looking back at the development paths of dual-antibodies and ADCs, none have found the right direction without decades of trial and error. Now, dual-antibody ADCs are just beginning, and experiencing some setbacks is quite normal.
In summary, the direction of dual-antibody ADCs is clear, the path is twisted, and the future will surely be bright.
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