Editor's Note: In recent years, with the advancement of innovative mechanisms and technologies, antibody-drug conjugates (ADCs) have become a research hotspot. ADC drugs have further promoted clinical development, clinical translation, and patient treatment outcomes. Recently, the high-level closed-door seminar "Planning and Action, Breaking Through the Billion-Dollar ADC Market," hosted by the Oriental Clinical Oncology Research Center, China Pharmaceutical University, and Shanghai Gaobo Oncology Hospital Affiliated to China Pharmaceutical University, was successfully held in Shanghai. Oncology Frontier invited Vice President Yong Yang of China Pharmaceutical University, President Jin Li of Shanghai Gaobo Oncology Hospital Affiliated to China Pharmaceutical University, and Executive President Chen Feng of Shanghai Gaobo Oncology Hospital Affiliated to China Pharmaceutical University to a roundtable discussion. They jointly explored the development trends of ADCs in China and collaborated to plan the future blueprint for ADCs. 

1 Oncology Frontier: ADC drugs have already changed clinical practice in multiple tumor fields. Could President Yang introduce the characteristics and development concepts of ADCs? What advantages do they have compared to chemotherapy and other strategies?

President Yong Yang: ADC drugs have become a very important type of biological therapy. Since the first ADC drug was marketed in 2000, revolutionary changes have occurred over the past 24 years in various aspects, including antibodies, linkers, and payloads. Various cytotoxins have been screened, and the affinity and humanization of antibodies have been optimized.

Regarding the currently marketed ADC drugs, the side effects, including allergies and off-target effects, are relatively small. Additionally, due to the strong bond between the linker and the payload, the blood toxicity is low. The cytotoxins are mainly released in the tumor microenvironment and exert their anti-tumor effects after lysosomal degradation, resulting in fewer systemic side effects compared to traditional chemotherapy drugs and higher precision. Furthermore, during the development of these drugs, it was found that ADCs could also elicit immune responses and could be widely combined with chemotherapy drugs or immunotherapy drugs, providing doctors with more options. For example, for HER-2 positive tumors, ADC drugs can be widely used in breast cancer, gastric cancer, and bladder cancer, and we are still expanding the indications.

On the other hand, the use of antibodies can also be expanded. Antibodies are typically used to block functional molecules to inhibit tumors. However, some targets are non-functional proteins, and blocking them does not produce a corresponding biological effect (such as blocking tumor progression). Our research has found that these can serve as biomarkers, further expanding the application fields of new antigens and ADC drugs.

For the payloads, apart from cytotoxins, immune activators such as specific agonists or other non-cytotoxic drugs can also be linked. I believe this treatment strategy is more advanced than traditional chemotherapy and radiotherapy, avoiding systemic treatment side effects and converting “cold” tumors to “hot” tumors, making it a research hotspot in the oncology field.

#2 Oncology Frontier: President Jin Li, could you introduce the current status and challenges of ADC drug research and development based on domestic and international research progress and practical experience?

President Jin Li: President Yang has just introduced the history and advantages and disadvantages of ADCs. Currently, the development of ADCs in China is at the forefront globally and can be considered part of the leading international echelon. Last year, four or five Chinese companies transferred international patents to multinational companies in Europe and the United States, further demonstrating the advanced nature of China’s ADC product development. Compared to traditional chemotherapy, ADCs are relatively precise targeted chemotherapy with higher efficacy and lower toxicity.

Currently, China’s research on targets such as BCMA, HER-2, and TROP-2 is relatively mature, and new targets like HER3 and CLDN18.2 are being deeply explored. I believe that universities can discover more novel specific proteins (new targets) through scientific research, pharmaceutical companies can develop corresponding ADC drugs, and hospitals can assist in clinical research, combining efforts to bring new drugs to market. Over the past five years, the ADC industry has been thriving.

However, we still face certain difficulties, which also bring hope. One of the current challenges is the lack of targets. For example, only 10% to 15% of gastric cancer patients are HER-2 positive, meaning that approximately 85% of gastric cancer patients currently have no targeted ADC drugs due to a lack of targets. Therefore, we need to discover new targets and develop new ADC drugs.

Moreover, although current ADC drugs have achieved certain efficacy, they still do not meet patients’ needs and doctors’ expectations. For example, the PFS for ADC drugs targeting HER-2 and CLDN18.2 in second- or third-line treatments is only about six months, and OS is only about one year. We hope to develop new linkers and payloads to increase PFS and OS to two years or even three years while further reducing toxicity. Overall, the efficacy and safety of ADC drugs have been accepted by patients, and we, as doctors, are willing to develop more effective ADCs to bring more benefits to patients.

Oncology Frontier: The recent ASCO conference was successfully held, with multiple domestically produced ADC drugs making their debut on the international stage. Based on the practical experience of the Gaobo team, could you share how research hospitals can help develop innovative drugs like ADCs?

Executive President Chen Feng: Firstly, research hospitals can comprehensively promote innovation in the entire biopharmaceutical industry, not just in the ADC field. The ADC field is currently a research hotspot, and China is relatively leading in this area globally. This sets higher requirements for our biotechnology and pharmaceutical companies, but we have little past experience to draw upon. One of the most important functions of research hospitals is to build interactive communication bridges for scientists, PIs, and enterprises to jointly discuss future development, including high-level seminars like this one on ADCs.

Secondly, as a research hospital, we pride ourselves on understanding the needs of researchers, PIs, and enterprises, allowing us to integrate the goals and needs of various parties. Currently, ADCs are rapidly iterating, with many previously undruggable targets now having new functions, and there have been multiple technological innovations in linkers and payloads. For these new ADC drugs, designing reasonable clinical trials, completing preliminary verification with minimal cost and fastest speed, and smoothly entering clinical research require early involvement of experienced clinical research experts like Professor Jin Li. From project design to participation, they can help enterprises avoid detours, save costs, and time.

Moreover, most enterprises face a very tortuous and difficult process when initiating clinical research. We have optimized the management mechanism, compressing the time from project initiation to formal enrollment within one month, far exceeding other peer hospitals. We also adjust resources based on enterprise needs, with extreme cases completing approval in as little as three days.

Finally, we aim to accelerate the listing of ADC drugs and conduct further clinical research post-listing. The hospital’s drug use strategy is flexible, with five regularly stocked ADC drugs; other new ADC drugs can be temporarily procured based on patient needs. ADC clinical application research conducted in the hospital adheres strictly to GCP standards for data recording, allowing enterprises to analyze and discover new indications.

#4 Oncology Frontier: The development of ADCs faces many challenges, requiring a deep understanding of pharmacological characteristics and drug safety features, including payload toxicity. How do you think we should address these side effects?

President Yong Yang: One of the main side effects of ADC drugs is antibody-induced allergic reactions. However, through the humanization (and even complete humanization) of IgG1 monoclonal antibodies, immunogenicity has been greatly reduced. Cytotoxic drugs can also cause ADC toxicity; for example, although both are topoisomerase inhibitors, the toxicity of DXd is about ten times that of SN38. Due to the stability of the linker, ADCs are relatively stable in the blood, releasing after entering tumor cells to kill surrounding tumor cells through the bystander effect. However, once these cytotoxic drugs enter the systemic circulation, they may cause severe toxic reactions, requiring special attention in non-clinical and clinical research.

Currently, the key is to select stable “toxins.” ADCs have become a general drug template, with antibodies as therapeutic targets and linkers connecting various drugs for treatment. Our team is also researching new payload drugs. Currently, payloads can be immune modulators or immune checkpoint inhibitors, which regulate immune responses and reduce toxicity. Additionally, ADCs can connect bispecific antibodies, such as CD3 monoclonal antibodies and tumor target monoclonal antibodies, to activate T cells for treatment. This design can significantly reduce ADC side effects. Overall, payloads have numerous options, including sRNA, mRNA, immune modulators, or immune checkpoint inhibitors, offering vast possibilities.

#5 Oncology Frontier: You shared the “Clinical Development Strategy of ADC Drugs” at the conference. How can we form new productive forces in clinical research to successfully bring new ADCs into clinical practice and further improve patient benefits?

President Jin Li: ADC Phase I clinical trials are different from traditional chemotherapy or targeted drugs. Phase I clinical trial design needs to consider drug characteristics. For ADC drugs, the dose-escalation trials and toxicity observations differ from previous chemotherapy and targeted drugs. Additionally, attention needs to be paid to the indications and clinical stages (first-line, second-line, third-line, etc.) of drug development. If the drug itself is effective and safe, how to develop it to maximize its efficacy and safety is a key consideration in clinical trial design. If the design is inadequate, it may result in suboptimal performance, akin to a student underperforming in an exam. Rigorous and reasonable clinical trial design can fully leverage the drug’s properties. Therefore, clinical trial development is crucial, and the process from animal experiments to large-scale clinical application, including determining cut-off values for biomarkers and quantitative pharmacology analysis, is indispensable.

#6 Oncology Frontier: How do you view the future application prospects of ADCs in oncology? What aspects of research and clinical practice need further improvement?

Executive President Chen Feng: The prospects for ADCs are very broad. As President Yang mentioned, we often say “everything can be conjugated,” reflecting the various possibilities of ADC drugs. ADCs can connect not only cytotoxic drugs but also RNA drugs, radiopharmaceuticals (radioactive elements), etc. Through linker optimization and technological iteration, drug toxicity can be continuously reduced, further enhancing the applicability of ADC drugs.

In most cases, cancer patients abandon treatment not due to a lack of drugs but because they cannot tolerate the side effects. Therefore, reducing toxicity brings more possibilities for patients and provides clinicians with more combination therapy options. We are very optimistic about the ADC field, and ADCs are one of the few areas where China leads internationally. We hope that ADC drugs can pave the way for Chinese innovative drugs to enter the global market, gaining better prospects.

President Yong Yang Dean of the School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Director of the New Drug Safety Evaluation Research Center Professor (Second Level) and Doctoral Supervisor Recipient of the State Council Special Government Allowance

President Jin Li President of Shanghai Gaobo Oncology Hospital Affiliated to China Pharmaceutical University Lifetime Professor at Tongji University Oriental Hospital Chairman of the Asian Oncology Alliance (FACO) Chairman of the CSCO Foundation Chairman of the Oncology Clinical Research Committee of the China Pharmaceutical Innovation and Research Development Association Vice Chairman of the Oncology Expert Committee of the National Health Commission’s Capacity Building and Continuing Education Former President of the Chinese Society of Clinical Oncology (CSCO) Chairman of the Gastric Cancer Expert Committee of CSCO Deputy Editor of Cancer Science

Executive President Chen Feng Vice President/General Manager of Shanghai Region, Gaobo Medical Group Executive President of Shanghai Gaobo Oncology Hospital Affiliated to China Pharmaceutical University Graduated from Peking Union Medical College (eight-year clinical medicine program) in 2009, joined the founding team of Beijing Tsinghua Changgung Hospital affiliated with Tsinghua University, engaged in hospital construction and management, and pursued further studies in hospital management in Taiwan Changgung Hospital three times. Subsequently held management positions at Tsinghua University Medical Center, Ocean Health Medical Management Co., Ltd., and Capital Medical Group. Joined Gaobo Medical Group in 2017, serving as Vice President, responsible for hospital operations management in Shanghai and Guangdong regions.