ADC Drugs—For the Past Decade

On November 25, CSPC (01093.HK) announced that its self-developed ADC drug SYSA1801 for the treatment of gastric cancer (including gastroesophageal junction cancer) was approved by the FDA as an orphan drug.

SYSA1801 is a Claudin-18.2 fully human monoclonal antibody-MMAE drug conjugate independently developed by CSPC. Preclinical in vitro and in vivo animal experiments show that SYSA1801 can effectively target tumor cells through Claudin-18.2 antibody and start internalization. The MMAE virus is introduced into tumor cells to treat gastric cancer and pancreatic cancer.

Gastric cancer is a rare disease in the United States, but has a high incidence rate in Asian countries such as China, Japan, and South Korea. It ranks first among various malignant tumors in China. In North America, about two-thirds of patients with gastric cancer are diagnosed as locally advanced or metastatic cancer. More than half of the patients have local recurrence or distant metastasis after initial treatment, and the five-year median survival rate of the disease after metastasis is less than 10 %. At present, the drugs and therapies for gastric cancer are very limited. Conventional chemotherapy and surgical resection are used mainly, and effective treatments are unmet clinical needs.

This qualification can speed up the clinical development, registration and marketing of SYSA1801. CSPC plans to submit clinical trial applications for the drug under investigation in China and the United States in 2021.

Antibody-drug conjugate (ADC) is a combination of highly targeted antibody drugs and powerful chemotherapeutics to accurately deliver drugs into tumor cells while avoiding chemotherapeutics from killing normal tissues, thereby reducing adverse reactions in the treatment process. The first ADC drug Mylotarg was approved for marketing in 2000, and ADC ushered in an outbreak in 2019. There are currently 9 drugs on the market, and 5 ADC drugs have been approved since 2019. According to EvaluatePharma and BCG, the global ADC drug R&D market is expected to reach US$12.9 billion in 2024. With continuous breakthroughs in ADC drug research and development technology, ADC drugs are approved one after another, bringing a high level of enthusiasm. At present, ADC R&D in the United States leads the world.

ADC drugs are used in the treatment of cancers. The disease targeted by the antibody is determined by the target of the antibody that specifically binds to the target highly expressed by tumor cells. The small molecule drug is brought into the cell through internalization, which is then released through proteasome effect, thereby destroying DNA or inhibiting tubulin, and ultimately leading to cell apoptosis.

Appropriate antigen target, highly specific antibody, efficient toxin molecule (Payload), linker, DAR (drug antibody ratio) value, these 5 aspects are the focus and essentials of ADC drug development.

The current ADC drugs can be roughly divided into three generations.

First-generation of ADC drugs

Only Gemtuzumab is on the market, which combines with mouse monoclonal antibody through non-degradable linker. Both the efficacy and activity of the drug are low. The concentration of the drug in the blood is lower than the effective concentration of the treatment. In addition, the low expression of the target antigen makes it impossible to kill cancer cells. The linker is relatively unstable and more toxic, and the mouse-derived antibodies are highly immunogenic.

Second-generation of ADC drugs

Improved targeting of tumor cells coupled with more effective small molecule inhibitors makes the second generation of ADCs show good clinical efficacy and safety.

Third-generation of ADC drugs

Optimizing monoclonal antibodies, linker, and toxic chemical small molecules have become the focus of the development of third-generation ADC drugs.

In the past ten years, ADC has made great progress through the selection of better cytotoxic agents, bioconjugation methods, better selection of targeted antigens, and antibody engineering optimization. By combining these novel technologies and biomarker selection strategies, it is believed that ADC will usher in a golden burst in the next decade.