China's first antibody-conjugated drug (ADC) was approved for the treatment of gastric cancer

On June 9, 2021, the National Food and Drug Administration (NMPA) of China announced that it has approved the listing of Rongchang Bioinjection Vedicuzumab (trade name: Aidexi) with conditions through the priority review and approval procedure, which is suitable for at least acceptance Treatment of patients with locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) with HER2 overexpression that has undergone two systemic chemotherapy
.

Vidicuzumab is an antibody-conjugated drug (ADC) targeting HER2
.

Contains human epidermal growth factor receptor-2 (HER2) antibody part, linker and cytotoxic drug monomethylaustatin E (MMAE)
.

It is reported that this is China's first ADC drug independently developed by a Chinese company
.

The approval of the drug for marketing provides a new treatment option for patients with locally advanced or metastatic gastric cancer
.

It is reported that the listing of vedicitumumab is based on a phase 2 clinical trial for gastric cancer
.

In this clinical trial, vedicitumumab showed excellent anti-tumor activity and well tolerated
.

Research data shows that as of June 22, 2020, for 127 patients with HER2 overexpression (IHC 2+ or IHC 3+) gastric cancer or gastroesophageal junction adenocarcinoma who have received second-line chemotherapy treatment, vedicitumumab The objective response rate (ORR) was 24.
4%, the median progression-free survival (PFS) was 4.
1 months, and the median overall survival (OS) was 7.
6 months
.

In addition, Vidicuzumab is currently undergoing clinical trials in China for urothelial cancer, HER2 low-expressing breast cancer, lung cancer, and cholangiocarcinoma
.

About ADC Antibody-drug Conjugate (ADC) is a new type of therapy that combines the powerful lethality of small molecule drugs and the high targeting of pure monoclonal antibodies.
It can take advantage of the extremely high specificity of antibodies.
The drug is accurately injected into tumor cells to avoid killing normal cells in the body, thereby reducing adverse reactions in the treatment process
.

ADC consists of three parts: antibody, linker and cytotoxin: 1.
Antibody component The antibody can specifically target a specific antigen, which is overexpressed in tumor cells but not expressed or underexpressed in normal cells
.

And it should have the lowest non-specific binding activity with other tissue cells
.

Antibodies have better stability and internalization efficiency when the entire ADC drug acts
.

At the same time, it has good pharmacokinetics (PK)/pharmacodynamics (PD) and biodistribution
.

2.
The linker component The linker acts as a bridge for ADC drugs and is connected to the antibody through cleavable or non-cleavable linkers.
The linker needs to be designed in a sophisticated manner.
It not only needs to be stable to prevent chain scission under physiological conditions, but also has a specific Location, such as the characteristics of tumor cell release
.

3.
Toxin component The small toxin molecule should have the characteristics of high toxic activity and low immunity
.

It also needs to have an active group connected to the linker and a clear mechanism of action (usually an anti-mitotic agent)
.

After injection into the body, the ADC binds to the target cell antigen to form an ADC-antigen complex, which then enters the cell through clathrin-mediated endocytosis and is encapsulated in the endosome
.

When the linker in the ADC is cleavable in the endosome, the drug can be released through hydrolysis, protease cleavage, and disulfide bond reduction cleavage
.

The uncut linker enters the next stage
.

Endosomes fuse with lysosomes
.

The proton pump on the lysosome creates an acidic environment to assist the lysosome to completely degrade the ADC drug (at this time, the ADC containing the non-cleavable linker is cleaved here)
.

After ADC drugs are released into the cytoplasm, they work by inserting into DNA or inhibiting microtubule polymerization, leading to apoptosis of target cells
.

Reference: https:// Pharmacy Quick Fact: Learn from the beginning of antibody-drug coupling (ADC) open reprint This article is open reprint: just leave a message in this article