Substrate anti-cancer new pet!Domestic 6 CLAUDIN18.2 drugs were approved for clinical research boom

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Substrate anti-cancer new pet!Domestic 6 CLAUDIN18.2 drugs were approved for clinical research boom

2021-11-25 14:50:07 10 ℃

Epidemiological data reveals "Chinese" gastric cancer, the current situation is not optimistic

According to the latest global cancer data in 2020, China's annual cancer has reached 4.57 million, of which the new patients with gastric cancer is about 480,000 (10.5%), and the top three, the world accounts for 43.9%.

Cancer types in the top ten of Chinese cancer new patients in 2020

In 2020, the death case of gastric cancer in my country was 370,000, accounting for 48.5% worldwide.

Cancer types in the top ten of Chinese cancer deaths in 2020

Due to the early lack of typical symptoms in patients with gastric cancer, it is difficult to self-examination. Once the diagnosis is already in advanced, more than 70% of patients with gastric cancer have been in advance, and there is a chance to lose surgery.

Moreover, the overall prognosis of gastric cancer is less than 10% to 30%, and the 5-year survival rate of 5 years in advanced gastric cancer is less than 10%. The results of the first-line treatment of late gastric cancer have shown that the total survival period (OS) is continuously extended, but The median survival period is still around 12 months.

The traditional treatment method of advanced gastric cancer has surgery, radiotherapy, and chemotherapy, but is low in advanced gastric cancer surgery, and the treatment of chemotherapy is poor.

In a word, the treatment of gastric cancer in China is grim!

In the past decade, targeted therapy and immunotherapy have been thoroughly changed the treatment of various cancers. Although trastum monoclonal against HER2-positive gastric cancer is targeted, the survival rate is very low, mainly due to disease progression and toxicity related to treatment. A area of ​​active development is to find an ideal monoclonal antibody (IMAb) to avoid unnecessary side effects. Based on this, many researchers launched a novel gastric cancer therapeutic target - Claudin 18.2, the discovery of this target also opened a new chapter in gastric cancer targeted treatment.

Half year 6 domestic Claudin18.2 drugs were approved, why Claudin 18.2 became "fragrant"

Claudin is a huge protein family, with more than 27 members, and its normal function is to maintain the adhesion and connection between cells. The protein of this family was used as a biological marker for predicting the prognosis of colon cancer, pancreatic cancer, hepatocyte carcinoma and thyroid cancer.

Claudins protein structure diagram

The study found that the different subtypes of Claudin have different expression distribution in different tissues, and its abnormal expression is related to the development of tumors.

Claudin18.2 (CLDN18.2) is a member of the Claudin protein family, located in the surface of the cell membrane, only low levels of gastric mucosa in the surface of the cell membrane, but in the pathological state, Claudin 18.2 is in a variety of tumors. The expression was significantly up-regulated, including 80% of gastrointestinal adenoma, 60% of pancreatic tumors. In addition, CLDN 18.2 activation can also be found in esophageal cancer, ovarian cancer and lung adenocarcinoma, therefore is a hot target for the treatment of cancer.

According to a non-cancer homes, the CLINICTRIALS and CDE (National Food and Drug Administration) have found that there are 6 Claudin18.2 products who have been approved in the first half of 2021, and most drugs are proposed to treat patients with advanced solid tumors.

Clinical Claudin18.2 products were approved in the first half of 2021

Due to the high-specific expression of the target in normal tissues, add activation expression in various cancers, making Claudin18.2 proteins have become an ideal target of solid tumor immunotherapy such as gastric cancer, pancreatic cancer. At the same time, due to gastric cancer is a large tumor species in China, Claudin 18.2 targets are expected to achieve bottleneck breakthroughs of gastric cancer new target drugs.

So, what are the hot treatments for this target target? Today, there is no cancer, Xiaobian, give you a detailed introduction.

CAR-T therapy

New hope of advanced gastric cancer! Domestic CAR-T therapy CT041 debut ESMO

Chimeric antigen receptor modified T cells (CAR-T) is undoubtedly one of the most expectations. This technique has made great progress in the treatment of various malignant tumors in recent years, and has been successfully applied to the treatment of a variety of blood malignant tumors.

Related Articles Links: In just 1 month, China paragraph 2, the world's sixth car-T therapy is approved! The late cancer patient has been saved!

However, about 90% of cancer cases worldwide are solid tumors, and CAR-T therapy has achieved certain effects in tumors such as liver cancer, gastric cancer, pancreatic cancer, but less, this is mainly due to target Difficulties in choice, CAR-T cells enter tumor tissue difficult, CAR-T cells are easily blocked by other immunosuppressive molecules or cells after entering tumor tissues.

Therefore, domestic and foreign scholars have made a variety of transformations in CAR-T, constantly discovering new targets for treating a variety of solid tumors.

Claudin18.2 (CLDN18.2) is a gastric-specific membrane protein that is considered to be a potential treatment target of gastric cancer and other cancer types. Based on this, Chinese researchers have developed the first CAR-T cells against Claudin18.2.

At the 2019 ASCO annual meeting, CAR-CLAUDIN18.2 T cells Treated the clinical data update of gastric cancer / pancreatic cancer, targeted Claudin18.2 Car T cells to treat 12 cases of metastatic adenocarcinoma (7 cases of gastric cancer, 5 cases of pancreatic cancer), no Severe adverse events, treatment of related death or severe neurotoxicity. In 11 cases: 1 case (gastric adenocarcinoma) is completely relieved; 3 cases (2 cases of gastric adenocarcinoma) are partially alleviated; 5 cases are stable; 2 cases progressed; the total objective relief rate is 33.3%. And, CAR-CLAUDIN18.2 T cells Treated the preclinical research results of gastric cancer showed that CAR-T cells targeted CAR-T cells in the mouse model were completely removed from the mouse model and did not take tapping toxicity.

At the European Tumor Internal Science Conference (ESMO) annual meeting held on September 16-21, the targeted CLAUDIN18.2 (CLDN18.2) autologous CAR-T product CT041 in Kokji pharmaceutical industry is demonstrated. The outstanding efficacy in system tumors can be described as a large color!

This study is China's IP clinical trial for China to carry out, multi-center, open labels. As of April 8, 2021, 37 cases of CLDN18.2 expressed positive in advanced digestive tumors were infused and completed at least 12 Zhou 's assessment.

These include 28 patients with gastroctivoma / gastroesophageal binding, 5 cases of pancreatic cancer and 4 other types of solid tumors, and 28 patients have a cell infusion dose of 2.5 × 108car-T cells, and 6 patients infuse 3.75 × 108, 3. Examples of patients infuse 5 × 108 Car-T cells. About 84% of patients have received at least 2 wires, and the number of median metastasis organs is 3.

The research data is quite bright!

1. Total efficacy: The objective relief rate of all patients reached 48.6%, and the disease control rate was 73%; the total objective relief rate of all gastric cancer patients was 57.1%.

2. Previous reception of at least 2-line treatment failed gastric cancer: The objective relief rate is 61.1%, and the disease control rate is 83.3%.

3.28 cases of gastric cancer / gastroesophageal binding part of cancer each subunue: A patient in patients with a past PD- (L) 1 inhibitor treatment It can be maintained at 50% or more.

4. Safety: CT041 is well tolerated, and there is no treatment related death or immunocytosis related nervous system toxic syndrome (ICANS).

Related article links: Yes! 73% of the disease control, new hope in patients with advanced gastric cancer! Domestic car-T therapy CT041 is stunning

On November 15, Car-T therapy ushered in good news for the progress in the field of solid tumors! The Coji Pharmaceutical Announcement, the European Pharmaceutical Administration (EMA) has been granted independently developed CAR-T product CT041 priority drugs (Prime) qualifications.

It is reported that the selected Prime helps shorten the time to market. It is worth mentioning that this is the world's first solid tumor car-t product for priority drug qualifications. This means that CT041 is expected to be the world's first physical tumor car-t product that is approved by the listing, thereby achieving the Breakthrough in the field of solid tumors.

2021 solid tumor anti-cancer "new pet" strike! Domestic 6 CLAUDIN18.2 drugs were approved for clinical research boom

At present, there is a number of CAR-T clinical trials with a variety of blood tumors and solid tumors in cancellation, which can consult the medical department to specifically evaluate the condition!

In addition, there are also a variety of CAR-T cell therapies targeted to CLDN18.2. For example, LB-1904 developed by a legendary organism is used to treat gastric cancer or pancreatic cancer, which has been experimented with clinical I. In addition, the legendary organism also launched a CAR-T cell formulation tar-CAR-T cell preparation targeted to Claudin18.2 for the treatment of patients with advanced gastric adenocarcinoma, and is currently undergoing clinical trial recruitment.

Antibody

Curriculous target "Highland", new drug Zolbetuximab benefited more than half of patients!

ZolbetuxImab (Imab362) is a class of monoclonal antibody drugs for Claudin 18.2 targets.

In all currently approved access to clinical trials, the fastest research and development progress is also Zolbetuximab, which is a global multi-center double-blind random III clinical trial.

In the data disclosed at the 2016 ASCO Assembly, the Zolbetuximab + Capox chemotherapy solution is used to treat local advanced or metastatic gastric cancer patients. The median has no progress in the survival period of 7.9 months, and the median survival period is 13.2 months; it is obvious than only The Capox chemotherapy solution 4.8 months and 8.4 months.

The II research data disclosed in 2019 also confirmed that Zolbetuximab was treated with advanced gastric cancer or gastrointestinal borders, and the clinical benefits reached 23%. At the same time, it can be observed from group analysis, Zolbetuximab is more significant for patients with higher expression levels, especially in expression of ≥70%, in particular. Currently, Zolbetuximab has been approved by FDA for stage III clinical trials, which is expected to get more valuable large-scale efficacy data as soon as possible. Recently, Zolbetuximab treatment of local advanced non-resection or metastasis stomach and gastrojun bids were approved by the National Drug Administration, officially began to recruit patients in China. If the cancer friends want to know the specific entry standard, please contact the Department of No Cancer Home Medicine.

The first anti-AB011 clinical recruitment of Claudin18.2 independently developed

AB011 is a recombinant human anti-Claudin18.2 monoclonal antibody injection, which is the first anti-Claudin18.2 of Claudin18.2, and the first humanization against the target.

Pre-clinical results show that AB011 has good safety and effectiveness. When used in combination with O'Soliplatin and 5-fluorouracil, a powerful body anti-tumor activity is exhibited in a tumor mouse model. At present, AB011 is launched in my country IP IP clinical study on the treatment of Claudin18.2 positive solid tumors.

Other monoclonal drugs entering clinical trials

01

TST001

TST001 is a new Claudin18.2 humanized monoclonal antibody, developed by my country, which combines claudin18.2 proteins through high affinity specificity, mediates ADCC and CDC mechanisms, direct targeting Claudin18.2 expression positive tumor cells.

In April 2020, TST001 has been approved in China and the United States. In China, TST001 was approved for the treatment of single-drug or joint standards in clinical trials to treat Claudin18.2 expression positive in advanced solid tumors, including but not limited to gastric / gastrogeneous gland cancers, pancreatic guidance, gallbladder Cancer, gallbladder cancer, lung adenocarcinoma, etc. Currently, TST001 is conducting a clinical trial in the United States and China.

02

M108 single anti-injection

The M108 is Claudin 18.2 monoclon, which is an ADCC enhanced monoclonal antibody that has independently developed in a cancerous tumor antigen against gastric cancer such as gastric cancer.

Compared to conventional antibody drugs, M108 monovarulently utilizes the immunological anti-tumor mechanism of the antibody, and fully mobilize the immune cells of the patient's body to kill tumor cells by enhanced ADCC effects. In vitro and in vivo antibody efficacy and physicochemical properties, M108 mono-injection demonstrates higher target specific binding, strong anti-tumor activity and good safety.

03

NBL-015

NBL-015 is a full-human source anti-Claudin-18.2 monoclonal antibody, which has been optimized by protein engineering and optimized ADCC, CDC and ADCP effects. Clinical precursor cell killing experiment, animal pancreatic cancer tumor elimination experiment and toxicity study showed that NBL-015 compared drugs had low immunogenicity, good safety, strong affinity, high affinity, and high antitumor activity, is expected to become the best Targeting drugs for treating pancreatic cancer and gastric cancer.

Double anti-drug

01

AMG910 is a bispecific antibody drug targeted to CD3 / CLAUDIN18.2 independently developed. Globally, Anjin is carrying out a clinical study to assess the safety, tolerance, pharmacokinetics and efficacy of patients with Claudin18.2 positive gastric cancer and gastroesophageal adenocarcinoma patients.

02

Q-1802 lyophilized powder needle

Q-1802 is a dual-specific antibody that can be used to target PD-L1 and Claudin18.2 simultaneously with its antibody engineering technology platform. According to animal preclinical studies, Q-1802 is better than the PD-L1 antibody and Claudin18.2 antibody. Currently, the drug has been approved into the clinical.

Xiaobian has something to say

From the above-mentioned small series, the Claudin18.2 target is a very potential target in the field of gastric cancer. It has become the focus of all parties. In the first half of 2021, the number of clinical trials carried out in China has been More than the United States, ranked first in the world.

It is believed that in the future, with the continuous progress of the targeted drug research, there will be more popular targets and targeted drugs, bringing more new hopes that have long survival for patients with malignant tumors.