-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
- Cosmetic Ingredient
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
The target of the drug can be met and sought
.
The Claudin 18.
2 target is simply born
for targeted drugs.
Before introducing the Claudin 18.
2 (CLDN 18.
2) target, let's take a look at Claudin (CLDN).
Claudin
is a family of proteins discovered in 1998 that acts as a physical and chemical barrier to maintain and control molecular exchange
between cells.
Claudin has 4 transmembrane domains that are involved in the regulation of physiological processes such as paracellular permeability and conductance, and are widely distributed in the stomach, pancreas and lung tissue
.
As an important molecule that makes up the tight junction of cells, Claudin determines the permeability of epithelial cells and also plays a role
in blocking the diffusion of proteins and lipids on the cell membrane surface.
Figure 1.
Claudin18.
2 protein structure, source: Reference 2 Claudin18.
2
is a member of the Claudin protein family, a protein
with a high degree of tissue expression specificity.
Under normal circumstances, Claudin18.
2 is usually buried in the gastric mucosa, and monoclonal antibodies basically do not reach Claudin18.
2
in normal tissues.
However, after malignancy, tight junction protein is destroyed, exposing the Claudin18.
2 epitope on the surface of tumor cells and becoming a specific target
.
Studies have shown that the presence of Claudin18.
2 protein can be detected on the surface of tumor cells in 70%-80% of gastric cancer patients and 60% of pancreatic cancer patients.
In addition, Claudin18.
2 is also highly expressed in various tumors such as esophageal cancer, lung cancer, ovarian cancer, colon cancer, and cholangiocarcinoma.
This means that Claudin 18.
2 is an ideal therapeutic target
.
In addition, whether it is stomach cancer or pancreatic cancer, effective treatment methods are extremely limited
.
In this context, Claudin18.
2 has attracted extensive attention
from domestic and foreign pharmaceutical companies.
PART.
01
The first high-profile debut of the world's leading Claudin 18.
2 of Zhongchuangsheng Group, a domestic pharmaceutical company entrant, dates back to 6 years ago
.
At the 2016 ASCO meeting, Ganymed reported the results of its Claudin18.
2 monoclonal antibody Zolbetuximab (IMAB362), when combining this new first-of-its-kind antibody with standard chemotherapy EOX (epirubicin, oxaliplatin, capecitabine).
When used as a first-line drug for the treatment of Claudin18.
2-positive gastric cancer and gastroesophageal junction adenocarcinoma, it can significantly prolong the median overall survival of patients (8.
4 months to 13.
2 months); Among the patients with the highest expression level of Claudin 18.
2, the median overall survival in the chemotherapy + Zolbetuximab group was 16.
7 months, compared with 9 months with chemotherapy alone, and it was safe and tolerated
in treatment.
Excellent data led to Ganymed's acquisition
of Astellas for $1.
4 billion.
Domestic pharmaceutical companies also immediately smelled the potential of Claudin 18.
2 target and entered the field
.
Many domestic biopharmaceutical companies such as BeiGene, I-Mab, Legend Biologics, and Remegen have poured into this track
with different technical methods such as monoclonal antibodies, bispecific antibodies, CAR-T cell therapies, and ADCs.
In the face of such great competition, Transcenta Group is full of
confidence.
This is because the Claudin 18.
2 project of domestic pharmaceutical companies is basically in the early stage
.
Transcenta Group's Claudin18.
2 monoclonal antibody TST001 is the second monoclonal antibody against Claudin18.
2 in the world after Astellas Zolbetuximab, and it is also the
fastest research progress in China.
TST001 was developed by Transcenta through its independently developed Immune Tolerance Barrier Breakthrough (IMTB) technology platform.
Highly affinity specifically binds to CLDN18.
2 protein and utilizes NK cells to mediate antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
The mechanism directly targets the killing of tumor cells
expressing the CLDN18.
2 protein.
Using advanced process technology, the fucose content of TST001 is greatly reduced in the production process, which further enhances the ADCC-mediated tumor killing activity
of TST001.
In mouse xenograft tumor experiments, TST001 showed stronger antitumor activity
than IMAB362 analogues.
On July 2, 2021, Transcenta Group announced that a rapid and confirmed partial tumor response resulting from TST001 monotherapy has been observed in patients with Claudin18.
2 expressing gastric cancer in the ongoing TST001 dose ramp-up trial, with encouraging
results.
On July 28, 2021, the FDA granted TST001 orphan drug designation
for the treatment of gastric cancer and gastroesophageal junction cancer.
At the same time, TST001 is also the first Claudin 18.
2 monoclonal antibody
developed simultaneously in China and the United States.
At the ESMO conference in September this year, Transcenta Group announced the interim safety and efficacy data of TST001 combined with capecitabine and oxaliplatin (CAPOX) in the first-line treatment of patients with locally advanced or metastatic gastric cancer and gastroesophageal junction cancer.
In this phase I/II clinical trial, a total of 51 patients were enrolled and treated, including 36 patients who received TST001 plus CAPOX at a dose of 6 mg/kg once every three weeks during the extended phase (median follow-up of 65 days).
。 In 15 patients with measurable lesions and at least one post-treatment tumor evaluation, the optimal overall response according to RECIST 1.
1 criteria was:
Eleven cases (73.
3%) achieved partial remission, and 4 cases (26.
7%) achieved disease stabilization, with a disease control rate of 100%.
Among them, 8 patients with medium/high expression of Claudin 18.
2 and 5 patients with unknown expression of Claudin 18.
2, 6 and 5 patients achieved partial remission
, respectively.
All enrolled patients in the study were evaluated
for safety and tolerability.
Most adverse events (with or without causation) in treatment are grade 1 to 2 and include nausea, hypoalbuminaemia, anaemia, vomiting, and low
platelet count.
Adverse events during treatment led to delayed dosing in 12 (23.
5%) patients and dose reduction in 5 (9.
8%) patients, but did not lead to patient discontinuation
.
These data show that TST001 combined with CAPOX for the first-line treatment of Claudin 18.
2-positive gastric cancer and gastroesophageal junction cancer patients has demonstrated good tolerability and encouraging antitumor activity
.
Transcenta has also developed a proprietary immunohistochemical (IHC) antibody to support the screening
of patients expressing Claudin 18.
2 in registered clinical trials.
At present, TST001 is being developed simultaneously in China and the United States, and is expected to enter the international phase III clinical trial
in 2023.
The clinical progress ranks second in the global R&D camp and first in
China.
PART.
02
TST001 has four unique advantages of continuous production process to build a moat From the perspective of technical route, the development of Claudin18.
2 targeted drugs has shown a momentum
of blooming 。 Compared with Claudin18.
2 monoclonal antibody, the obstacles faced by Claudin18.
2 ADC drugs and Claudin18.
2 bispecific antibody drugs mainly come from the increased cost caused by the complexity of the production process, and the clinical use experience is not as rich as that of monoclonal antibody drugs; and the high cost is also the constraint of Claudin18.
2 CAR-T therapy
.
Therefore, Transcenta Group chose monoclonal antibody R&D and combination drug
use when setting up the R&D project.
In addition to the above advantages, TST001 also has the following unique features: #TST001 Other unique features01
has high affinity, a wide range of treatment compared to Zolbetuximab, TST001 has a higher affinity and a wider
range of treatments.
Zolbetuximab's clinical data, while good, has certain limitations
.
Since Zolbetuximab was an antibody developed 10 years ago, the technology is not as mature as it is now, so it does not have a high enough affinity
.
This also makes it effective only for patients with high expression of Claudin18.
2, and not for patients with moderate or low expression levels, so Zolbetuximab applied for first-line therapy
.
TST001 is a next-generation antibody designed by Transcenta Group using immune tolerance barrier breakthrough technology, which has higher affinity and stronger NK cell-mediated ADCC tumor killing activity, which also means that TST001 may be effective for patients with high, medium and low expression levels of Claudin18.
2, and can be used as first-line, second-line and end-line therapy, with a broader market
。 02Implement the declaration of China and the United States
Transcenta Group has been developing TST001 simultaneously in China and the United States from the beginning, and will have a larger market in the future, as well as better pricing power
in the United States.
Since TST001 is also effective in end-line patients, it may be possible to register with a single-arm test in a shorter
time.
This will save the company a lot of time and money costs
.
In order to achieve precision therapy, Claudin 18.
2 targeted drugs also require companion diagnostic tools to screen potentially effective populations, and antibody development for companion diagnostics is extremely technically difficult
.
Transcenta Group developed companion diagnostics alongside the development of TST001, which can be delivered to patients simultaneously after the drug is on the market, without waiting or relying on the launch
of other companion diagnostic products.
of the Phase III study of TST001.
Usually when a drug enters the late stage of development, it will involve changes
in the production process of the product caused by the expansion of production scale.
However, products that use continuous production can use the same production process
from the submission of IND application to product approval.
In this case, a 500L fermenter produced continuously for one month can produce antibodies equivalent
to the annual capacity of a 10,000-liter tank using the traditional perfusion process.
If 12 batches are produced a year, the antibodies produced can support the therapeutic dosage
of 30,000 patients.
Transcenta Group's production base in Hangzhou has 3 such fermenters, which can produce 1 ton of antibody stock solution a year, which can meet the needs
of product commercialization.
And it can significantly reduce production costs, greatly improve product competitiveness and profitability
.
In terms of corporate governance, on August 8 this year, Transcenta Group announced the appointment of Dr.
Caroline Germa as Executive Vice President and Chief Medical Officer
of Global Drug Development 。 Dr.
Germa is a distinguished medical oncologist and drug development leader with over 20 years of industry experience from early clinical trials to late stage clinical trials and registration, holding key positions
in large multinational pharmaceutical companies such as Pfizer, Novartis, BMS, and AstraZeneca.
At Transcenta, Dr.
Germa will be responsible for leading the global development and translational research teams to advance the company's pipeline molecules, conducting regulatory trials to obtain regulatory approvals from multiple global regulatory bodies to ensure safety and compliance, and leading the company's global clinical collaboration
with existing and potential business partners.
It is believed that the addition of Dr.
Germa will accelerate the clinical progress
of Transcenta's product pipeline.
"
PART.
03Other
potential product pipeline
Zolbetuximab currently has two indications for gastric cancer and pancreatic cancer research is being carried out, and Transcenta is based on these two, The possibility
of TST001 in other gastrointestinal tumors such as biliary tract tumors was further explored.
Figure 2.
Part of Transcenta's tumor pipeline, source: Transcenta Group's official website
In addition, Transcenta Oncology product line includes TST005 (PD-L1/TGFβ), TST003 (BMP antagonist antibody), MSB0254 (VEGFR2) and MSB2311 (PD-L1).
and other products are under development, and these products have the potential to
be used in combination with TST001.
TST003
Among them, TST003 is a high-affinity monoclonal antibody
targeting Gremlin1 that has attracted much market attention.
As a member of the TGF-β superfamily, Gremlin 1 is a regulatory protein highly expressed in stromal cells of a variety of human cancers (such as esophageal cancer, pancreatic cancer, gastric cancer, colon cancer, lung cancer, breast cancer and prostate cancer, etc.
), which is produced by tumor-associated fibroblasts or tumor cells and is associated with tumor formation, which can promote the proliferation, migration, invasion and metastasis
of cancer cells.
In preclinical studies, TST003 has demonstrated antitumor activity in human tumor xenograft (PDX) models expressed in target expression as a single agent or in combination with targeted drugs, and has shown synergistic antitumor activity
with immune checkpoint inhibitors in multiple tumor models.
In May 2022, researchers from Transcenta Group and Shanghai Jiao Tong University published
the results of the study of TST003 for the treatment of androgen-negative/low-activity prostate cancer in Nature Cancer.
The results of this study revealed that Gremlin1 protein can promote the plasticity of prostate tumor cells and promote the occurrence and development of castration-resistant prostate cancer, and also proved the synergistic antitumor activity
of TST003 and enzalutamide on human castration-resistant prostate cancer models.
The clinical application of TST003 is exciting
.
TST003 is a true First in class product
.
On September 14, Transcenta Group announced that the clinical trial application of TST003 was approved
by the US FDA.
From the perspective of progress, Transcenta Group will lead the research and development
of Gremlin1 monoclonal antibody globally.
Figure 3.
Transcenta Group's non-oncology pipeline, source: Transcenta Group official website
In addition to the oncology pipeline, Transcenta Group's products are also involved in orthopedics, nephrology and other fields
.
TST002
TST002 (Blosozumab) is a humanized sclerotinumab drug candidate for severe osteoporosis, which has been authorized for development and commercialization by Lilly in Greater China and has completed Phase II clinical studies
in the United States and Japan.
Transcenta Group has successfully completed technology transfer, established an independent manufacturing process at its own manufacturing site, completed all preclinical trials
required for GMP production for clinical research and CDE requirements to conduct clinical trials in China.
At present, there is no anti-clerotin antibody therapy
on the market in China.
In September 2021, TST002 was approved for clinical research
in China.
More than 100 million people in China suffer from various degrees of osteoporosis, including 4 million with severe osteoporosis, and if TST002 is approved, it will benefit a large number of osteoporosis patient groups
.
TST004
TST004 is a humanized monoclonal antibody targeting mannan binding lectin serine protease 2 (MASP2) and developed for the treatment
of IgA nephropathy (IgAN).
IgA nephropathy is a chronic kidney disease with a high prevalence and very limited treatment options, and the development of TST004 helps to address an unmet clinical need
.
Currently, Transcenta is working with Le Bon Pharma to develop and commercialize TST004 for the treatment of certain indications related to kidney and blood diseases (excluding ophthalmic and infectious disease indications)
in Greater China.
Transcenta Group is a clinical-stage biopharmaceutical company
with comprehensive capabilities in biodrug discovery, R&D, process development and manufacturing.
In September 2021, the company officially landed on the Hong Kong Stock Exchange and became a Hong Kong listed company
.
Transcenta Group has always regarded the research and development of Claudin 18.
2 monoclonal antibody drug as an important strategy
of the company.
According to statistics from brokers, in 2019, the number of gastric cancer patients worldwide was about 1.
06 million
.
At 80%, the number of gastric cancer patients suitable for Claudin's 18.
2 targeted drug exceeds 800,000
worldwide.
Due to eating habits and other reasons, China is a country
with a high incidence of stomach cancer.
In 2019, the number of gastric cancer patients in China was about 460,000
.
At the same rate, about 368,000 people are eligible for Claudin's 18.
2 targeted drug
.
Even if the annual treatment cost is 50,000 yuan, the domestic market size will easily exceed 10 billion
.
The huge potential market may also be the reason for
the competition of domestic companies to layout.
PART.
04
brief summary
Under the current domestic innovative drug Fast Follow strategy, the speed of product development is more important
.
Transcenta's core product TST001 is currently at the forefront of the global R&D camp and has significant clinical advantages
.
In addition, the company has also developed companion diagnostic antibodies, which will contribute to the precise clinical development
of TST001.
In the future, in the fierce market competition, it will cover more patient groups
.
It is expected that TST001 will be approved for listing as soon as possible and realize its commercial value
.
Transcenta Group prospectus link: https://www1.
hkexnews.
hk/app/sehk/2021/103326/documents/sehk21040105003_c.
pdf; 2.
Prabhsimranjot Singh, Sudhamshi Toom and Yiwu Huang，Anti-claudin 18.
2 antibody as new targeted therapy for advanced gastric cancer，Journal of Hematology & Oncology（2017）10:105； 3.
Claudin18.
2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results.
Nat Med.
2022 May 9；4.
Evaluation and reflection on claudin 18.
2 targeting therapy in advanced gastric cancer.
Chin J Cancer Res.
2020 Apr; 32(2):263-270;5.
Transcenta Group: Claudin18.
2 monoclonal antibody TST001 will start global registration clinical trial, clinical progress second in the world, broad market space", Arterial Network, 2022-04-01
.
Columnist
Hour light
With a background in biochemistry and molecular biology, he has been engaged in molecular typing of esophageal squamous cell carcinoma, and is familiar with the pathogenesis and medication regimen
of solid tumors.
Now I use discovering and disseminating knowledge as a means of making a living, learning endlessly, hoping that I will always maintain a humble attitude and plasticity, and meet the golden age
of medicine with all of you.
