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The concept of “magic bullet” targeted therapy was proposed as early as the early 20th century. With the advent of hybridoma technology and the development of humanized monoclonal antibody technology, breakthroughs have been made in the research and development of ADC drugs. As of now, there are more than a dozen ADC drugs approved for marketing worldwide, half of which have been approved in the last five years.
In 2021, the first domestically produced ADC drug, RC48 (Aidiqi) from Rongchang Bio, was launched, marking the rise of domestic ADCs. After several years of technological accumulation, some domestic companies’ ADC research and development technologies have matured, allowing them to secure a place internationally.
Perhaps influenced by last year’s significant transactions in the ADC field, many ADC pipelines have recently begun to accelerate. According to statistics from the Yao Times team, after entering 2024, three Claudin18.2 ADCs announced entering Phase III clinical trials, all of which are led or participated in by domestic pharmaceutical companies.
ADC: Starting with Choosing a Suitable Target Antigen
The structure of ADCs is well-known, consisting of antibody + linker + payload. The antibody binds to the specific target antigen on the tumor, the linker connects the antibody to the payload, and the payload is responsible for killing cancer cells.
An ideal ADC drug must possess high specificity, stability, efficient intracellular payload delivery capability, as well as tolerability and safety. Almost every element affects the final efficacy of the ADC. Therefore, at the beginning of ADC development, all key components must be carefully screened, including target antigens, antibodies, payloads, linkers, and conjugation methods.
The target antigen expressed on tumor cells guides ADC drugs in recognizing tumor cells, determining the mechanism by which cytotoxic payloads are delivered to cancer cells. Thus, choosing a suitable target antigen is the primary consideration for ADCs.
Ideal target antigens need to meet the following three criteria:
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To reduce off-target toxicity, the target antigen should only be expressed or primarily expressed in tumor cells, and not expressed or minimally expressed in normal tissues. -
The target antigen should be non-secretory because secreted antigens in circulation can lead to ADC binding outside the tumor site, thus decreasing tumor targeting and safety. -
The ideal target antigen should be internalized after binding with the corresponding antibody, allowing the ADC-antigen complex to enter cancer cells and release the cytotoxic payload through appropriate intracellular transport pathways.
A report from Huajin Securities shows that the top three popular target points in the ADC research field are HER2, Trop-2, and Claudin18.2. The first two have been mature anti-tumor drug targets validated over many years, while Claudin18.2 was discovered later, and corresponding monoclonal antibody products are currently only approved in Japan.
Image source: Huajin Securities report
Why Claudin18.2?
In 1998, Professor S. Tsukita and his team in Japan discovered a new family of transmembrane proteins, which play a barrier role in tight junctions between cells, thus naming them Claudins, derived from the Latin word “claudere,” which means “to close.”
Claudin18.2 is a member of the Claudins family, encoded by the CLDN18 gene. Its characteristic is that in normal tissues, Claudin18.2 is only expressed at low levels on the surface of differentiated epithelial cells in the gastric mucosa and is deeply embedded in tight junction complexes. However, when cancer leads to the disruption of cell tight junctions, the Claudin18.2 epitopes become exposed on the surface of tumor cells, becoming a specific target.
With this tumor-specific high expression, Claudin18.2 ADC can accurately recognize and bind to Claudin18.2 on the surface of tumor cells, while avoiding unnecessary damage to normal tissues.
Moreover, Claudin18.2 also shows strong disease accessibility, being expressed in many tumors, including gastric cancer, pancreatic cancer, esophageal cancer, and ovarian cancer. In an immunohistochemical analysis study involving 414 patients with different tumor types, 4.1% (N=17) of subjects were Claudin18.2 positive, including pancreatic cancer (16.7%, 1/6), gastric cancer (14.1%, 12/85), colorectal cancer (0.9%, 2/203), cholangiocarcinoma (6.3%, 1/16), and urogenital/others (2.2%, 1/46).
Additionally, Claudin18.2 has been confirmed to be highly expressed in primary tumors, and it also exhibits expression characteristics in metastatic lesions. In one study, pancreatic ductal adenocarcinoma showed 59.2% (103/174) of Claudin18.2 expression, with 54.6% strongly expressed (N=95). In lymphatic metastases, 69.4% (N=34) expressed Claudin18.2, and similar results were found in liver metastasis samples.
This means that ADCs targeting Claudin18.2 may have the potential to expand to various other types of tumors, with a very high upper limit of accessibility.
Claudin18.2 ADC: Accelerate! Accelerate!
From the overall track, the currently researched/marketed Claudin 18.2 drugs almost cover most mainstream technical routes. According to information from the Zhihuiya database, there are currently 37 Claudin 18.2 CAR-T therapies in research, 33 Claudin 18.2 bispecific antibody drugs, 29 Claudin 18.2 monoclonal antibody drugs, and 28 Claudin 18.2 ADC drugs.
Among them, 7 drugs are in clinical Phase III or above, including 4 Claudin 18.2 monoclonal products and 3 Claudin 18.2 ADC products.
In terms of monoclonal antibodies, in addition to already having the world’s first Anstey drug, the other three are Osemitamab from Chuangsheng Group, M108 from Mingji Bio, and ASK589 from Aosaikang, among which Osemitamab from Chuangsheng Group is the second Claudin 18.2 drug to enter Phase III clinical trials globally.
Entering 2024, Claudin18.2 ADCs have begun to accelerate. So far, three companies have announced the initiation of relevant Phase III clinical trials.
(1) In February 2024, Innovent Biologics registered the Phase III G-HOPE-001 study of IBI343 on clinicaltrials.gov, aiming to study the efficacy of IBI343 monotherapy in patients with previously treated Claudin 18.2 positive, HER2 negative gastric/gastroesophageal junction adenocarcinoma (Registration No: NCT06238843).
Innovent’s official information shows that IBI343 utilizes site-specific conjugation technology, with the small molecule toxin being Exatecan (TOPO1i toxin).
Image source: Innovent Biologics official website
(2) In March 2024, AstraZeneca registered the Phase III clinical trial of AZD0901 (CMG901) on the Chinese Drug Clinical Trial Registration and Information Public Service Platform, aiming to study the treatment of advanced or metastatic gastric cancer in second-line or above therapy (Registration No: CTR20240730).
AZD0901 is not an AstraZeneca self-researched product. In February 2023, AstraZeneca reached an agreement with KYM (KYM Biosciences Inc, a joint venture between Lepu Biopharma and Connoisseur) for a maximum price of approximately $1.1 billion, granting AstraZeneca exclusive global rights for the research, development, registration, production, and commercialization of CMG901.
According to publicly available information from AstraZeneca, CMG901 consists of a Claudin 18.2 monoclonal antibody, a protease-degradable linker, and the cytotoxic small molecule Monomethyl Auristatin E (MMAE).
(3) In April 2024, Lixin Pharmaceuticals registered the Phase III clinical study of LM-302 on clinicaltrials.gov, aiming to study the treatment of locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma positive for CLDN18.2 (Registration No: NCT06351020).
According to information from Lixin Pharmaceuticals, LM-302 is formed by combining a recombinant humanized anti-Claudin 18.2 monoclonal antibody with the cytotoxic payload Monomethyl Auristatin E (MMAE).
Image source: Lixin Pharmaceuticals official website
In addition, good news has recently come from HengRui Medicine’s Claudin18.2 ADC. HengRui announced that its subsidiary has received the NMPA’s approval for the issuance of the “Drug Clinical Trial Approval Notice,” allowing the company’s independently developed Claudin18.2 ADC (SHR-A1904) to conduct clinical studies for the treatment of Claudin18.2 positive advanced solid tumors in combination therapy in Phase Ib/III.
2. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy
3. Company official websites
Cover image source: pixabay
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