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    Home > Biochemistry News > Biotechnology News > Will the country welcome the first cell therapy target but get together and become a gold-sinking highlight?

    Will the country welcome the first cell therapy target but get together and become a gold-sinking highlight?

    • Last Update: 2021-06-28
    • Source: Internet
    • Author: User
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    Four years ago, in 2017, the legendary creatures under KingScript, one of the leading CDMOs in China, made their debut at the American Society of Clinical Oncology (ASCO) Annual Meeting (ASCO)
    .

    That year, Legend Bio announced at the conference that the self-developed targeted chimeric antigen receptor T cell (CAR-T) therapy targeting B cell maturation antigen (BCMA), cilta-cel, had an ORR (objective response rate) of 100%.
    The experimental data immediately caused international shocks

    .

    Today, four years later, cell therapy is already in a trend of accelerating global commercialization and listing, and domestic CAR-T companies have also sprung up like bamboo shoots after a rain
    .

    At the ASCO annual meeting in 2021, in addition to Legendary Biology, domestic cell therapy companies such as Sibiman Biology, Genxi Biology, Baiji Gene, Yuanqi Biology, Shenzhen Puruijin Biology, etc.
    have also unveiled their representative researches

    .

    But at the same time, behind the prosperous development of cell therapy, there are also hidden worries such as expensive treatments and clustering of CD19 targets
    .

    CAR-T therapy with high hopes of ``eliminating cancer''

    CAR-T therapy with high hopes of ``eliminating cancer''

    Since the 1970s, cell therapy has gone through 50 years of history
    .
    But scientists have been fighting for more than 100 years in order to successfully make their own immune system fight cancer

    .

    When cell therapy with the advantages of "precision strike" similar to targeted therapy is available, in addition to the mature application in the treatment of hematological tumors, more refractory diseases such as solid tumors that have not been clinically met are being accelerated.

    .

    Cell therapy is divided into two types: immune cell therapy and stem cell therapy
    .
    Among them, the application of immune cell therapy in cancer treatment is mainly realized through adoptive immune cell therapy to improve the immunogenicity of tumor cells and the sensitivity to effector cell killing, and stimulate and enhance the body's anti-tumor immune response

    .
    The CAR-T therapy currently approved for marketing is a hot spot in the field of immune cell therapy

    .

    The three main categories of cell therapy

    Source: China Securities Research Institute

    CAR-T cell therapy is to construct autologous or allogeneic T cells that specifically target tumor cell expression antigen markers (CAR) to mediate tumor immune killing effect, which is not restricted by MHC and has a wider application
    .

    Therefore, immune cell therapy, as a new anti-cancer method, has significant advantages such as good curative effect, low or no side effects, and no drug resistance.
    It has become the following traditional therapy (surgery, radiotherapy and chemotherapy) and targeted therapy (small molecule targeted therapy).
    Drugs and monoclonal antibody drugs)

    .

    Advantages and disadvantages of immunotherapy compared with traditional treatment methods

    Source: Compilation of public information, Zheshang Securities Research Institute

    The current popular track, but the targets are clustered seriously

    The current popular track, but the targets are clustered seriously

    From the perspective of R&D layout, Novartis, Gilead Sciences, Celgene, Bristol-Myers Squibb, etc.
    are all well-known global pharmaceutical giants in the cell therapy track

    .

    In August 2017, Kymriah developed by Novartis was approved by the U.
    S.
    FDA to be officially marketed, becoming the world's first CAR-T therapy approved for marketing.
    It has a milestone significance for the treatment of refractory/relapsed patients under 25 years of age.
    Cell precursor acute lymphoblastic leukemia (ALL) patients

    .

    In October of the same year, Kite Pharma, which was acquired by Gilead Sciences for US$11.
    9 billion, ushered in the company’s first approved CAR-T therapy Yescarta, which is indicated for the treatment of relapsed or refractory large B-cell lymphoma ( LBCL) Adult patients

    .

    Three years later, Tecartus, another cell therapy developed by Kite Pharma, was also approved for the market for the treatment of adult patients with relapsed/refractory mantle cell lymphoma (MCL)
    .

    This year, Breyanzi and Abecma developed by Bristol-Myers Squibb (BMS) were approved for marketing in February and March 2021, respectively, and both are used to treat relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
    .

    Although the historical process in the field of cell therapy has gone through half a century, there are only the above five CAR-T cell therapies that have been approved for marketing in the world
    .

    Overview of CAR-T products that have been marketed worldwide (as of March 28, 2021)

    Source: official website of each company, Zhongtai Securities Research Institute

    Domestically, although no CAR-T therapy has been approved for marketing, Fosun Kate (a joint venture of Fosun Pharma and Kite Pharma) and WuXi Juno (a joint venture of WuXi AppTec and Juno Therapeutics) have two CAR-Ts.
    Both are already in the listing application stage and will be approved soon

    .

    Two domestic CAR-Ts are under application for listing

    Source: Insight, Bohai Securities Research Institute

    GenScript’s holding company Legend Biologics developed a CAR-T therapy targeting BCMA (cilta-cel), which has also previously submitted a marketing application to the US FDA and EU EMA for the treatment of relapsed/refractory Patients with multiple myeloma (R/R MM)
    .

    On May 26 this year, the US FDA has accepted the priority review of cilta-cel’s Biological Products Licensing Application (BLA) ("Priority Review Acceptance").
    If the review can be completed before November 29, it will be approved as soon as the end of this year.
    Launched, it is expected to become the world's second CAR-T cell immunotherapy targeting BCMA after Abecma jointly developed by Bristol-Myers Squibb and bluebird bio

    .

    However, behind the current fierce cell therapy track, there are also hidden worries such as serious target clustering and excessive concentration of treatment fields
    .

    The five CAR-T therapies that have been approved for listing and the CAR-T therapies that are about to be approved for listing by three domestic companies all target CD19 or BCMA, of which CD19 targets mostly
    .
    At the same time, the field of treatment is mainly concentrated on hematological tumors such as lymphoma.
    So far, no solid tumor has been approved, and the market share of solid tumors accounts for more than 90% of all tumors, which restricts the market space in the field of cell therapy

    .

    CD19 target has serious homogeneity, new targets help

    CD19 target has serious homogeneity, new targets help

    Why will CD19 become the most popular target for CAR-T therapy and the most research and development pipeline?

    The advantage of the CD19 target is that it can most effectively activate T cells to initiate the entire immune response, and has more indications than other targets
    .
    Therefore, for CAR-T therapy, CD19 is an excellent antigen

    .

    Typical second-generation CAR-T technology targeting CD19

    Source: Zheshang Securities Research Institute

    According to Kang'antu data, the main reason why most of the targets of CAR-T cell immunotherapy are CD19 are:

    CAR is a type of synthetic receptor that can change the specificity, function and metabolism of T cells
    .
    CAR consists of a T cell activation domain (usually including the zeta chain of the CD3 complex) and extracellular immunoglobulin heavy and light chains used to direct specificity

    .
    These minimal structures are called first-generation CARs, and their antigen recognition is independent of HLA, but due to their limited signaling capabilities, they will not direct a continuous T cell response

    .
    Chimeric co-stimulatory receptors can enhance proliferation and provide anti-apoptotic effects in human primary T cells.
    This paves the way for dual-signal transduction CAR, which can effectively promote the expansion of functional T cells when repeatedly exposed to antigens.
    Increase

    .
    These receptors are called second-generation CARs and can produce long-lasting "living drugs", which are the basis of current CAR-T cell therapy

    .

    CD19 was chosen as the first target not only because it is frequently expressed in B-cell leukemia and lymphoma, but also because it has a broader and higher level of expression relative to other potential targets such as CD20 or CD22
    .
    The expression of CD19 in normal tissues is limited to the B cell lineage, so the predicted on-target/off-tumor (on-target/off-tumor) will be limited to B-cell aplasia.
    This side effect can be achieved by immunoglobulin Alternative therapies relieved

    .

    We further reasoned that CAR may first cause B cell depletion rather than a potential antibody response, especially its murine components
    .
    In a 2003 study, a single infusion of a CD19-specific CAR engineered human peripheral blood T cell was shown to eradicate existing lymphoma and leukemia in tumor-bearing mice.
    This discovery has promoted CD19 CAR therapy Clinical transformation

    .

    The number of CAR-T drugs under research worldwide (by target)

    Source: Clinical trials, Huachuang Securities

    In addition to CD19, the BCMA, CD22, and CD20 targets are also one of the popular targets for CAR-T drug research and development, but the current research and development pipeline is relatively small, so it is not crowded
    .

    According to public information, half of the clinical trials of CAR-T cell immunotherapy drugs in the United States target CD19, and more than 40% in China.
    BCMA, a popular target second only to CD19, has fewer clinical trials in China than CD20.
    , CD22 and GPC3, accounting for only 5%

    .

    This means that there is still much room for improvement in new targets for global CAR-T drug development in the future, and there are also more studies on solid tumor targets such as HER-2, GD2, and EGFR
    .

    After all, in the case of severe homogeneity of CD19 targets, the development of new targets, other therapeutic areas, or a differentiated model for solid tumor research and development has become the development trend of the cell therapy industry
    .

    Cell therapy industry trends: differentiation

    Cell therapy industry trends: differentiation

    It is not difficult to see that those cell therapy companies with differentiated characteristics are also more favored by capital
    .

    For example, the legendary creature that was once a blockbuster at the ASCO annual meeting is the holding company of KingScript, one of the leading CDMOs in China, and is also China’s first listed CAR-T cell therapy company.
    It was held on June 5, 2020.
    Listed on NASDAQ in the United States

    .

    Unlike the crowded CD19 targets chosen by other companies, Legend Bio's CAR-T drug development is mainly based on BCMA targets
    .
    In particular, the company reached a cooperation with Jassen Janssen (Johnson & Johnson) in 2017, signed a cooperation agreement for global development and commercialization of cilta-cel, and received an initial payment of US$350 million

    .

    It is also supported by the rich clinical trial experience of Johnson & Johnson, a multinational pharmaceutical giant, that Legend Bio's R&D pipeline is progressing rapidly
    .
    In May of this year, the company also received an investment of US$500 million from Hillhouse Capital

    .

    Legendary Bio's R&D pipeline

    Source: Company's official website

    At the recent American Society of Clinical Oncology (ASCO) Annual Meeting (ASCO), many differentiated CAR-T R&D pipelines were also unveiled
    .

    For example, like Legendary Bio, Genxi Bio, which is also listed on NASDAQ in the United States, also announced the BCMA/CD19 dual-targeting autologous CAR-T product data for the treatment of multiple myeloma (MM) at the conference.

    .

    Sibyman Bio, which landed on the US capital market in 2014, announced the completion of the privatization transaction on February 20 this year, delisting from Nasdaq, and led by Yunfeng Fund as a buyer group.
    The total value of the transaction is about 410 million.
    US dollars

    .

    At this conference, Sibiman Biological also had two researches on CAR-T therapy selected as oral reports
    .
    One is the CD19×CD20 dual-target CAR-T cell therapy C-CAR039, and the other is the new second-generation CAR-T therapy C-CAR066 that targets the CD20 antigen

    .

    Headquartered in Guangzhou, Baiji Gene is a wholly-owned subsidiary of Hedy Group.
    It is a "brother relationship" with Biotech, a science and technology board listed company controlled by Hedy Group

    .

    At the ASCO conference, Baiji Gene made an oral report on CAR-T therapy targeting CLL1 for the treatment of childhood relapsed/refractory acute myeloid leukemia, in clinical phase I (with certain potential for drug development) The target CLL1, which is abnormally highly expressed on childhood AML cells and leukemia stem cells, but almost not expressed on normal hematopoietic stem cells)
    .
    Preliminary test results show that Anti-CLL1 CAR-T has excellent clinical treatment potential and good tolerability

    .

    In recent years, CAR-T therapy has also achieved a lot of good results in conquering solid tumors
    .

    For example, Yongtai Bio, which will be listed on the Hong Kong Stock Exchange in 2020, has 3 CAR-T products that target CD19 and also has a multi-target clinical indication that is in phase II clinical trials to prevent recurrence after liver cancer surgery.
    Click on the tumor immune cell product EAL® (this is also the only immune cell product approved to enter the phase II clinical trial of solid tumor treatment in China, and the follow-up plan is to conduct research on gastric cancer, lung cancer and other indications)

    .

    Yongtai Biological R&D pipeline

    Source: Company's official website

    In addition, Yuanqi Biotech (founded in 2015 and received nearly 100 million yuan in Pre-A round of exclusive investment from Qiming Venture Capital at the end of 2019), together with Zhejiang University’s Lishui Central Hospital and Shanghai Changzheng Hospital, announced its first announcement at this ASCO annual meeting.
    Evaluate the latest clinical research data (Abstract ID: 4095) of CAR-T drugs targeting GPC3 (Ori-CAR-001) in the treatment of relapsed/refractory hepatocellular carcinoma (HCC)

    .
    The preliminary data of the study showed that Ori-CAR-001 showed good safety and effectiveness in GPC3-positive relapsed/refractory patients

    .

    From a general perspective, these differentiated cell therapy companies have either landed on the US and Hong Kong stock markets, or gained the favor of well-known investment institutions
    .
    After all, continuous financing is a sharp weapon to advance the progress of the product development pipeline

    .

    Concluding remarks

    Concluding remarks

    In summary, although there are currently CD19 targets in the field of cell therapy, with more and more capital intervention, the progress of the CAR-T therapy development pipeline with targets such as BCMA and CD20 is also accelerating
    .
    In particular, there have been many major breakthroughs in the research and development of cell therapy in the field of solid tumors in recent years, and the future prospects are promising

    .

    Reference materials:

    1.
    Kang Antu, "What are the common CAR-T cell immunotherapy?
    Why are most targets CD19?

    2.
    Imeda Industry Research, Zongge 2025, "The Cell Therapy Track of Capital Chasing, Which Company Is More Worth Investing?"

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