Leman Biotech Files IPO Prospectus Highlighting Its Proprietary Meta10 Immune Metabolic Reprogramming Technology to Overcome CAR-T Cell Exhaustion

Jan 06, 2024 07:33 CST Updated 07:33

Leman Biotech

Developer of Novel Tumor Immunotherapy Drugs

January 6, 2023 / eMedClub News /--At the beginning of the New Year, the founding team of Leman BioAutocrine IL-10 CAR-T CellsThe study, officially published in Nature Biotechnology, also brings new hope for the future development of CAR-T cell therapy products.As CAR-T therapy demonstrates remarkable efficacy in B-cell malignancies, while people place high hopes on CAR-T products, they have also initiated technical challenges to address various difficulties in clinical practice, such as the treatment of solid tumors, tumor recurrence, and insufficient durability of efficacy.

Data on the CAR-T cell phenotype before and after infusion, compared with data from preclinical in vivo models, indicate the limiting role of CAR-T cell exhaustion in clinical outcomes.Breaking Through T Cell Exhaustion，The scientific community has been trying to reverse T cell exhaustion programs epigenetically, from deleting exhaustion-related T cell transcription factor expression to immune checkpoint blockade. However, due to the unclear exhaustion mechanism after CAR-T product infusion, most efforts can only partially reverse the exhausted transcriptional phenotype.

The main causes of T cell exhaustion include T cell dysfunction due to increased expression of immune heterotypic receptors, as well as changes in the expression levels of chemokine receptors and adhesion molecules within the tumor microenvironment or suppressive interactions between immune cells.Soluble Immunosuppressive FactorsIncreaseAdd(such as IL-10, IL-35) also largely contribute to the T cell exhaustion state. In 2021, Dr. Tang Li and Dr. Guo Yugang's research team found that the immunosuppressive factor IL-10 can enhance the oxidative phosphorylation metabolism of tumor-specific terminally exhausted T cells, effectively overcoming and alleviating T cell exhaustion. By administering an IL-10-Fc fusion protein with an extended half-life, combined with CAR-T therapy, terminally exhausted T cells can be revitalized.

More importantly, they found that T cells differentiate into terminally exhausted T cells due toStrong antigen stimulationAlthough IL-10 has a strong regulatory effect on reversing terminally exhausted T cells, the short half-life and low tumor enrichment make it difficult for exogenous IL-10 administered via intravenous injection to effectively reach the target site.

The 6th Symposium on Tumor Immunotherapy and Cell Treatment Technology

Challenges and Clinical Experience in CAR-T Frontline Treatment Development
Clinical Development Progress of CD19 Dual-Target CAR-T
Innovative Space in Hematologic Tumor Cell Therapy
Rapid Construction of CAR-T Process Platform
Strategies for the Armed Upgrade of CAR-T in Solid Tumors
How TCR-T Overcomes Tumor Antigen Escape
Frontier Breakthroughs in Universal Cell Therapy
Innovative Development of Solid Tumor Targets
mRNA Technology Empowers Cell Drug Development
Non-Viral Vector CAR-T
Logic Gate Design in Cell Drugs
Innovative Design of CAR Molecules
Opportunities for China-produced CAR-T to Enter Overseas Markets

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Leman's founding team precisely identified this key point,Globally, it is the first to apply metabolic reprogramming to cancer immunotherapy using CAR-T therapy.Constructed a metabolic-enhanced IL-10 CAR-T cell product that can maintain the integrity of mitochondrial structure and function in the tumor microenvironment and enhance oxidative phosphorylation metabolism in a mitochondrial pyruvate carrier (MPC)-dependent manner.The product can simultaneously express CAR and secrete IL-10, demonstrating enhanced cell proliferation capacity and superior tumor-killing activity, which the research team refers to as "metabolic armoring."

The product's resistance to T cell exhaustion is mainly reflected in two aspects: one is through metabolic reprogramming, where T cells can enhance oxidative phosphorylation metabolism to achieve sustained proliferation; secondly, it not only allows for proliferation but also maintains better cytotoxic activity. Therefore, from these two aspects, the metabolically reprogrammed T cells have overcome the exhausted state.

In multiple solid tumor models, including melanoma models, breast cancer lung metastasis models, colon cancer subcutaneous tumor models, and human pancreatic cancer NSG mouse orthotopic models, the productAchieved in situ solid tumors or metastatic solid tumorsComplete RegressionMeanwhile, the metabolically enhanced IL-10 CAR-T cells can induce stem cell-like immune memory responses,Achieve lasting immune protectionIn terms of clinical safety, this product does not affect the concentration of IL-10 in peripheral blood and other tissues, and no adverse reactions related to IL-10 were observed in mouse models.

▲ Schematic Diagram and Efficacy Example of Metabolism-Enhanced IL-10 CAR-T (Source: Official WeChat Account)

Following the successful administration of the first patient with Leman Biotech's metabolism-enhanced CD19 CAR-T injection (Meta10-19), Dr. Yugang Guo stated in an interview that the success of the Meta10-19 product trial not only demonstrates the excellent safety of the Meta10 platform but also far exceeds expectations in terms of efficacy, proving the potential of metabolism-enhanced CAR-T. It has been validated,Meta 10 can be perfectly combined with various immunotherapies., whether it's CAR-T, TCR-T, TILs, or immune checkpoint antibodies, their efficacy can be significantly enhanced, showing enormous potential.

It is worth noting that the first patient'sThe dosing amount is only 5% of the conventional CD19 CAR-T dosing amount., but still achieved complete remission and was discharged from the hospital. This will significantly reduce the preparation cycle and production costs. Dr. Guo preliminarily estimates that the expansion time can be shortened from two weeks to 2-3 days, and the production cost will be controlled to within 100,000 yuan. This means that the future retail price of this product may not exceed 300,000 yuan, with a very high possibility of being included in medical insurance.

▲ Leman Biotech Platform (Image Source: Official Website)

When talking about future directions, Dr. Guo stated that Leman Biotech is an innovative drug research and development company based on "immune metabolic reprogramming + artificial intelligence." Regarding the Meta10-19 project, the company hopes to commercialize it through licensing out while focusing on its strengths. It aims to consolidate its leading position in immune metabolic reprogramming technology, achieve breakthroughs and iterations in innovative technologies for solid tumors as soon as possible, and build a technological moat. It is reported that the biggest highlight of Leman Biotech's second-generation product is...Autonomously Optimized Metabolic Regulators, while it is difficult for peers to imitate this technology. The optimized sequences and the extent of optimization will become core competitiveness. The company has currently established three major pipelines: biomacromolecule pipeline, metabolism-enhanced CAR-T pipeline, and AI super-factor pipeline. Promoting the development of new antibodies through AI algorithms and optimizing various components of CAR-T are also key focuses for future development.

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