Typesetting | Shuicheng WenIn September 2022, Pfizer（Pfizer）、Bayer（Bayer）, Novartis（Novartis）, Eli Lilly（Eli Lilly）And Bristol-Myers Squibb（BMS）The venture capital arms of these five major pharmaceutical giants invested in aBiotechnology Startups——Capstan Therapeutics, Invested in$165 million(Including $63 million in seed funding and $102 million in Series A funding)。On March 20, 2024, the company announced the completion$175 millionB Round Financing, this round of financing was led byRA Capital led the investment, existing investors continued to follow up, and Johnson & Johnson was added.Forbion、New investors such as Mubadala Capital, Perceptive Advisors, and Sofinnova Investments.This financing will be used to support Capstan Therapeutics' leadingIn Vivo CAR-T Cell Therapy——CPTX2309, in order to carry outAutoimmune DiseasesEarly clinical proof-of-concept and further development of its targeted lipid nanoparticle technology（tLNP）R&D pipeline.It is reported that,CPTX2309 is based onCapstan Therapeutics' tLNP technology specifically delivers mRNA payloads encoding anti-CD19 CAR to CD8-expressing T cells, effectively constructing CAR-T cells in situ within the body. This approach rapidly eliminates B cells in the blood and lymphatic tissues to reset the immune system, without facing the challenges associated with traditional ex vivo CAR-T cell therapies.Capstan Therapeutics has not yet disclosed which autoimmune disease or diseases this therapy will target.In the context of a downturn in biotech funding,What Makes This Startup So Charming?Let's look at the keywords:LNP、mRNA、In Vivo CAR-T, the founding team includesCarl June(Pioneer of CAR-T Cell Therapy)，Drew Weissman(Nobel Laureate, Founder of mRNA Technology)，Jonathan Epstein(Inventor of in vivo CAR-T technology).From left to right: Carl June, Drew Weissman, Jonathan EpsteinTargeted Lipid Nanoparticle Technology——tLNPCapstanProprietary to the companyTargeted Lipid Nanoparticle Technology（tLNP）Composed of three interconnected parts——Non-viral Delivery System、Cell-Specific Targeting MoleculesAndPayloads Designed for Diseases。Non-viral Delivery System：Based on Lipid Nanoparticles（LNP）The delivery system has the potential for safe and repeatable in vivo administration, unlocking new clinical applications.Cell-Specific Targeting Molecules: Functionalize antibodies or antibody fragments by conjugating them to the surface of nanoparticles, resulting in targeted lipid nanoparticles.（tLNP）, to precisely deliver the payload.Payloads Designed for Diseases: Using mRNA to encode chimeric antigen receptors（CAR）, gene editing systems, and other therapeutic proteins.UtilizeTargeted LNP（tLNP）AndmRNATechnology, the in-situ CAR therapy developed in the body, targets two types of cells respectively——T cellsAndHematopoietic Stem CellsTargeting the former, it is used to treat blood cancers, solid tumors, as well as fibrotic diseases and autoimmune diseases. Targeting the latter, it is used to treat hereditary blood disorders.LNP-mRNA, Creating In Situ CAR-T in VivoThe establishment of the company is mainly based on the founding team's publication in early 2022 inScienceA heavyweight research paper:CAR-T cells produced in vivo to treat cardiac injury(CAR-T Cell Therapy for Heart Injury Produced In Vivo)。The research team developed aIn Vivo Generated Transient Engineered CAR-T Cell Therapy, through the injection of lipid nanoparticles（LNP）Delivering mRNA to reprogram T cells, enabling them to recognize cardiac fibrosis cells, thereby reducing fibrosis and restoring heart function in a mouse model of heart failure.This method, similar to mRNA vaccines, requires only a single injection to generate CAR-T cell therapy in the body, offering the potential to address the current challenges of complex processes, long cycles, and high costs associated with CAR-T therapies.In this new study, the research team designed a novel CAR-T cell therapy based on mRNA technology, which reprograms T cell receptors through mRNA to target fibroblast activation protein.（FAP）, UseLipid Nanoparticles（LNP）For delivery, LNP carriers have been widely applied and validated in COVID-19 mRNA vaccines. This LNP carrier can recognize CD5, which is highly expressed on the surface of T cells, thereby specifically targeting T cells and generatingFAP-CAR-T Cells。Therapeutic experiments conducted on mouse models of cardiac injury showed that after CD5/LNP-encapsulated mRNA was injected into the mice, these mRNA molecules successfully entered the T cells of the mice and effectively reprogrammed them to target and attack activated fibroblasts. This reprogramming was temporary, as the mRNA did not integrate into the T-cell genome, and after a few days, the T cells returned to their original state and no longer targeted fibroblasts.In just a few days, mRNA-induced reprogramming generated a large number of CAR-T cells, significantly reducing cardiac fibrosis and restoring the heart to its normal size and function.
This transient engineered CAR-T cell therapy developed in the study, which generates CAR-T cells in vivo through targeted LNP delivery of mRNA, greatly expands the application prospects of CAR-T and mRNA technologies. Moreover, this approach is more controllable, simpler in process, and has the potential to significantly reduce the cost and price of CAR-T cell therapy.In recent years, some clinical studies have shown,CAR-T Cell TherapyCorrectSystemic Lupus ErythematosusThe patient experienced a positive therapeutic effect, offering a new, safe, and effective treatment option for systemic lupus erythematosus patients.The Dawn of Curing Autoimmune Diseases —— CAR-TFebruary 2024, "The New England Journal of Medicine》（NEJM）Published an article titled:CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-upResearch Paper.The paper reported on 15Autoimmune DiseasePatient(8 namesSystemic Lupus ErythematosusPatients, 4Systemic SclerosisThe patient and 3 othersIdiopathic Inflammatory MyopathyPatient)After receiving CAR-T cell therapy, they no longer showed symptoms or needed new treatments, and the first group of patients treated have remained disease-free for over two years. This outcome has sparked hope for a complete cure for autoimmune diseases.
Pioneer of CAR-T Cell TherapyCarl JuneProfessor once inCellThe journal published a commentary article pointing out,Larger-scale studies and longer-term follow-up are still needed to confirm.The Effect of CAR-T Cell Therapy on Lupus Erythematosus, but the results that have been released show great promise. In fact, these studies indicate that systemic lupus erythematosus may be an easier target for CAR-T cell therapy than B-cell tumors. Moreover, the number of disease-driving B cells in systemic lupus erythematosus is much lower than in B-cell tumors. Therefore, treating autoimmune diseases like systemic lupus erythematosus with CAR-T cell therapy may require a much lower dose, which would significantly reduce the immunological side effects associated with CAR-T cell treatment.It is worth mentioning that, on March 21, 2024,Researchers from Capstan Therapeutics, Inc. recently published in "Proceedings of the National Academy of Sciences of the United States of America》(PNAS) published an article titled：IL7 increases targeted lipid nanoparticle–mediated mRNA
expression in T cells in vitro and in vivo by enhancing T cell
protein translation Research Paper.The study showed,Interleukin-7（IL7）CanSelective enhancement of mRNA protein translation levels delivered to T cells can be utilized to improve the expression of tLNP-delivered mRNA in vivo.https://www.capstantx.com/https://www.science.org/doi/10.1126/science.abm0594https://www.nejm.org/doi/full/10.1056/NEJMoa2308917https://www.pnas.org/doi/10.1073/pnas.2319856121
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