Capstan Therapeutics: Injecting mRNA to generate CAR-T in vivo
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Capstan Therapeutics: Injecting mRNA to generate CAR-T in vivo
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Capstan Therapeutics: Injecting mRNA to generate CAR-T in vivo.
The venture capital arms of five pharmaceutical giants , Pfizer , Bayer , Novartis , Eli Lilly and Bristol-Myers Squibb (BMS) , have come together to invest in a biotech start-up Company – Capstan Therapeutics .
Why is this startup so attractive? Let’s look at the key words: LNP , mRNA , in situ CAR-T in vivo , the founding team includes Carl June (father of CAR-T) , Drew Weissman (founder of mRNA technology) , Jonathan Epstein (inventor of in situ CAR-T technology in vivo ) people).
From left to right: Carl June, Drew Weissman, Jonathan Epstein
On September 14, 2022, Capstan Therapeutics announced the completion of $165 million in financing (including $63 million in seed financing and $102 million in Series A financing) to advance in vivo in situ CAR-T therapy to the clinic .
Capstan also announced the appointment of Laura Shawver as president and CEO. Laura Shawver had previously served as CEO of two new drug development companies, Synthor x and Silver back .
The company’s in situ CAR technology consists of three interrelated components— a non-viral delivery system , a cell-specific targeting molecule , and a disease-engineered payload .
Non-viral delivery systems : Lipid nanoparticle (LNP) -based delivery systems have the potential for safe and reproducible in vivo drug delivery to unlock new clinical applications.
Cell-specific targeting molecules : Functionalize antibodies or antibody fragments onto the nanoparticle surface to generate targeted lipid nanoparticles (tLNPs) for precise payload delivery.
Disease-specific payloads : mRNA encoding chimeric antigen receptors (CARs) , gene editing systems, and other therapeutic proteins.
Using targeted LNP (tLNP) and mRNA technology, the developed in situ CAR therapy in vivo targets two types of cells-T cells and hematopoietic stem cells, respectively, targeting the former for the treatment of blood cancers, solid tumors, and fibrosis Diseases and Autoimmune Diseases.
Targeting the latter for the treatment of inherited blood disorders.
The establishment of the company is mainly based on a blockbuster research paper published by the founding team in Science at the beginning of this year: CAR-T cells produced in vivo to treat cardiac injury (CAR-T cells produced in vivo to treat cardiac injury) .
The research team developed a transient engineered CAR-T cell therapy generated in vivo by injecting mRNA delivered by lipid nanoparticles ( LNPs ) to reprogram T cells to recognize cardiac fibrotic cells, thereby reducing fibrosis, Restoration of cardiac function in a mouse model of heart failure.
This method is similar to an mRNA vaccine. It only takes one injection to generate CAR-T cell therapy in the body, which is expected to solve the current problems of complex process, long cycle and high price of CAR-T therapy .
CAR-T cell therapy , the full name is chimeric antigen receptor T cell therapy. In 2017, the FDA approved the first CAR-T cell therapy for the treatment of leukemia, which opened a new era of CAR-T cell therapy.
However, until now, CAR-T cell therapy has required harvesting a patient’s own T cells, which are then genetically reprogrammed in the lab to recognize specific cancer cells, so that they can be identified and killed when infused back into the body.
The whole process is complicated and time-consuming, so the price is very expensive, and the price is often hundreds of thousands of dollars.
The CAR-T cell therapies currently on the market are all for the treatment of blood cancers, but they have also shown promising results in many other types of diseases.
As early as 2019, Jonathan Epstein ‘s team at the Perelman School of Medicine at the University of Pennsylvania published a paper in Nature confirming that CAR-T cell therapy can target overactive cardiac fibroblasts to restore cardiac function .
However, this CAR-T cell therapy has a serious drawback in the treatment of cardiac fibrosis-related diseases because fibroblasts have important functions in the human body, especially in wound healing.
In vitro reprogrammed CAR-T cell therapy, once injected into the human body, can exist in the human body for months or even years, thereby inhibiting fibroblasts for a long time and impairing functions such as wound healing.
In this new study, the research team designed a novel CAR-T cell therapy based on mRNA technology, recoding T cell receptors through mRNA to target fibroblast activation protein (FAP) , using lipid nanoparticles Particles (LNP) are used for delivery, and LNP vectors have been widely used and validated in COVID-19 mRNA vaccines.
The LNP vector can recognize CD5 highly expressed by T cells, thereby specifically targeting T cells to generate FAP-CAR-T cells .
Then, the research team conducted a treatment experiment on a mouse model of cardiac injury.
The mRNA was encapsulated by CD5/LNP and then injected into the mouse. These mRNA molecules successfully entered the mouse T cells, effectively reprogrammed the T cells, and made them tick.
Targeted attack on activated fibroblasts. This reprogramming was temporary, the mRNA was not integrated into the T cell genome, and after a few days, the T cells recovered and no longer targeted fibroblasts.
Importantly, in just a few days, the mRNA induced reprogramming of large numbers of CAR-T cells, resulting in a significant reduction in cardiac fibrosis in mice and restoration of normal heart size and function .
Since mRNA can only be stable in the body for a short period of time (about a week) , this in vivo-generated engineered CAR-T cell therapy is transient and does not resemble traditional viral vector-based in vitro reprogrammed CAR-T cell therapy.
As long-term effects, it does not inhibit fibroblasts for a long time and impair functions such as wound healing.
Traditional CAR-T cell therapy requires the extraction of patient’s T cells, genetic modification, reprogramming and expansion in the laboratory and then infusion into the patient.
The whole process is complicated and costly, making this breakthrough treatment method difficult to promote.
The transient engineered CAR-T cell therapy developed in this study, which delivers mRNA through LNP to generate CAR-T in vivo, greatly expands the application prospects of CAR-T and mRNA technology.
Moreover, this method More controllable and simpler in process, it is expected to significantly reduce the cost and price of CAR-T cell therapy.
References :
https://www.capstantx.com/
https://www.science.org/doi/10.1126/science.abm0594
https://www.science.org/doi/10.1126/science.abn0851
Capstan Therapeutics: Injecting mRNA to generate CAR-T in vivo
(source:internet, reference only)
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