Global Leader! Bonal Bio's Allogeneic CAR-T Therapy for Autoimmune Diseases Published in Cell, Demonstrating Significant Commercial Potential

July 16, 2024Focusing on Gene and Cell TherapyBRL Medicine Inc.(hereinafter referred to as "BRL Medicine") announced that its new collaboration with East China Normal University and Shanghai Changzheng Hospital...First-Generation Allogeneic Universal CAR-T Therapy (TyU19) for the Treatment of Autoimmune DiseasesThe research findings were officially published on July 15 in the top international academic journalCellPublished on.The title of the paper is“Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis”，Vice President of Production and CMC at BRL MedicineDr. Tan BingheCo-first author of the paper, Founder & Chairman of BRL MedicineProfessor Liu Mingyao`, Co-founder & Vice President`Du BingTeachGrantCo-corresponding author of the paper。

It is worth mentioning that,This is the first international report of the successful use of allogeneic universal CAR-T in treating autoimmune diseases, and it has been published in a top journal.CellFirst Publication of CAR-T Therapy Research for Autoimmune Diseases。This not only represents a critical breakthrough for BRL Medicine in the field of CAR-T, particularly in allogeneic universal CAR-T therapy for autoimmune diseases, but also signifies a qualitative leap in technological differentiation and innovation within the cell and gene therapy sector.

CellPublication (Click on the "Read Original" at the end of the article to view the original text)

In this study, TyU19, used by BRL Medicine, is based on a proprietary universal cell platform (TyUCell).^®) developed CD19 UCAR-T, an allogeneic universal CAR-T cell therapy product targeting the CD19 antigen, which hasHigh accessibility, low cost, stable quality, etc.Many features have shown significant efficacy and high safety in clinical trials.

It is worth celebrating that BRL Medicine previously relied on the product "Allogeneic Chimeric Antigen Receptor T-Cell Injection with Targeted CD19 Gene Modification" (Pipeline Code: BRL-301).The Investigational New Drug (IND) application was approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) in July 2023., used to treat B-cell acute lymphoblastic leukemia. AndThis timeCellThe research成果 published in the journal as an Article represents another major important application scenario for BRL Medicine's next-generation UCAR-T product, TyU19——"Autoimmune Diseases"。

TyU19 is a novel UCAR-T product developed by the BRL Medicine scientific team, incorporating years of research expertise in gene editing, immune recognition, and immune cell therapy. It utilizes a sophisticated multi-gene and selective gene editing strategy (Figure 1).Not only does it effectively avoid the risk of graft-versus-host disease (GvHD) that may exist in allogeneic cell transplantation,StillPerfectly overcame the most critical technical barrier in the development of allogeneic universal CAR-T products, namely, the rejection of allogeneic cells by the patient's immune system., which truly realizes the generalization of immune cell therapy products on the basis of ensuring the safety and effectiveness of cell products.。

Figure 1. Design and in vivo effects of BRL Medicine's UCAR-T product "TyU19"

Clinical studies have shown that during the treatment process, there is no need for intensive lymphodepletion pretreatment (lower than autologous CAR-T), and the infused cells can rapidly expand and be maintained long-term in the patient's body, effectively eliminating CD19-positive target cells. This technological breakthrough of TyU19 lays a solid foundation for its excellent efficacy and high safety in treating patients with tumors and autoimmune diseases.

Autoimmune diseases are a group of heterogeneous diseases with a common basis of impaired immune tolerance. Clinically, immunosuppressants are often used to treat autoimmune diseases, but there are issues such as long treatment cycles, high recurrence rates, increased risks of infection and tumors, and some patients being unable to tolerate the treatment or experiencing poor efficacy. Targeted B-cell monoclonal antibodies offer new therapeutic options, but problems like recurrence after discontinuation, infections, and suboptimal efficacy in some patients still exist. Given the critical role of B cells in autoimmune diseases, teams both in China and internationally have attempted to apply CAR-T therapy to autoimmune diseases, which has already demonstrated excellent safety and efficacy. However, for both oncology and autoimmune disease indications, marketed or investigational products remain focused on autologous CAR-T therapies. This time,TyU19, developed by BRL Medicine, is an allogeneic universal CAR-T product that uses cells from healthy donors. It features high accessibility, low cost, and stable quality, and has demonstrated significant efficacy and safety in clinical trials.

In this study,Research Team Successfully Treats 3 Patients with Refractory Autoimmune Diseases Using BRL Medicine's UCAR-T Product TyU19Among them, one case was immune-mediated necrotizing myositis (IMNM), and two cases were systemic sclerosis (SSc). The IMNM subject was a 42-year-old female who, after receiving TyU19 cell therapy, did not exhibit any symptoms of fever or cytokine storm. Moreover, the patient's Total Improvement Score (TIS) rapidly increased (within 2 months) from a baseline of 72.5 to 100 and remained at this level during subsequent follow-ups. Imaging and pathological examinations also showed that the muscle inflammation in the patient had been significantly alleviated.

This study also enrolled two subjects with severe SSc. After receiving TyU19 cell therapy, the CRISS scores of all patients significantly improved within a few months; moreover, regarding skin fibrosis, the modified Rodnan skin scores (mRSS) of both patients significantly decreased.

Moreover,After TyU19 treatment, B cells were completely depleted in all patients, and autoantibodies were thoroughly eliminated in IMNM patients.(Figure 2);The critical organ fibrosis damage in 2 SSc patients was reversed and continued to improve during the 6-month monitoring period.(Figure 3)The entire treatment process was well-tolerated, with no observed cases of cytokine release syndrome (CRS), graft-versus-host disease (GvHD), or immune effector cell-associated neurotoxicity syndrome (ICANS).

Figure 2. Clinical Assessment of IMNM Patients

Figure 3. Clinical Assessment of SSc Patients

Professor Liu Mingyao, Chairman of BRL Medicine, stated:"First of all, we would like to express our heartfelt gratitude to the researchers and patients for their support and trust in BRL Medicine. The breakthrough progress achieved by BRL Medicine in the field of UCAR-T therapy for autoimmune diseases, as well as the recognition from top international academic journals, is undoubtedly another milestone for BRL Medicine. Currently, most CAR-T products on the market or under development are autologous products, whereas TyU19, the UCAR-T product developed by BRL Medicine, represents a typical next-generation product. Its most prominent advantage lies in being derived from healthy donor cells, which allows it to be mass-produced as an off-the-shelf product. It features immediate availability, convenience, safety, low cost, and excellent efficacy, comprehensively overcoming many pain points associated with autologous CAR-T products, such as high personalization, long manufacturing cycles, high failure risks, and extremely high costs. We believe that TyU19 will undoubtedly lead the future direction of the CAR-T field."

Despite the promising therapeutic outcomes of autologous CAR-T in treating hematologic malignancies, its inherent attribute of personalized customization poses significant challenges for commercial promotion. Therefore,Off-the-shelf allogeneic CAR-T with perfect commercial attributes has become the most important development direction in the immune cell therapy industry.However, the development of allogeneic universal CAR-T generally faces several significant technical challenges.

"The development of allogeneic universal CAR-T has always been the biggest technical challenge in the industry. Existing gene editing strategies can effectively disrupt the TCR structure to prevent patients from developing graft-versus-host disease (GvHD), but the rejection problem faced by allogeneic CAR-T cells in patients' bodies has never been effectively resolved."Traditional allogeneic universal CAR-T therapies have consistently posed significant challenges in clinical settings, including the risk of severe infections due to excessive immune suppression, short persistence in the body, and suboptimal efficacy, greatly limiting their clinical accessibility.After 8 years of dedicated research and hard攻关, the research team of this project has effectively solved the aforementioned problems using gene-editing technology. The developed TyU19 achieved long-term persistence and effective killing in patients under FC preconditioning conditions lower than those required for autologous CAR-T.Safety, efficacy, and other indicators have reached or even exceeded those of traditional autologous CAR-T."This is also the most important reason why TyU19 has become the world's first successful allogeneic universal CAR-T therapy for autoimmune diseases."Professor Du Bing, co-corresponding author of the paper and head of CAR-T research and development at BRL Medicine, explained.

In response to this,The first author of the paper, TyUCell^®Dr. Binghe Tan, the technical inventor and project leader, stated:"After years of technical research and iterative upgrades, TyU19 has shown excellent performance in the earlier treatment of B-cell acute lymphoblastic leukemia (B-ALL) and in the recent treatment of autoimmune diseases, fully demonstrating that our new generation of universal CAR-T product has successfully achieved design concept validation. It has also successfully obtained IND approval for the B-ALL indication, smoothly paving the way for the product’s pharmaceutical and clinical development. Currently, based on the characteristics of autoimmune diseases, our team is further conducting pharmaceutical and non-clinical studies of the product, making every effort to advance the domestic and international registration work of this product, striving to bring safe, effective, and affordable universal cell therapy drugs to the clinic as soon as possible for the benefit of patients."

Compared with similar products at home and abroad,BRL Medicine's New Generation UCAR-T Product Has the Following Clinical Advantages:

BRL Medicine's UCAR-T product has achieved effective immune escape through systematic gene editing and modification. During the treatment process, there is no need for HLA typing screening of patients, enabling true off-the-shelf availability and significantly expanding the product's applicability. Moreover, a production scale of over 200 doses per batch has been achieved, which not only greatly reduces production costs but also shortens patient waiting time, substantially enhancing the convenience of using cell therapy products in clinical practice and demonstrating outstanding advantages in clinical treatment.

BRL Medicine's UCAR-T product does not require additional lymphodepletion or immunosuppression for patients. By adopting only conventional or even lower lymphodepletion regimens, it can achieve complete elimination of tumor cells while effectively avoiding risks such as infection, agranulocytosis, and slow lymphocyte recovery caused by excessive immunosuppression in patients, demonstrating extremely high clinical safety.

The T cells of BRL Medicine's UCAR-T product are derived from young and healthy donors, whose activity is far superior to the immune cells of patients with long-term hematological diseases. After infusion, they exhibit excellent expansion potential and persistence. In the early IIT research of the product, BRL Medicine's UCAR-T has already demonstrated significant and durable tumor clearance capabilities, rapidly achieving complete disease remission.

It can be said that BRL Medicine's next-generation UCAR-T product has addressed the key pain points and challenges in the CAR-T treatment industry, achieving a comprehensive enhancement in efficacy, safety, and clinical accessibility, with significant industrialization advantages. Its excellent clinical safety, treatment outcomes, and extremely low production costs allow more patients with autoimmune diseases and cancer to fully benefit from the high-tech advantages of CAR-T therapy. Currently, BRL Medicine has comprehensively laid out a multi-target, multi-indication universal CAR-T for the treatment of autoimmune diseases. In the future, BRL Medicine will continue to expand the application of UCAR-T in this disease area and fully promote its clinical translation and application in autoimmune diseases and cancer treatment, aiming to provide better treatment options for a wide range of patients.

Paper link:
https://doi.org/10.1016/j.cell.2024.06.027