Shanghai Cellular Therapy Group's BZD1901, the World’s First Autocrine Nanobody CAR-T Therapy, Receives IND Approval for Phase I/II Clinical Trials

Source: PharmaCloud Database

Professor Qijun Qian, Chairman and CEO of Shanghai Cell Therapy Group, first proposed the concept of autocrine antibody cytotoxic cell drugs internationally in 2010, which improves/enhances by altering the local tumor microenvironment.CAR-TEfficacy in the treatment of solid tumors, and received a Chinese invention patent authorization in March 2015. This is the conceptual prototype of the Baize T-cell. Subsequently, more than 30 related patents were applied for around this unique product concept, forming a systematic patent moat. However, there were still some challenges at that time. Technically, CAR-T cells have difficulty in autocrine high-level antibodies, thus failing to effectively change the tumor microenvironment in a real sense.

In 2018, Professor Qijun Qian met with internationally renowned antibody expert Professor Weimin Zhu, the inventor of rabbit monoclonal antibodies. After in-depth discussions, they agreed to establish a world-class nanobody discovery platform utilizing camelid B cells.ImmunityLibrary features, gene sequencing, and artificial intelligence were utilized to extensively search for nanobodies with high expression and high stability. This idea received strong support from the Shengzhou Municipal Government of Zhejiang Province, leading to the establishment of a 4,100-acre camel breeding base in Shengzhou. Concurrently, advanced nanobody R&D platforms were set up in Shanghai and San Francisco, USA. In 2019, the nanobody R&D platform successfully screened out nanobodies such as MSLN and PD-1 that met the expected functional characteristics, which were then applied to CAR-T cells. In vivo and in vitro studies demonstrated excellent antibody secretion levels and tumor-killing effects.

On October 28, 2019, Sun Yan, co-founder, vice president, and president of cell therapy at Shanghai Cell Therapy Group, led a team to officially initiate the project for the world’s first autocrine nanobody CAR-T cell drug product targeting tumors and their immunosuppressive microenvironment (anti-PD1 MSLN-CAR-T), marking the start of drug development and clinical-stage proof-of-concept for Baize T cells (CAR-T with autocrine antibodies) in the treatment of solid tumors.

Sun Yan introduced that BZD1901, as the world's first self-secreted nanobody CAR-T cell drug independently developed in China, adopted non-viral gene writing technology and high-expression self-secreted nanobody technology during its development. The application of these innovative technologies in this product not only brings significant potential for breakthroughs in solid tumor efficacy but also presents severe challenges for the entire product development process. Particularly, the challenge lies in developing a CAR-T product process based on an innovative non-viral vector, with production success rates no less inferior—and potentially superior—to viral vectors, while significantly reducing CAR-T product costs through the non-viral vector. At the same time, achieving high robustness and strong commercial feasibility for the non-viral vector-based product process is critical. Additionally, formulating and implementing clinical development strategies for CAR-T products based on self-secreted antibodies also present substantial challenges. To overcome these difficulties, Shanghai Cell Therapy Group launched three major initiatives focused on BZD1901’s process, clinical trials, and product supply, leveraging mature tools and methodologies to continuously advance and deepen related research efforts. In early 2021, the process front made a breakthrough first, completing the integration of new processes, scale-up verification, technology transfer, and the successful preparation of over 25 batches of clinical samples with a 100% success rate within just three months, while significantly improving product quality.

Sun Yan said that with the resolution of product supply issues, the clinical battlefield reached over 2,800 target indication patients in 3-4 months, rapidly advancing the exploration of sensitive indications, dosage, and efficacy. It completed the clarification of more than two potential sensitive indications and discovered breakthrough efficacy potential in mesothelin-positive rare diseases. This prepared the product for rapid market entry to address some urgent clinical needs. Meanwhile, translational medicine, based on the correlation study of BZD1901’s in vivo and in vitro as well as clinical data, gradually revealed the unique anti-tumor mechanism of the innovative nanobody-armed cell drug concept, promoting further research into the scientific and clinical aspects of this innovative drug category, laying a solid foundation for the launch of a series of nanobody-armed cell drug products.