BP2301

1. CAR-T structure and mechanism of action
A chimeric antigen receptor (CAR) is a synthetic protein introduced into T cells to redirect antigenic specificity and to enhance cellular anti-tumor functionality. Viral or non-viral vectors are used to transduce the gene encoding CAR into the T cells collected from the patient.

The CAR typically consists of an extracellular antigen-binding domain from an antibody and an intracellular T-cell activation and signaling domain.

The antigen recognition domain of CAR consists of the variable regions of heavy (VH) and light (VL) chains of tumor antigen-specific monoclonal antibody linked as a single chain (scFv). The receptor is designed to allow CAR-T cells to target and lyse cancer cells. In addition to the antigen-binding site, the CAR gene contains signal transduction domain, which triggers activation signals in the CAR-T cells and releases cytotoxic proteins such as perforin and granzymes.

2. How CAR-T cell therapy works
Patient's T cells are reprogrammed with CAR ex vivo to recognize and attack cancer cells expressing the cancer-specific antigen.

(1) Collect white blood cells, including T cells, from a patient.

(2) Transfect CAR-encoding genes into the T cells.

(3) Expand the CAR-T cell population in culture.

(4) Infuse CAR-T cells into the patient's blood.

(5) CAR-T cells proliferate in the patient's body and attack cancer cells.

3. Characteristics of BP2301 BP2301 targets the HER2 antigen and uses a non-viral vector (PiggyBac transposon) to transfer the gene encoding HER2 CAR into T cells, which leads to high proliferative capacity and long-term persistence of CAR-T cells.

Most CAR-T therapies use viral vectors for CAR gene transfer, which leads to limited engraftment and a response duration lasting from a few days to a few weeks. This could cause a potential limitation of CAR-T cell efficacy in solid tumors that have an immunosuppressive tumor environment where long-term persistence of anti-tumor effects is required. To overcome this, BP2301 uses a non-viral gene transfer method established by Professor Yozo Nakazawa's team and the newly developed CAR-T cell culture method (patent applied jointly with BrightPath). The BP2301 T cell subset is largely composed of young memory T cells (TSCM, TCM), which have stem cell-like properties and differentiate into effector cells upon antigenic stimulation. Such a cell population rich in young memory T cells exhibits high proliferative capacity and achieves long-term persistence of anti-tumor effects, which is expected lead to better clinical efficacy.

BP2301 was developed by Dr. Yozo Nakazawa, Professor and Chairman of the Department of Pediatrics, Shinshu University School of Medicine, and Dr. Shigeki Yagyu, Assistant Professor, Department of Pediatrics, Kyoto Prefectural University of Medicine.

An investigator-initiated clinical trial of BP2301 in solid tumors (osteosarcoma) was initiated in 2020.

While viral vectors serve as a tool for efficient gene transfer into host cells, the clinical use of viral vectors requires high-quality production facilities and extensive safety testing. In contrast, the non-viral gene transfer method established by Professor Nakazawa has the advantage of being easy to use with simplified equipment without compromising the anti-tumor effects of output products.

PiggyBac transposon-mediated HER2-CAR-T cells exert anti-tumor efficacy against cholangiocarcinoma

SITC 2023

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Development of piggyBac transposonmediated HER2-CAR-T cells for the treatment of solid tumors

AACR 2022

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