二重特異性抗体とは？

Bispecific antibodies (bsAbs) are engineered molecules designed to target two different antigens or epitopes. This dual-targeting capacity sets them apart from traditional monoclonal antibodies (mAbs), which bind to a single antigen. This unique ability makes bsAbs especially promising in therapeutic applications, particularly in cancer treatment.¹

Therapeutic Potential of Bispecific Antibodies (bsAbs) 

Multi-specific antibodies refer to antibodies with more than one binding site. These multi-specific antibodies increase antibody-mediated effects, such as disrupting multiple tumor-associated antigens (TAA) or increased recruiting and activation of immune cells, because they have multiple antigen-binding sites.²

Moreover, bsAbs can be customized to engage not only T cells but other components of the immune system, such as natural killer (NK) cells or macrophages, offering flexibility in immune system engagement. This flexibility holds great promise for treating cancers that are resistant to traditional therapies, as it opens new avenues for immune system modulation.

Related: Bispecific Antibodies: Design, Development, and Therapeutic Potential 

Mechanism of Action and Design of bsAbs 

The functional design of bsAbs is key to their success in targeting two different sites. These antibodies are engineered to bind to two distinct antigens: one often found on the surface of a tumor cell and the other on an immune effector cell, such as a T cell. By bringing these two cell types into close proximity, bsAbs facilitate the immune cell’s ability to destroy the cancer cell.

One of the most prominent examples of bsAbs in action is blinatumomab, a bispecific T cell engager (BiTE). Blinatumomab binds to CD19, a protein commonly expressed on B-cell malignancies, and CD3, a component of the T cell receptor complex. By bridging these two cells, it leads to the activation of T cells and subsequent killing of the B-cell malignancy. This approach has shown remarkable success in clinical trials, particularly in treating certain leukemias and lymphomas.

The structural engineering of bsAbs involves various formats, from tandem single-chain variable fragments (scFv) to more complex full-length antibodies with dual Fab regions. These configurations allow bsAbs to be fine-tuned for specific therapeutic needs, enhancing their stability, half-life, and efficacy. They are typically divided into two categories based on the Fc region: IgG-like subtypes containing an Fc region and non-IgG-like subtypes without an Fc region.

Related: Engineered Antibody Formats: A Historical Perspective

Advantages Over Monoclonal Antibodies (mAbs) 

While monoclonal antibodies (mAbs) have been transformative in cancer therapy, their single-target approach has limitations, especially in dealing with the heterogeneous nature of cancer. Tumor cells often express multiple antigens, and single-target therapies may allow for the survival of cancer cells that do not express the target antigen. This can lead to treatment resistance and recurrence of the disease. 

In contrast, bsAbs offer the advantage of dual targeting, which increases their ability to counteract the complexity of tumor biology. By binding to two different antigens, bsAbs can overcome antigen escape, a common issue in cancer therapies where tumors evolve to lose the target antigen. Moreover, the ability of bsAbs to simultaneously recruit immune cells adds to their cytotoxic effects, leading to more efficient tumor cell killing. 

The versatility of bsAbs also allows for combination strategies in cancer treatment. For example, bsAbs can be used in conjunction with other therapies, such as immune checkpoint inhibitors or small molecule drugs, to enhance therapeutic efficacy. This combination approach is a promising area of research, as it leverages the strengths of multiple therapeutic modalities to attack cancer from different angles. 

Applications in Cancer and Beyond

Although cancer treatment has been the primary focus of bsAbs, their potential applications extend beyond oncology. Autoimmune diseases, infectious diseases, and inflammatory conditions are all areas where bsAbs are being explored. In autoimmune diseases, bsAbs could be designed to block inflammatory pathways while simultaneously promoting immune regulation, offering a novel approach to treating conditions like rheumatoid arthritis or lupus. 

In infectious diseases, bsAbs could be engineered to bind both a pathogen and an immune effector cell, promoting more efficient pathogen clearance. This approach is particularly appealing in the context of viral infections, where the ability to enhance immune recognition of infected cells could improve treatment outcomes. 

Furthermore, bsAbs are being investigated for their role in tissue regeneration and repair, particularly in diseases where specific cell types need to be targeted for regeneration. By binding to both a regenerative cell population and a signaling molecule, bsAbs can direct the body’s natural repair processes to sites of tissue damage. 

References: 

1. Ma, J., Mo, Y., Tang, M., Shen, J., Qi, Y., Zhao, W., Huang, Y., Xu, Y., & Qian, C. (2021). Bispecific Antibodies: From Research to Clinical Application. Frontiers in Immunology, 12, 626616. https://doi.org/10.3389/fimmu.2021.626616

2. Elshiaty, M., Schindler, H., & Christopoulos, P. (2021). Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer. International Journal of Molecular Sciences, 22(11), 5632. MDPI AG. Retrieved from http://dx.doi.org/10.3390/ijms22115632