Looking to the Future of Bispecific Antibody Production

A recent study has been published exploring the trends in bispecific antibody (bsAb) production and their future potential. Conducted by a multi-institutional research team, the findings were published in the Journal of Chromatography A (1).

Microbiology. Antibodies attack virus. 3d illustration | Image Credit: © vipman4 - stock.adobe.com

Bispecific antibodies (bsAbs) are antibodies that have two distinct binding domains, which can bind to two antigens or two epitopes (an antigen part) of the same antigen simultaneously (2). BsAb development has been revolutionized by genetic engineering approaches, which has enabled the creation of a variety of molecular structures. Their therapeutic potential has led to the creation of over 50 different formats of recombinant bsAbs. While increasing bsAbs’ valency can provide various advantages for therapeutic applications, it also presents unique challenges when producing bsAb-specific byproducts. Despite the abundance of detailed reviews discussing various bsAb formats and the corresponding upstream and downstream technologies and strategies designed to minimize drawbacks, scientists still need to explore therapeutic applications further.

Rational development, selecting the proper expression system, and designing constructs help enable successful production of novel antibodies in sufficient quantities. While optimized downstream processing protocols for monoclonal antibodies (mAbs) provide solid foundations for purifying bsAbs, further optimization is often necessary due to inherent structural differences, physicochemical properties, and bsAb-related byproducts. In this review, the scientists looked at recent trends in bsAb production, focusing on the practical application of various expression platforms and protein purification approaches that are suitable and impactful for the bsAb bioprocess development, with a particular focus on cell- and cell-free-based heterologous production. They describe existing bioanalytical methods and novel development considerations to support rational bsAbs design and explain the need for further progress and streamlined development of the abovementioned.

Key developments they highlighted include improvements in modular antibody design, novel expression systems, and optimization of bioprocessing techniques to enhance stability, yield, and efficacy. The unique structures of bsAbs introduce more complicated molecular engineering challenges than traditional mAbs, making careful consideration vital to further development. These therapies are meant to target multiple pathways simultaneously, which can enhance their effectiveness when compared to conventional treatments.

The scientists predict the next decade will bring advances in the clinical application of bsAbs and mAbs. With more bsAbs being developed as crucial biotherapeutics, it is essential to create more comprehensive and rigorous early development criteria. The most promising candidates can be selected through evaluating opportunities in the early discovery phase, which can be efficiently conducted in a rapid and high-throughput fashion while using minimal amounts of materials. According to the scientists’ conclusions, “Such progress can potentially enhance both process productivity and product quality, especially given the significant clinical promise of bsAbs.”

Developing and clinically implementing bsAbs and mAbs holds great promise for meeting significant unmet medical needs across various disease states, which can help create more effective and targeted treatment options. For example, in oncology, they can better engage the immune system’s ability to attack tumors or offer new strategies for neutralizing pathogens that cause infectious diseases. While there are more developments to be made, this shows the potential bsAbs and mAbs have for making various processes easier and more streamlined.

References

(1) Karbyshev, M. S.; Kalashnikova, I. V.; Dubrovskaya, V. V.; et al. Trends and Challenges in Bispecific Antibody Production. J. Chromatogr. A 2025, 1744, 465722. DOI: 10.1016/j.chroma.2025.465722

(2) Bispecific Antibodies: An Area of Research and Clinical Applications. https://www.fda.gov/drugs/spotlight-cder-science/bispecific-antibodies-area-research-and-clinical-applications (accessed 2025-2-5)