Clinical development of cancer-specific antibodies based on the CasMab method

Targeting only cancer cells: Creating a stream of antibody drugs with reduced side effects

In recent years, antibody drugs have come to account for a very large share of biopharmaceutical sales. Antibodies of all formats have been developed-including bispecific antibodies (BsAb) and small-format antibodies (scFv and nanobody)-in addition to the conventional immunoglobulin G (IgG). Their application in various modalities has grown rapidly, including antibody-drug conjugates (ADC), T cell engagers (TCE), and chimeric antigen receptor T cell (CAR-T) therapy. In particular, the clinical application of BsAb-ADC combinations is gaining momentum, and presentations on BsAb-ADC clinical trials now dominate international oncology conferences. However, clear answers have yet to emerge regarding the optimal combination of target molecules, desirable antibody properties, and other questions. Furthermore, despite many pharmaceutical companies and academic researchers pursuing CAR-T therapy for solid tumors, not a single product has been launched on the market anywhere in the world. While there are clearly many problems yet to be solved, Tohoku University remains committed to developing the most fundamental building block-the monoclonal antibody-rather than chasing the increasingly crowded field of modality development. Monoclonal antibody development is probably the most unglamorous work in biopharmaceutical development, yet every day I am struck by just how deep the craft of antibody creation goes.

Tohoku University has focused its efforts on developing cancer-specific antibodies known as CasMab® (Cancer-Specific Monoclonal Antibody). Regardless of which modality an antibody is applied to, toxicity to normal tissue is always a concern. However, the number of molecules that are highly expressed specifically in cancer cells is limited, and ideal target molecules are becoming scarce. With this in mind, we reasoned that if we could develop antibody drugs with no side effects, even against proteins that are highly expressed in normal cells, treatment options for intractable cancers could advance dramatically. We therefore pursued breakthrough technology development to solve this problem over the ten years of two predecessor AMED programs: the Basic Science and Platform Technology Program for Innovative Biological Medicine and the Science and Technology Platform Program for Advanced Biological Medicine, through which a total of 56 antibody drug seeds were out-licensed to companies. Although fewer than two years have passed since the Research and Development Program for Innovative Biologics began, we have already out-licensed CasMab antibodies against two membrane proteins to industry partners.

When we examine the differences between proteins expressed in normal and cancer cells, almost no differences in amino acid mutations or glycan structure can be found. Nevertheless, we have succeeded in developing our own method to obtain CasMab antibodies that specifically recognize the subtle structural changes seen in cancer cells. A CasMab targeting HER2-which is highly expressed in breast and gastric cancers-was out-licensed to a company, and a clinical trial in the United States using it as a CAR-T therapy began in January 2024. Fortunately, no toxicity has been reported to date. Tohoku University will continue its research and development with the goal of rapidly and precisely creating CasMab antibodies against intractable cancers. As noted, antibody production is unglamorous work, but our laboratory is equipped with numerous analytical instruments (currently, 14 flow cytometers) and carries out antibody production in a high-throughput manner. We also operate a large number of cell culture devices (currently, 32 CO₂ incubators) to support large-scale antibody production. Through this steady, patient work, we will continue out-licensing drug seeds to pharmaceutical companies one after another.

We believe the right division of roles is for academia to focus on developing drug seeds of a kind unmatched elsewhere, and for pharmaceutical companies to take the lead on clinical trials once those seeds have been transferred. Out-licensing from academia to industry is an important step, but it is not the ultimate goal. What matters is advancing drug seeds into clinical trials, getting them to patients, and saving those who are suffering from cancers with no current treatment options. We will continue developing CasMab antibodies one after another, pressing forward in our effort to overcome intractable cancers.