Science and Technology Platform Program for Advanced Biological Medicine


Rapid de novo generation of bispecific fully human antibodies and their seamless optimization

<Project Leader> Hidetaka Seo, PhD

Graduate School of Arts and Sciences, The University of Tokyo

Hidetaka Seo

When we are infected with pathogens like viruses or bacteria, our immune system produces proteins named “antibodies”, which recognize the individual pathogens. Antibodies bind specifically to pathogens and inactivate them, or antibodies bound to pathogens become “flags” for the immune system to exclude pathogens. Making use of these properties of antibodies, “therapeutic antibodies” have been developed as drugs for cancer, autoimmune diseases and infectious diseases etc. For example, some therapeutic antibodies bind to the surfaces of tissue cells and these tissue cell-antibody complexes are removed by immune system, and others induce signals in the tissue cells to commit suicide when they bind to the tissue cells. Therapeutic antibodies are highly effective and, as antibodies are proteins naturally produced in our bodies, they are highly safe, which makes them the most successful type of drug these days. However, there are concerns that the discovery of novel lead therapeutic antibodies would be more difficult in the future because of the “exhaustion” of the therapeutic targets and the limited mode of action of antibodies. “Bispecific antibody”, which recognizes two targets simultaneously, is one of the most anticipated formats of the next generation therapeutic antibodies. In fact, some therapeutic bispecific antibodies have been approved which cross-link cancer cells and immune cells, resulting in the killing of the cancer cells by the immune cells. However, the discovery of the bisipecific antibody-based drug candidates requires complicated and laborious experimental processes, prolonging the overall discovery timeline. So far, we have developed an in vitro method to generate monoclonal antibodies, namely the ADLib system, as a platform technology to generate therapeutic lead antibodies rapidly. In this project, utilizing the result of the basic studies on immunoglobulin gene rearrangements and chromosome structure, we are developing a bispecific version of the ADLib system. Our goal is to build a technology that isolates the antigens specific bisopecific clones effectively and rapidly by simple process including cell culturing and magnetic beads selection. We also aim to develop a method to enhance the binding activities of these bispecific antibodies seamlessly using the obtained clones. Through this project, the rapid and effective generation of bispecific antibodies and their optimization will be enabled, accelerating the development of the next generation therapeutic antibodies.

Figure 1 Figure 1: The principle of the ADLib system. The immunoglobulin genes of DT40 cell, an avian derived immune cell line, are diversified when cells are treated with a drug named TSA. As this cell line displays antibodies on their surfaces, the cells presenting the antibodies that react with targets can be isolated using magnetic beds conjugated with targets followed by the purification by magnets. The secreted type of antibodies can be recovered from the medium. Since DT40 cells proliferate rapidly, the antibodies can be obtained within 10 days at the shortest.
Figure 2 Figure 2: The antibody selection by the ADLib system. The tubes containing the mixture of the cells and the magnetic beads conjugated with targets are placed in magnets. The cells presenting the antibodies that react with targets are isolated.
Figure 3 Figure 3: The antibody-presenting cells isolated by the ADLib system are analyzed by flow cytometer.
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