Science and Technology Platform Program for Advanced Biological Medicine


Highly bioorthogonal chemistry for multifunctional antibody-drug conjugates

<Project Leader> Takamitsu HOSOYA

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University

Takamitsu HOSOYA

Antibody-Drug Conjugates (ADCs) are biopharmaceuticals that consist of an antibody and a payload, such as anticancer drug. Many pharmaceutical companies are currently working on research of the development of new ADCs, and some ADCs are used for treatment for patients with intractable cancer. An antibody part in an ADC binds to the receptors on the surface of cancer cells with high specificity, and thus is taken up into cancer cells selectively. After degradation in lysosomes under their low pH environment, the payloads are released in cancer cells. Therefore, compared to the conventional dosing of anticancer drugs, the treatment with ADCs allows the drugs to reach the affected part in the body efficiently, exhibiting higher therapeutic effects. According to this mechanism, it seems desirable to introduce as many anticancer drugs into an antibody as possible. However, some research groups reported that the suitable ratio of a drug to an ADC for the highest therapeutic effect was 3 to 5. This would be because the introduction of a large number of highly hydrophobic anticancer drug caused the decrease of hydrophilicity of the ADCs. As a result, fewer drugs could reach the affected area, and the therapeutic effect would decrease. In order to further enhance the efficiency of ADCs, it is necessary to develop a new method to introduce a large number of anticancer drugs into an antibody while maintaining its high hydrophilicity.
In this research project, we would like to tackle this problem by applying the highly hydrophilic skeleton, such as carbohydrates and amino acids, as the platform to connect the drugs to the antibody. Our group has been developing the multi-click chemistry, which enables to introduce some functional molecules to the platform sequentially. We will achieve the introduction of anticancer drugs into antibodies with remaining hydrophilicity through the development of the new highly hydrophilic platform and the sophistication of the multi-click chemistry. We have strong cooperative relationship between RIKEN, who has a new technology on the stimuli-responsive cleavable linker that enables the release of anticancer drugs from the ADCs, and Shinshu University, who has the knowledge and equipment to evaluate of the efficiency of ADCs. The successful achievement of this project will not only reduce the drug dosage and the treatment cost, but also broaden the scope of anticancer drugs, promoting entry of many pharmaceutical companies into the development of ADCs. Furthermore, this technology, which can deliver a large number of compounds to the affected part, would open the door to the application of ADCs for other diseases.

Figure 1 Figure 1: Aim of this project: Development of the highly bio-orthogonal chemistry for multifunctional antibody-drug conjugates
Figure 2 Figure 2: Click reaction: Cycloaddition between azides and alkynes
Figure 3 Figure 3: Multi-click chemistry developed by our group
Figure 4 Figure 4: Cooperative relationship between TMDU, RIKEN, and Shinshu University


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