The Summary of the Project

Drug design using molecular dynamics of computer simulation

 Advanced cancer with relapse and metastases are the leading causes of death in Japan. Besides the physical suffering caused by cancer, multiple organ failures, and the side effects of surgery, chemotherapy, or radiation therapy, patients must also face a significant financial burden associated with cancer treatment.

 Howrver, at present, there is a critical need for technological advances because antibody drugs have a low response rate with limited application in spite of high treatment cost. Furthermore, total remission is still difficult to achieve.

 MDADD (Molecular Dynamics for Antibody Drug Development/Antibody-structure-based design Projects) is a funded from the Japanese Government as one of 30 programs for World Leading Innovative R&D on Science and Technology.. In MDADD, leading researchers from different fields came together sharing the common research goal of developing multifunctional antibodies that can be used for targeted treatment of advanced cancer.

 The project is directed by Dr. Tatsuhiko Kodama at the Research Center for Advanced Science and Technology, the University of Tokyo. Dr. Tatsuhiko Kodama is an advocate of "Genome Antibody Drug Development. His research group has also generated one of the world's largest monoclonal antibody libraries."

 Through the screening of the monoclonal antibody library, a lead monoclonal antibody for cancer will be selected using PET imaging and cancer-bearing animals.

 X-ray crystal structure of the antigen-antibody complex will be determined. A thermodynamic analysis will be carried out to further improve the stability of the structure of the antigen-antibody complex. Based on this information, a construct of a single-chain variable fragment (scFv) fused with streptavidin (SA) with reduced antigenicity,will be expressed in and purified from Escherichia coli.

 Biotin labeled with γ-emitting radionuclides will be used for PET diagnostics and biotin labeled with β-emitting radionuclides will be used for treatment. With this approach, we will develop pre-targeting drugs that are safe for humans.

 Our primary goal is to have these drugs available for clinical use within three years. The first goal is to have our first-generation antibody drugs for hepatoma approved for clinical use in the world. The next goal is to submit our second generation RIT lung cancer antibody drugs and third generation gastrointestinal cancer drugs for pre-targeting treatment for clinical trials.

 Another goal is to increase the response rate and efficacy of antibody drugs for advanced cancer, as well as reducing medical costs, and developing the technology for computerized structure-based design for Multifunctional Antibodies. It is our hope to make our country's antibody drugs the best in the world through continuous innovation.