Annual Report 2021
Division of Developmental Therapeutics
Masahiro Yasunaga, Yoshikatsu Koga, Hiroki Takashima, Ryo Tsumura, Hirobumi Fuchigami, Takahiro Anzai, Rumi Fujioka, Chihiro Morizono, Hiroko Shinohara, Yuniko Hamane, Shigehiro Koganemaru, Kenji Takashima, Yu Shibahara, Junichiro Harada, Tamaki Hirakawa, Shiqi Yang, Fang Yu Liu, Jinrui Jiang, Mikiko Itsukaichi, Kensuke Harada, Mamiko Shimada, Shinji Saijo, Shingo Hanaoka
Introduction
The Division of Developmental Therapeutics has been involved in basic research on drug delivery systems (DDSs) and antibody therapeutics including monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), radioimmunotherapy (RIT), and bispecific antibodies (BsAbs). We have applied for patents for all mAbs established by our division. In addition, we are introducing several cell biology approaches to develop innovative immunoregulation methods to improve the efficacy of antibody drugs in clinics. Furthermore, we are also developing novel cancer diagnosis and treatment techniques using original mass spectrometry and bioinformatics technologies.
The Team and What We Do
- Development of antibody drugs and their deployment to pharmaceutical companies
- Research and development of immunoregulation methods linked to next-generation antibody technology
- Conducting translational research utilizing mass spectrometry
Research activities
1. DDSs in cancer chemotherapy
A drug delivery system (DDS) is a technology that enables drugs to be delivered to the desired tissues or cells (targeting) via a specialized drug carrier (material). The required amount of drugs can be released through particular drug formulations (controlled release). Anticancer agents can become distributed throughout the whole body, leading to adverse side effects, but DDS drugs can target the tumors alone, enhancing the action of the drugs and minimizing the toxicities.
2. Development of original antibody therapeutics by us
Although clinical applications of antibody therapeutics have progressed, they have not been applied to refractory cancers such as pancreatic cancer and diffuse gastric cancer. We reported that drug delivery could be disturbed by the dense stroma in such cancers (i.e., the tumor stromal barrier). To overcome the tumor stromal barrier, we are developing novel antibody drugs that can penetrate into tumor cells efficiently. Moreover, molecular imaging allows precise evaluation of antibody drugs by visualizing the entire pharmacological process. In addition, refractory or remnant tumor cells themselves are likely to be resistant to general chemotherapy. Alpha emitters with high-energy and linear-energy transfer, which exert greater cytotoxicity, could be used for the treatment of chemoresistant refractory cancer. Hence, we are pursuing pharmaceutical research and development of ADCs and RIT in collaboration with professionals in various research fields.
We are also developing T cell-dependent bispecific antibodies (T-BsAbs) that can eliminate tumor cells independently of MHC engagement; this is expected to become a novel type of immunotherapy against refractory cancer. However, immune deserts and T cell exhaustion are major obstacles to the clinical application of T-BsAbs against solid tumors. Accordingly, we are exploiting some breakthrough technologies in order to overcome these drawbacks.
We have found various cell surface molecules specific to colorectal cancer and created mAbs that correspond to these molecules. We are developing an anti-TMEM 180 mAb for clinical application.
Furthermore, we have proposed a concept of immune targeting; anti-IL-7R ADC is effective in both lymphoid malignancies and autoimmune diseases.
3. Advanced mass spectrometry and bioinformatics systems
Mass spectrometry (MS) allows us to visualize payloads released from ADCs and observe the signature of drug-induced cell injury by monitoring changes in biomolecules and metabolites influenced by them. Such approaches are helpful for elucidating the bystander effect and immunogenic cell death (ICD), which lie at the cutting edge of ADC research. Therefore, we are able to evaluate the mechanism of action (MOA), pharmacokinetics (PK), and pharmacodynamics (PD) of new drugs. Moreover, we will develop novel diagnostic methods using MS and bioinformatics systems.
Education
1) Doctoral student
Graduate School of Frontier Sciences, the University of Tokyo: two students
Juntendo University: two students
2) Masters students
Graduate School of Frontier Sciences, The University of Tokyo: five students
Future Prospects
We are developing ADCs and RIT as armed therapeutic antibodies against refractory cancers such as pancreatic cancer and brain tumors. We are developing new technologies for strict temporal and spatial regulation of host T cells (T cells as DDSs) through taking a unique drug discovery approach based on host factors as well as the drugs themselves. Our advanced mass spectrometry and bioinformatics analysis capabilities can support the effective translation of preclinical research into research involving humans. Our cutting-edge research, such as co-clinical trial projects, DDS work, and molecular imaging studies, will also promote the development of new drugs through interdisciplinary and industry-academia collaboration.
List of papers published in 2021
Journal
1. Kamakura D, Asano R, Yasunaga M. T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity. Pharmaceuticals (Basel, Switzerland), 14:2021
2. Takashima H, Koga Y, Manabe S, Ohnuki K, Tsumura R, Anzai T, Iwata N, Wang Y, Yokokita T, Komori Y, Mori D, Usuda S, Haba H, Fujii H, Matsumura Y, Yasunaga M. Radioimmunotherapy with an 211 At-labeled anti-tissue factor antibody protected by sodium ascorbate. Cancer science, 112:1975-1986, 2021
3. Anzai T, Saijou S, Ohnuki Y, Kurosawa H, Yasunaga M, Matsumura Y. TMEM180 contributes to SW480 human colorectal cancer cell proliferation through intra-cellular metabolic pathways. Translational oncology, 14:101186, 2021
4. Tsumura R, Anzai T, Manabe S, Takashima H, Koga Y, Yasunaga M, Matsumura Y. Antitumor effect of humanized anti-tissue factor antibody-drug conjugate in a model of peritoneal disseminated pancreatic cancer. Oncology reports, 45:329-336, 2021
5. Manabe S, Takashima H, Ohnuki K, Koga Y, Tsumura R, Iwata N, Wang Y, Yokokita T, Komori Y, Usuda S, Mori D, Haba H, Fujii H, Yasunaga M, Matsumura Y. Stabilization of an 211At-Labeled Antibody with Sodium Ascorbate. ACS omega, 6:14887-14895, 2021
6. Shiraishi T, Ikeda K, Tsukada Y, Nishizawa Y, Sasaki T, Ito M, Kojima M, Ishii G, Tsumura R, Saijou S, Koga Y, Yasunaga M, Matsumura Y. High expression of TMEM180, a novel tumour marker, is associated with poor survival in stage III colorectal cancer. BMC cancer, 21:302, 2021