Annual Report 2022
Division of Developmental Therapeutics
Masahiro Yasunaga, Yoshikatsu Koga, Hiroki Takashima, Ryo Tsumura, Hirobumi Fuchigami, Takahiro Anzai, Boran Osman, Chihiro Morizono, Hiroko Shinohara, Shigehiro Koganemaru, Chikako Funasaka, Hideki Tanaka, Kenji Takashima, Yu Shibahara, Yusuke Abe, Shiqi Yang, Hao Shi, Fang Yu Liu, Jinrui Jiang, Mikiko Itsukaichi, Kensuke Harada, Jira Huma, Yuka Tada, Teppei Azuma, Sota Matsumoto, Mamiko Shimada, Shinji Saijo, Shingo Hanaoka, Yuki Fujiwara, Junichiro Harada.
Introduction
We are developing next generation therapeutic antibodies such as antibody-drug conjugates (ADCs), radioimmunotherapy (RIT), and bispecific antibodies (BsAbs) using drug delivery system (DDS) and molecular imaging. Moreover, we have applied for patents for all monoclonal antibodies established by our division. In addition, we utilize several cell biology approaches to develop innovative immunoregulation methods to improve the efficacy of antibody drugs in clinics. Furthermore, we are developing a novel cancer diagnosis and treatment using original mass spectrometry and bioinformatics technologies.
The Team and What We Do
- Development of antibody drugs and their derivation to pharmaceutical companies
- Research and development of immunoregulation methods linked to next-generation antibody technology
- Conducting translational research utilizing mass spectrometry
Research Activities
1. DDS 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 be distributed throughout the whole body, leading to adverse side effects, but DDS drugs can target tumors only, enhancing the efficacies and minimizing the toxicities.
2. Development of our original antibody therapeutics
Although clinical applications of antibody therapeutics have progressed, they have not been applied to refractory cancers such as pancreatic cancer (PC) and brain tumor. We reported that drug delivery could be disturbed by the dense stroma in PC (i.e., the tumor stromal barrier). We have established mixed spheroid models composed of pancreatic cancer cells and cancer associated fibroblasts, and PC-PDX models, which is useful to exploit anti-PC antibody drugs via the evaluation of both antibody delivery and efficacy against tumor stromal barrier. Moreover, blood brain barrier (BBB) strongly suppresses the delivery of antibody drugs in brain tumor. Therefore, we have established preclinical orthotopic models of brain tumor and visualized the antibody delivery through BBB. Accordingly, we are developing novel ADCs with DDS technologies in order to overcome tumor stromal barrier and BBB. Furthermore, 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 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 independent of MHC engagement; which is expected to be a novel type of immunotherapy against refractory cancer. However, an immune desert and T cell exhaustion are major obstacles to the clinical application of T-BsAbs against solid tumors. Therefore, we are exploiting some breakthrough technologies in order to overcome these drawbacks.
We discovered TMEM180 as a novel colon cancer-specific protein and created anti-TMEM180 antibody drug. More recently, first in human clinical trial of anti-TMEM180 antibody drug has been started. 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 monitor the relevant biochemical or metabolic changes influenced by them. MS is also 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 a novel diagnostic method using MS and bioinformatics systems. Currently, we have established a breath biopsy platform consisting of breath collection and MS-based analysis.
Education
1) Doctoral students
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: eight students
Future Prospects
We are developing ADCs and RIT as armed therapeutic antibodies against refractory cancers such as PC and brain tumors. We are also developing new biotechnologies for good-chemotaxis activation and infiltration of host T cells (T cells as DDSs) to change cold tumors to hot tumors through taking a unique drug discovery approach based on host factors as well as the drugs themselves. Our advanced mass spectrometry, including breath biopsy, can support the translational researches of various types of drugs. Our cutting-edge research, such as the co-clinical trial project, DDS, and molecular imaging studies, will also promote the development of new drugs through interdisciplinary and industry-academia collaboration.
List of papers published in 2022
Journal
1. Koganemaru S, Kawai T, Fuchigami H, Maeda N, Koyama K, Kuboki Y, Mukohara T, Doi T, Yasunaga M. Quantitative analysis of drug distribution in heterogeneous tissues using dual-stacking capillary electrophoresis-mass spectrometry. British journal of pharmacology, 180:762-774, 2023
2. Takashima H, Ohnuki K, Manabe S, Koga Y, Tsumura R, Anzai T, Wang Y, Yin X, Sato N, Shigekawa Y, Nambu A, Usuda S, Haba H, Fujii H, Yasunaga M. Tumor Targeting of (211)At-Labeled Antibody under Sodium Ascorbate Protection against Radiolysis. Molecular pharmaceutics, 20:1156-1167, 2023
3. Fuchigami H, Matsumura Y. Characterization of antibody clones that bind exclusively to insoluble fibrin. Blood coagulation & fibrinolysis, 34:20-27, 2023
4. Hoshino Y, Hanaoka K, Sakamoto K, Yasunaga M, Kojima T, Kotani D, Nomoto A, Sasaki E, Komatsu T, Ueno T, Takamaru H, Saito Y, Seto Y, Urano Y. Molecular design of near-infrared (NIR) fluorescent probes targeting exopeptidase and application for detection of dipeptidyl peptidase 4 (DPP-4) activity. RSC chemical biology, 3:859-867, 2022
5. Takakusagi Y, Sugyo A, Tsuji AB, Sudo H, Yasunaga M, Matsumura Y, Sugawara F, Sakaguchi K, Higashi T. The natural sulfoglycolipid derivative SQAP improves the therapeutic efficacy of tissue factor-targeted radioimmunotherapy in the stroma-rich pancreatic cancer model BxPC-3. Translational oncology, 15:101285, 2022
6. Takashima K, Koga Y, Anzai T, Migita K, Yamaguchi T, Ishikawa A, Sakashita S, Yasunaga M, Yano T. Evaluation of Fluorescence Intensity and Antitumor Effect Using Real-Time Imaging in Photoimmunotherapy. Pharmaceuticals (Basel, Switzerland), 15:223, 2022
7. Ohnuki K, Yoshimoto M, Haba H, Manabe S, Takashima H, Yasunaga M, Takenaka Y, Fujii H. Protection from contamination by (211)At, an enigmatic but promising alpha-particle-emitting radionuclide. EJNMMI physics, 9:39, 2022
8. Anzai T, Saijou S, Takashima H, Hara M, Hanaoka S, Matsumura Y, Yasunaga M. Identification of CD73 as the Antigen of an Antigen-Unknown Monoclonal Antibody Established by Exosome Immunization, and Its Antibody-Drug Conjugate Exerts an Antitumor Effect on Glioblastoma Cell Lines. Pharmaceuticals (Basel, Switzerland), 15:837, 2022