Annual Report 2024

Division of Developmental Therapeutics

Masahiro Yasunaga, Yoshikatsu Koga, Hiroki Takashima, Ryo Tsumura, Hirobumi Fuchigami, Boran Osman, Chihiro Morizono, Hiroko Shinohara, Yayoi Shino, Sachie Fujita, Misaki Kuboyama, Shigehiro Koganemaru, Chikako Funasaka, Yu Shibahara, Shiqi Yang, Hao Shi, Wang Chenwei, Liang Huiqing, Mayu Oka, Yu Takeda, Rikuto Nakamura, Yuri Nakamura, Kosuke Masago, Yuki Nitta, Motochika Hamada, Shoko Hamamoto, Yuki Tsuji, Mamiko Shimada, Hiroshi Tsugawa, Takahiro Anzai, Shinji Saijo, Shingo Hanaoka

Introduction

 We are advancing next-generation therapeutic antibodies, including antibody-drug conjugates (ADCs), radioimmunotherapy (RIT), and bispecific antibodies (BsAbs), through innovative drug delivery systems (DDS) and molecular imaging. All monoclonal antibodies generated in our division have been patented, ensuring robust intellectual property protection. We are also developing molecular genetics and cell biological strategies to regulate T cells, thereby enhancing the activity of T cell-dependent BsAbs. A major challenge is achieving efficient brain delivery, for which shark-derived IgNAR antibodies, with their exceptional anti-denaturation stability, intratumoral penetration, and active targeting potential, represent a highly promising platform. Furthermore, we are pioneering novel cancer diagnostics and therapeutics by integrating proprietary mass spectrometry with advanced bioinformatics, aiming to translate innovation into precision medicine solutions.

The Team and What We Do

• Development of antibody therapeutics and technology transfer to pharmaceutical companies.
• Research and development of immunoregulation methods related to next-generation antibody technologies.
• Conducting translational research utilizing mass spectrometry.

Research Activities

1. Development of novel antibodies

 We are developing novel antibodies using drug delivery systems (DDS) and molecular imaging. In addition to anti-IL-7R antibodies, we filed a patent application for novel recycling antibodies. We also conducted functional analysis of target molecules for anti-TMEM180 antibodies, which are currently under first-in-human (FIH) clinical trials.

2. Development of ADCs

 We developed anti-IL-7R ADC-PBD and demonstrated that it could eradicate leukemic cells in both systemic and CNS-infiltrating leukemia models. Furthermore, in T cells derived from type 1 diabetes patients, we confirmed that conjugation with molecular targeted agents suppressed IL-7R signaling hyperactivation and exerted anti-inflammatory effects.

3. Development of α-RIT

 We established a development platform for α-RIT using two isotopes, ²¹¹At and ²²⁵Ac, and confirmed their efficacy in animal models. We further demonstrated that ascorbic acid suppresses protein damage induced by α-particles and can be used as an additive for RIT formulation and storage. In addition, we developed anti-IL-7R-RIT (²¹¹At) and confirmed its strong cytotoxic effects in vivo.

4.  Development of bispecific antibodies and T cell engagers (TCEs) with T cell regulation

 We demonstrated the mechanisms of action (MOAs) of TCEs as follows: (1) immunological synapse-dependent cytotoxicity, (2) cytokine-dependent cytotoxicity, and (3) enhanced T cell migration. We also explored candidate molecules involved in T cell exhaustion, a major resistance factor in TCE therapy, and confirmed that the introduction of multiple genes could induce anti-exhaustion effects in T cells, thereby restoring the efficacy of TCEs.

5. Research and development of brain antibody delivery

 We identified Claudin5 and ZO1 as key regulators of antibody delivery across the blood-brain barrier and of T cell migration.

6. Application of shark antibody IgNAR to antibody therapeutics

 We established a platform for the generation of shark antibodies (IgNAR) and successfully cloned the full-length sequence including the constant region.

7. Development of advanced mass spectrometry methods

 We established a method to measure tumor tissue-bound antibodies against cancer antigens. In addition to quantifying anti-EGFR antibodies, we demonstrated the feasibility of quantifying anti-HER2 antibodies and filed a patent application. Furthermore, we constructed a platform for breath biopsy (exhaled breath mass spectrometry) and initiated clinical research and sample measurement.

Education

1) Doctoral students

 Graduate School of Frontier Sciences, the University of Tokyo: four students

 Juntendo University: one student

2) Master's students

 Graduate School of Frontier Sciences, The University of Tokyo: nine students

Future Prospects

 In addition to DDS and molecular imaging, we aim to develop novel antibody therapeutics with enhanced delivery efficiency by applying protein engineering and amino acid modification technologies. For ADCs, we will promptly obtain non-clinical proof of concept (PoC) and pursue early clinical application. Regarding α-particle RIT, we will improve the precision of critical technologies such as antibody carriers and linkers to accelerate clinical development, with hematological malignancies as the initial target. In parallel with the development of original bispecific and trispecific antibodies, we will conduct a comprehensive analysis of anti-exhaustion factors in T cells to enhance the efficacy of TCEs. We will elucidate the molecular basis of CNS infiltration control and the mechanism of brain-spinal cord delivery mediated by anti-IL-7R ADCs. The functionality of shark antibody IgNAR will be evaluated, and its differences in properties from mammalian IgG will be clarified. Furthermore, we will develop innovative antibody delivery methods by applying tissue engineering and regenerative medicine technologies. Finally, we will advance clinical research on breath biopsy and accelerate its implementation as a non-invasive diagnostic approach.

List of papers published in 2024

Journal

1. Koganemaru S, Fuchigami H, Morizono C, Shinohara H, Kuboki Y, Furuuchi K, Uenaka T, Doi T, Yasunaga M. Potential Mechanisms of Interstitial Lung Disease Induced by Antibody-Drug Conjugates Based on Quantitative Analysis of Drug Distribution. Molecular cancer therapeutics, 24:242-250, 2025

2. Koganemaru S, Fuchigami H, Yamashita H, Morizono C, Sunakawa H, Kawazoe A, Nakamura Y, Kuboki Y, Shitara K, Yano T, Doi T, Yasunaga M. Quantitative Analysis of the Concentration of Trifluridine in Tumor Hypoxic Regions Using a Novel Platform Combining Functional Endoscopy and Mass Spectrometry. Clinical pharmacology and therapeutics, 115:62-70, 2024

3. Tsumura R, Anzai T, Koga Y, Takashima H, Matsumura Y, Yasunaga M. Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models. Cancer science, 115:3986-3996, 2024