Laboratory of Antibody Design

1. Members

Project Leader	NAGATA Satoshi
Senior Researcher	MASUTA Yuji
Project Researcher	ISE Tomoko
Collaborative Research Scientist	DING Hao, INAI Yuta,  SUZUKI Koichiro, INOUE Masaki
Visiting Researcher	IWASAKI Takuya
Technical Assistant	TANAKA Mikiko, KATO Kayoko,SATOH Reiko
Administrative Assistant	MORI Megumi

 

2. Research Overview

Overall goal of the Antibody Design Project is the development of next-generation antibody-based drugs that maximize therapeutic efficacy. We focus on the epitope—the binding structure of an antibody which can transcends molecular boundaries—and explore strategies to design binding modes for various antibody-based drugs, aiming to develop unique high-performance antibody seeds that can be applied in clinical settings.

In vivo, epitopes form three-dimensional conformations and are specifically recognized by antibody paratopes (the antibody’s binding sites). Noting that dynamic binding modes play a pivotal role in determining antibody function, we are developing proprietary techniques to identify and characterize a diverse range of epitope structures presented in vivo as functional units, thereby enabling us to design appropriate antibody paratopes. We are also working on technologies that combine two different antibodies—each specific to distinct epitopes—into a single bispecific antibody, thereby creating novel binding modes unattainable by natural antibodies. By simultaneously advancing these technologies for high-demand drug discovery targets, we strive for early practical implementation in society.

 

3. Research Background

We often forget that the term “antibody” was never originally just a simple name for a particular substance. The term “antibody” emerged to refer to “something” produced within a multicellular organism’s body when foreign substances such as viruses or bacteria enter, in order to expel those invaders. Later, in mammals, the term came to correspond to proteins known as immunoglobulins (Ig), which can bind to antigens. However, the situation is more complex: immunoglobulins are not a single uniform substance, and each antigen-binding site differs, resulting in extraordinary diversity.

Because of that diversity, it was once very difficult to use mixed antibody populations as drugs that could be administered to large patient groups. However, with the invention of hybridoma cells that produce monoclonal antibodies, various antibody engineering technologies were developed, transforming the field. Today, more than 150 monoclonal antibody products have been approved as significant biopharmaceuticals, treating a broad spectrum of diseases once difficult to address with conventional medications.

Yet, has the technology for making antibodies reached a plateau, leaving no room for further development? Certainly not. We believe the portion of an antibody’s potential used clinically remains small. Our lab works on novel technologies that harness this unexploited potential of antibodies to develop next-generation antibody therapeutics. We focus on the antibody’s binding region, called the epitope. Different antibodies bind to different epitopes (antibody-binding sites on antigens), displaying diverse functions. For instance, even for the same membrane receptor A, some antibodies act as agonists, activating the receptor in a manner similar to its natural ligand, while others are antagonists, blocking the ligand’s binding and preventing activation.

To fully realize next-generation antibody therapeutics, we must search for and identify antibodies based on functional epitopes (a coined term), rather than simple binding epitopes. Globally, the concept of functional epitopes has yet to be established. Therefore, we are working on methodologies to appropriately describe and identify these functional epitopes, creating new antibodies that exert distinct functions.

 

4. Research Content

Under Construction

Specialized Research Topics

1. Developing methods for inducing and producing various functional antibodies by leveraging self-tolerance mechanisms and comparative immunology
2. Creating antibodies that recognize molecular complexes formed in vivo
3. Establishing functional antibody design methods utilizing binding-mode profiling and AI
4. Generating bispecific artificial antibodies by designing their binding modes
5. Developing indicators of antibody binding specificity that account for off-target profiles in vivo

 

5. Recent Publications

 

1. Akiba H, Ise T, Satoh R, Abe Y, Tsumoto K, Ohno H, Kamada H, Nagata S. Generation of antagonistic biparatopic anti-CD30 antibody from an agonistic antibody by precise epitope determination and utilization of structural characteristics of CD30 molecule. Antib Ther. 2025 Jan 14;8(1):56-67. doi: 10.1093/abt/tbaf002. PMID: 39958564; PMCID: PMC11826918.
2. Tsugawa Y, Furukawa K, Ise T, Takayama M, Ota T, Kuroda T, Shano S, Hashimoto T, Konishi H, Ishihara T, Sato M, Kamada H, Fukao K, Shishido T, Yoshikawa M, Takahashi T, Nagata S. Discovery of anti-SARS-CoV-2 S2 protein antibody CV804 with broad-spectrum reactivity with various beta coronaviruses and analysis of its pharmacological properties in vitro and in vivo. PLoS One. 2024 Dec 2;19(12):e0300297. doi: 10.1371/journal.pone.0300297. PMID: 39621673; PMCID: PMC11611099.
3. Asano R, Nakakido M, Pérez JF ,Ise T, Caaveiro JMM, Nagata S, Tsumoto K. Crystal　structures of human CD40 in complex with monoclonal antibodies dacetuzumab and bleselumab. Biochem Biophys Res Commun.2024 Apr 18;714:149969.doi:10.1016 /j.bbrc.2024.149969.
4. Hiroki Akiba, Junso Fujita, Tomoko Ise, Kentaro Nishiyama, Tomoko Miyata, Takayuki Kato, Keiichi Namba, Hiroaki Ohno, Haruhiko Kamada, Satoshi Nagata*, Kouhei Tsumoto*. Development of a 1:1-binding biparatopic anti-TNFR2 antagonist by reducing signaling activity through epitope selection.　Commun Biol 6, 987 2023. DOI:10.1038/s42003-023-05326-8
5. Kensuke Suzuki, Masaki Tajima, Yosuke Tokumaru, Yuya Oshiro, Satoshi Nagata, Haruhiko Kamada, Miho Kihara, Kohei Nakano, Tasuku Honjo, Akio Ohta. Anti-PD-1 antibodies recognizing the membrane proximal region are PD-1 agonists that can downregulate inflammatory diseases. SCIENCE IMMUNOLOGY 8, no. 79 (Jan 13 2023): eadd4947. 2023.　DOI:10.1126/sciimmunol.add4947.
6. Yamaguchi T, Hoshizaki M, Minato T, Nirasawa S, Asaka MN, Niiyama M, Imai M, Uda A, Chan JF, Takahashi S, An J, Saku A, Nukiwa R, Utsumi D, Yasuhara A, Kwok-Man Poon V, Chung-Sing Chan C, Fujino Y, Motoyama S, Nagata S, Penninger JM, Kamada H, Yuen KY, Kamitani W, Maeda K, Kawaoka Y, Yasutomi Y, Imai Y, Kuba K. ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury. Nature Commu 12(1): 6791, 2021. DOI: 10.1038/s41467-021-27097-8.
7. Urano E, Okamura T, Ono C, Ueno S, Nagata S, Kamada H, Higuchi M, Furukawa M, Kamitani W, Matsuura Y, Kawaoka Y, Yasutomi Y. COVID-19 cynomolgus macaque model reflecting human COVID-19 pathological conditions. Proc Natl Acad Sci U S A 118(43):e2104847118, 2021. DOI: 10.1073/pnas.2104847118.
8. Asaka MN, Utsumi D, Kamada H, Nagata S, Nakachi Y, Yamaguchi T, Kawaoka Y, Kuba K, Yasutomi Y. Highly susceptible SARS-CoV-2 model in CAG promoter-driven hACE2-transgenic mice. JCI Insight 6(19): e152529, 2021. DOI： 10.1172/jci.insight.152529.
9. Akiba H, Ise T, Nagata S, Kamada H, Ohno H, Tsumoto K. Production of IgG1-based bispecific antibody without extra cysteine residue via intein-mediated protein trans-splicing. Sci Rep 11(1):19411, 2021. DOI: 10.1038/s41598-021-98855-3.
10. Akiba H, Satoh R, Nagata S, Tsumoto K. Effect of allotypic variation of human IgG1 on the thermal stability of disulfide-linked knobs-into-holes mutants of the Fc for stable bispecific antibody design. Antibody Therapeutics 2(3):65-69, 2019. DOI: 10.1093/abt/tbz008.
11. Ambegaonkar AA, Nagata S, Pierce SK, Sohn H. The Differentiation in vitro of Human Tonsil B Cells With the Phenotypic and Functional Characteristics of T-bet+ Atypical Memory B Cells in Malaria. Frontiers in Immunology 10: 852, 2019. DOI: 10.3389/fimmu.2019.00852
12. Shancer Z, Liu XF, Nagata S, Zhou Q, Bera TK, Pastan I. Anti-BCMA immunotoxins produce durable complete remissions in two mouse myeloma models. Proc Natl Acad Sci U S A 116(10):4592-4598, 2019. DOI: 10.1073/pnas.1821733116

 

Laboratory of Antibody Design

E-mail	satoshi-nagata*nibiohn.go.jp (replace * by @)