The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
Generation of antagonistic biparatopic anti-CD30 antibody from an agonistic antibody by precise epitope determination and utilization of structural characteristics of CD30 molecule
Open accessPublished version of a preprint
Abstract
Background: CD30 is a member of the tumor necrosis factor receptor superfamily. Recently, blocking CD30-dependent intracellular signaling has emerged as potential strategy for immunological regulation. Development of antibody-based CD30 antagonists is therefore of significant interest. However, a key challenge is that the bivalent form of natural antibody can crosslink CD30 molecules, leading to signal transduction even in the absence of specific ligand, CD153. Biparatopic antibodies (BpAbs) offer a solution, using two different variable fragments (Fvs) to bind distinct epitopes on a single antigen molecule. BpAbs format is an attractive alternative of natural antibody by potentially avoiding unwanted crosslinking and signaling induction. Methods: We systematically characterized 36 BpAbs, each designed with pairs of Fvs binding to nine distinct epitopes across the CD30 extracellular domain. We first identified the precise epitope sites of the nine antibodies by assessing the binding to multiple orthologous CD30 proteins and mutants. We then produced the 36 BpAbs and analyzed their biological activities and binding modes. Results: Among 36 BpAbs, we identified both potent ligand-independent agonists and ligand-blocking antagonists, with many displayed reduced signal activation, including 1:1-binding antagonists derived from AC10, a strong agonist developed for lymphoma therapy. Epitope dependency in reduced signaling activity was observed and associated with the flexible nature of CD30 protein. Conclusions: We successfully developed antagonistic BpAbs against CD30 by controlling the stoichiometry of antibody–antigen binding mode. This study elucidated the mechanism of signaling induction, informing the design strategies of the development of biparatopic antibodies.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs
Altschul, S. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.17.3389 · Cited by 73,302
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Clustal W and Clustal X version 2.0
Larkin, M., Blackshields, G., Brown, N. P., Chenna, R., McGettigan, P., McWilliam, H., Valentin, F., Wallace, I. M., Wilm, A., López, R., et al. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm404 · Cited by 28,598
ColabFold - Making protein folding accessible to all
Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391
UniProt: the Universal Protein knowledgebase
Apweiler, R. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh131 · Cited by 7,593
UniProt: the Universal Protein Knowledgebase in 2023
The UniProt Consortium, Bateman, A., Martin, M.-J., Orchard, S., Magrane, M., Ahmad, S., Alpi, E., Bowler-Barnett, E. H., Britto, R., Bye-A-Jee, H., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkac1052 · Cited by 7,210
Signalling pathways of the TNF superfamily: a double-edged sword
Aggarwal, B. B. (2003) · Nature Reviews Immunology · doi:10.1038/nri1184 · Cited by 2,793
NF-κB in biology and targeted therapy: new insights and translational implications
Guo, Q., Jin, Y., Chen, X., Ye, X., Shen, X., Lin, M., Zeng, C., Zhou, T., & Zhang, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01757-9 · Cited by 2,327
Varadi, M., Bertoni, D., Magana, P., Paramval, U., Pidruchna, I., Radhakrishnan, M., Tsenkov, M., Nair, S., Mirdita, M., Yeo, J., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkad1011 · Cited by 2,052 · cited 1×
“High homology regions exist within CRD1-3 and CRD4-6, likely due to gene duplication (Fig.”
The TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond
Dostert, C., Grusdat, M., Letellier, E., & Brenner, D. (2018) · Physiological Reviews · doi:10.1152/physrev.00045.2017 · Cited by 526
Katz, J. B., Janik, J. E., & Younes, A. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-0488 · Cited by 368
The roles of tertiary lymphoid structures in chronic diseases
Sato, Y., Siliņa, K., van den Broek, M. F., Hirahara, K., & Yanagita, M. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00706-z · Cited by 326
Ansell, S. M., Horwitz, S. M., Engert, A., Khan, K. D., Lin, T. S., STRAIR, R. K., Keler, T., Graziano, R. F., Blanset, D. L., Yellin, M. J., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.07.8972 · Cited by 251
van der Weyden, C., Pileri, S. A., Feldman, A. L., Whisstock, J. C., & Prince, H. M. (2017) · Blood Cancer Journal · doi:10.1038/bcj.2017.85 · Cited by 249
Forero, A., Leonard, J. P., Younes, A., Rosenblatt, J. D., Brice, P., Bartlett, N. L., Bosly, A., Pinter‐Brown, L. C., Kennedy, D. A., Sievers, E. L., et al. (2009) · British Journal of Haematology · doi:10.1111/j.1365-2141.2009.07740.x · Cited by 248
Fischer, P., Nacheva, E. P., Mason, D., Sherrington, P., Hoyle, C. F., Hayhoe, F. G. J., & Karpas, A. (1988) · Blood · doi:10.1182/blood.v72.1.234.234 · Cited by 214
Principles of antibody-mediated TNF receptor activation
Wajant, H. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.109 · Cited by 146
Reducing affinity as a strategy to boost immunomodulatory antibody agonism
Yu, X., Orr, C. M., Chan, H. T. C., James, S., Penfold, C. A., Kim, J., Inzhelevskaya, T., Mockridge, C. I., Cox, K. L., Essex, J. W., et al. (2023) · Nature · doi:10.1038/s41586-022-05673-2 · Cited by 119
CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Sato, Y., Oguchi, A., Fukushima, Y., Masuda, K., Toriu, N., Taniguchi, K., Yoshikawa, T., Cui, X., Kondo, M., Hosoi, T., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146071 · Cited by 115
CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury
Sato, Y., Oguchi, A., Fukushima, Y., Masuda, K., Toriu, N., Taniguchi, K., Yoshikawa, T., Cui, X., Kondo, M., Hosoi, T., et al. (2022) · Institutional Repositories DataBase (IRDB) · Cited by 82
Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity
Yu, X., Chan, H. T. C., Fisher, H., Penfold, C. A., Kim, J., Inzhelevskaya, T., Mockridge, C. I., French, R. R., Duriez, P. J., Douglas, L. R., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.04.013 · Cited by 74
Targeting CD30/CD30L in Oncology and Autoimmune and Inflammatory Diseases
Oflazoglu, E., Grewal, I. S., & Gerber, H. (2009) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-89520-8_12 · Cited by 74
Schneider, C., & Hübinger, G. (2002) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428190290033288 · Cited by 68
Diagnostic, prognostic and therapeutic role of CD30 in lymphoma
Pierce, J. M. R., & Mehta, A. (2016) · Expert Review of Hematology · doi:10.1080/17474086.2017.1270202 · Cited by 67
Biparatopic antibodies: therapeutic applications and prospects
Niquille, D. L., Fitzgerald, K. M., & Gera, N. (2024) · mAbs · doi:10.1080/19420862.2024.2310890 · Cited by 55
Sun, X., Yamada, H., Shibata, K., Muta, H., Tani, K., Podack, E. R., Iwakura, Y., & Yoshikai, Y. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1002229 · Cited by 51
The benefits of clustering in TNF receptor superfamily signaling
Vanamee, É. S., & Faustman, D. L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1225704 · Cited by 51
Nagata, S., Salvatore, G., & Pastan, I. H. (2003) · Journal of Immunological Methods · doi:10.1016/s0022-1759(03)00192-3 · Cited by 48
Self-citationYang, Y., Yeh, S. H., Madireddi, S., Matochko, W. L., Gu, C., Sanchez, P. P., Ultsch, M. H., Boenig, G. D. L., Harris, S. F., Leonard, B. C., et al. (2019) · mAbs · doi:10.1080/19420862.2019.1625662 · Cited by 48
Ise, T., Maeda, H., Santora, K., Xiang, L., Kreitman, R. J., Pastan, I. H., & Nagata, S. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.87.11.1 · Cited by 42
Self-citationCell membrane-specific epitopes on CD30: Potentially superior targets for immunotherapy
Nagata, S., Ise, T., Onda, M., Nakamura, K., Ho, M., Raubitschek, A. A., & Pastan, I. H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502975102 · Cited by 37
Self-citationNovel anti-CD30 recombinant immunotoxins containing disulfide-stabilized Fv fragments.
Nagata, S., Onda, M., Numata, Y., Santora, K., Beers, R., Kreitman, R. J., & Pastan, I. H. (2002) · PubMed · Cited by 36
Self-citationCD30 Expression and Its Functions during the Disease Progression of Adult T-Cell Leukemia/Lymphoma
Nakashima, M., & Uchimaru, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24108731 · Cited by 36
Liu, X., Zhao, Y., Shi, H., Zhang, Y., Yin, X., Liu, M., Zhang, H., He, Y., Lu, B., Jin, T., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12097-6 · Cited by 36
An improved understanding of TNFL/TNFR interactions using structure-based classifications
Magis, C., van der Sloot, A. M., Serrano, L., & Notredame, C. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.06.002 · Cited by 34
The Diversity and Similarity of Transmembrane Trimerization of TNF Receptors
Zhao, L., Fu, Q., Pan, L., Piai, A., & Chou, J. J. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.569684 · Cited by 33
Fukushima, Y., Sakamoto, K., Matsuda, M., Yoshikai, Y., Yagita∥, H., Kitamura, D., Chihara, M., Minato, N., & Hattori, M. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111373 · Cited by 28
Nagata, S., Numata, Y., Onda, M., Ise, T., Hahn, Y., Lee, B., & Pastan, I. H. (2004) · Journal of Immunological Methods · doi:10.1016/j.jim.2004.06.009 · Cited by 27
Self-citationOptimizing TNFR2 antagonism for immunotherapy with tumor microenvironment specificity
Yang, M., Tran, L., Torrey, H., Song, Y., Perkins, H., Case, K. B., Zheng, H., Takahashi, H., Kühtreiber, W. M., & Faustman, D. L. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.5ab0320-415rrrrr · Cited by 23
Akiba, H., Fujita, J., Ise, T., Nishiyama, K., Miyata, T., Kato, T., Namba, K., Ohno, H., Kamada, H., Nagata, S., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-05326-8 · Cited by 16
Self-citationCD30 as a therapeutic target in adult haematological malignancies: Where are we now?
Veyri, M., Spano, J., Bras, F. L., Marcelin, A., & Todesco, È. (2023) · British Journal of Haematology · doi:10.1111/bjh.18841 · Cited by 14
Senescence-associated T cells in immunosenescence and diseases
Fukushima, Y., Ueno, R., Minato, N., & Hattori, M. (2024) · International Immunology · doi:10.1093/intimm/dxae056 · Cited by 14
Yue, D., You, Y., Zhang, X., Wang, B., Wang, X., Qi, R., Yang, F., Meng, X., Yoshikai, Y., Wang, Y., et al. (2019) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.04.009 · Cited by 11
Akiba, H., & Tsumoto, K. (2020) · Translational and Regulatory Sciences · doi:10.33611/trs.2_1 · Cited by 8
Self-citationAkiba, H., Ise, T., Nagata, S., Kamada, H., Ohno, H., & Tsumoto, K. (2021) · Scientific Reports · doi:10.1038/s41598-021-98855-3 · Cited by 7
Self-citationCD30 influences germinal center B-cell dynamics and the expansion of IgG1-switched B cells
Wang, Y., Rambold, U., Fiedler, P., Babushku, T., Tapken, C. L., Hoefig, K. P., Hofer, T. P. J., Adler, H., Yildirim, A. Ö., Strobl, L. J., et al. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01219-w · Cited by 5
Editorial: TNFRSF agonists: mode of action and therapeutic opportunities
Obermajer, N., Zwolak, A., & Wajant, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1328100 · Cited by 4
Flagged first, then by citations
1 of the 48 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Nagata, 2009, Abstract #860: monoclonal antibodies to non-ligand-binding sites on CD30 induce agonistic effects and growth inhibition of human lymphoma cells, Cancer Res, 69, 860
Cited by
Sorted by citations
Otsuki, T., Matsumoto, S., Fujita, J., Miyata, T., Namba, K., Kanada, R., Okuno, Y., Kamada, H., Ohno, H., & Akiba, H. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110548 · Cited by 2
Self-citationAkiba, H., Nakashima, K., Ichinose, T., Watanabe, H., & Ono, M. (2026) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5c01515 · Cited by 1
Self-citationMultimodal Physicochemical Characterization of Cross-Linking Activities of Biparatopic Antibodies
Akiba, H., Shiba, K., Tsumoto, K., Ohno, H., & Kamada, H. (2026) · Methods in molecular biology · doi:10.1007/978-1-0716-5037-0_2
Self-citation
Metadata
- Authors
- Akiba, H., Ise, T., Satoh, R., Abe, Y., Tsumoto, K., Ohno, H., Kamada, H., & Nagata, S.
- Affiliations
- Kyoto University (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- National Institute of Health Sciences (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Corresponding author
- Akiba, Hiroki
- Nagata, Satoshi
- ORCID
- Venue
- Antibody Therapeutics
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-01
- Volume
- 8
- Issue
- 1
- Pages
- 56-67
- ISSN
- 2516-4236 (ISSN-L)
- PMC
- PMC11826918
- OpenAlex
- W4406357435
- Cited by
- 3
- References
- 48
- Citations by year
- 2026: 2 · 2025: 1
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Antibody Therapeutics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- Funders
- AMED (JP22ak0101099, JP24ama121042)
- JSPS (JP24K01270)
- Takeda Science Foundation
- Kyoto University Foundation
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- CD30, biparatopic antibody, antagonistic antibodies, agonistic antibodies, epitope mapping, ligand-independent signaling, TNF receptor superfamily, antibody design, lymphoma treatment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
