mAbs最新文献

{"title":"Setting expectations for current and future directions of native mass spectrometry in the biopharmaceutical industry.","authors":"Elizabeth Hecht, Esther Martin, Idlir Liko, Andrew Mahan, Aniruddha Sahasrabuddhe, Nastaran N Tajoddin, Iain D G Campuzano","doi":"10.1080/19420862.2026.2699078","DOIUrl":"10.1080/19420862.2026.2699078","url":null,"abstract":"<p><p>While native mass spectrometry (native-MS) has been widely explored in academic laboratories, its practical role within biopharmaceutical research remains less clearly defined. In this perspective, we present an industry-driven view of how native-MS is currently applied, where it offers unique advantages over established analytical technologies, and where alternative methods remain more practical for routine characterization. Within biopharma workflows, characterization strategies traditionally rely on orthogonal techniques such as size-exclusion chromatography (SEC), ion-exchange chromatography (IEX), electrophoresis, light scattering, calorimetry, and denaturing liquid chromatography (LC) MS. Native-MS complements these methods by enabling direct assessment of intact molecular assemblies, including monoclonal antibodies (mAbs), multispecific antibodies, antibody-drug conjugates (ADCs), glycoproteins, and protein complexes. Applications include evaluation of higher-order assembly, ligand or cofactor binding, stoichiometry of target complexes, and heterogeneity that may be obscured under denaturing conditions. However, challenges related to throughput, sensitivity, automation, and accessibility have limited widespread adoption in industrial laboratories. Emerging developments, including chromatographic hyphenation, online buffer exchange (OBE), improved automation, and charge-detection MS (CDMS), are beginning to address these constraints. We argue that the future impact of native-MS in biopharma will depend on integrating these technological advances with platformed analytical workflows and software capable of supporting high-throughput characterization across therapeutic pipelines. We hope that the ideas raised in this article spur debate on when, how, and if native-MS would or should see increased adoption.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2699078"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148447744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibodies to watch in 2026.","authors":"Silvia Crescioli, Hélène Kaplon, Alicia Chenoweth, Yu-Shin Hsu, Kieran Pinto, Vaishali Kapoor, Janice M Reichert","doi":"10.1080/19420862.2026.2614669","DOIUrl":"10.1080/19420862.2026.2614669","url":null,"abstract":"<p><p>The Antibodies to Watch article series provides annual updates on commercial late-stage clinical development, regulatory review, and marketing approvals of antibody therapeutics. Since the first article was published in 2010, the late-stage pipeline has grown from 26 antibody therapeutics to over 200, while during the same time numerous molecules in late-stage studies either transitioned to regulatory review and were approved or were terminated. In this installment of the series, we recap first marketing approvals granted to 19 antibody therapeutics in 2025, discuss 26 molecules currently in regulatory review, including the bispecific antibody-drug conjugate izalontamab brengitecan, and predict which molecules of the 209 currently in the commercial late-stage pipeline might transition to regulatory review by the end of 2026. Most antibody therapeutics in the latter category are for non-cancer indications (16/21, 76%) and have a conventional format (13/21, 62%), but the category also includes numerous antibody-oligo or -drug conjugates, such as delpacibart etedesiran, delpacibart zotadirsen, zeleciment rostudirsen, sonesitatug vedotin, trastuzumab pamirtecan, and ifinatamab deruxtecan, as well as the bispecific petosemtamab. As antibody therapeutics development is a global enterprise, we also discuss trends in annual first approvals granted to antibody therapeutics in any country since 2010, stratified by the antibody's country of origin, documenting the notable increases in the total number of first approvals and those approved first in China. Finally, to benchmark the time typically required for clinical development and regulatory review, we calculated this period for recently approved antibody therapeutic products stratified by their therapeutic area, mechanism of action, format, and country of origin. Our data show that the development and approval period were typically ~6 years, but on average this period was shorter for China-originated products.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2614669"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12826703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginkgo Datapoints Antibody Developability Competition outcomes: limited model performance and a call for data standardization.","authors":"Lood van Niekerk, Joshua Moller, Seth Ritter, Porfirio Quintero-Cadena, Rich Cohen, Georgia Channing, Michael Chungyuon, Laura Rand, Alexander Smith, Aanal Bhatt, Yolaine Pierre, Blake Harris, Xiang Ao, Lucia Grippo, Maximilian Schwenk, Adam Rosenbaum, Olga Allen, Nimra Asi, Jiang Zhu, Aviral Singh, Daksh Sammi, Rushikesh Jadhav, Antonín Dušek, Shyam Chandra, Valentin Badea, Nels Thorsteinson, Nathaniel Blalock, Jeonghyeon Kim, Oliver M Turnbull, Ameya Kulkarni, Vivek Kohar, Netsanet Gebremedhin, Charlotte M Deane, Peter M Tessier, Ammar Arsiwala","doi":"10.1080/19420862.2026.2634216","DOIUrl":"10.1080/19420862.2026.2634216","url":null,"abstract":"<p><p>The Ginkgo Datapoints Antibody Developability (AbDev) Competition, a blinded benchmark for developability prediction characterized entirely on a single, industrial-scale experimental platform, was conducted from September 8 to November 18, 2025. We benchmarked predictors across five biophysical properties - hydrophobicity, thermostability, self-association, expression titer, and polyreactivity - using a public training set of 246 clinical antibodies and a blinded, held-out test set of 80 antibodies. We received submissions from 113 teams spanning 25 countries, 38 companies, and 39 universities. Winning submissions differed by assay. Top Spearman's ρ values on the test set reached 0.708 (hydrophobicity), 0.392 (thermostability), 0.356 (polyreactivity), 0.337 (self-association), and 0.310 (titer). Cross-validation scores from the public training set consistently exceeded held-out test performance, indicating overfitting and limited out-of-distribution generalization. Together, these results provide a standardized snapshot of current antibody developability modeling capabilities and highlight a key bottleneck: available datasets are too small and heterogeneous to support robust, assay-spanning prediction. Meaningful progress will require larger, standardized, and diverse experimental datasets - with harmonized protocols and rich metadata - to train and validate models that generalize reliably for future antibody discovery campaigns.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2634216"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASD: antigen-specific antibody database.","authors":"Arkadiusz Czerwiński, Paweł Dudzic, Konrad Wójtowicz, Igor Jaszczyszyn, Weronika Bielska, Sonia Wrobel, Samuel Demharter, Roberto Spreafico, Victor Greiff, Konrad Krawczyk","doi":"10.1080/19420862.2026.2623330","DOIUrl":"10.1080/19420862.2026.2623330","url":null,"abstract":"<p><p>The development of computational models addressing therapeutic antibodies faces significant challenges. Particularly, the prediction of binding affinity across a diverse set of measurements, due to the scarcity of data. A critical data element is the set of antibody-antigen interaction pairs associated with sequences. To address this issue, we developed the Antigen Specific Antibody Database (ASD, https://naturalantibody.com/agab/), a database aggregating antibody-antigen interaction data from multiple studies with standardized formatting and annotations. Our dataset compilation strategy resulted in data from 15 distinct sources, resulting in 1,097,946 unique antibody-antigen interactions (with 9575 unique antigens). The ASD captures diverse affinity measures and qualitative binding assessment, along with metadata including UniProt and PDB identifiers, target protein names, confidence levels, and experimental conditions such as type of measured affinity, source organism, and germline genes. Through this integration drive, we make available an ample resource of interaction data gathered from the public domain to act as a foundation for model development and further data generation.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2623330"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P329G-engager: a universal mix & match antibody-based adaptor platform for cancer immunotherapy.","authors":"Marlena Surowka, Diana Darowski, Idil Hutter-Karakoc, Christina Claus, Claudia Ferrara-Koller, Anne Freimoser-Grundschober, Thomas Hofer, Johannes Sam, Reto Gianotti, Andrzej Sobieniecki, Denis Assisi, John Challier, Stephane Leclair, Ekkehard Mössner, Maria Amann, Pablo Umaña, Christian Klein","doi":"10.1080/19420862.2025.2602993","DOIUrl":"10.1080/19420862.2025.2602993","url":null,"abstract":"<p><p>Targeting various combinations of tumor antigens and immune cell receptors is of increasing importance in antibody-based cancer immunotherapy. Here, we present a novel modular P329G-engager platform that enables rapid combination of primary tumor-targeting and secondary immune effector antibodies. The platform utilizes two antibodies, each selected from: 1) a set of tumor-targeting adaptor antibodies, bearing P329G mutations in the Fc region, and 2) a set of P329G-targeting (bispecific) cell engagers, including innate and T cell engagers, costimulators and immunocytokines. Specifically, upon defining a tumor-associated cell surface target, a primary adaptor - tumor antigen-binding IgG1 antibody with Fc-silencing P329G L234A L235A mutations - is administered. Subsequently, a secondary antibody recognizing the P329G mutation is chosen from a panel of effector cell engagers with different modes of action - ADCC-competent P329G-innate cell engagers (P329G-ICE), P329G-T cell bispecifics (P329G-TCB), P329G-costimulators (P329G-CD28/4-1BBL), or P329G-immunocytokine (P329G-IL2v). <i>In vitro</i> assays showed that all P329G-targeting modalities induce anti-tumoral and/or immunomodulatory activity when both components were combined. <i>In vivo</i>, tumor shrinkage and T cell infiltration were confirmed in tumor-bearing humanized mice treated with P329G-mutated CEACAM5 adaptor IgG and P329G-TCB. Individually, neither the adaptor nor the P329G-TCB induced efficacy, validating the requirement for primary and secondary antibody assembly for T cell-engaging activity. These results provided evidence for the <i>in vivo</i> assembly and subsequent pharmacological activity, and provide preclinical proof-of-concept for the P329G-engager platform as an efficacious tool in drug discovery. Ultimately, this modular approach may enable mix-and-match drug assembly as a novel therapeutic principle in immunotherapy.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2602993"},"PeriodicalIF":7.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12710928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical safety evaluation of the dipeptidyl peptidase 3 inhibiting antibody Procizumab in rodents and non-human primates.","authors":"Dirk van Lier, Magali Genest, Adrien Picod, Francesca Manicone, Bruno Garcia, Theo Ikenna Uba, Anika Schroeter, Karine Santos, Antoine Herpain, Alexis Nguyen, Feriel Azibani, Alexandre Mebazaa, Matthijs Kox, Peter Pickkers","doi":"10.1080/19420862.2026.2672800","DOIUrl":"10.1080/19420862.2026.2672800","url":null,"abstract":"<p><p>The cytosolic protease dipeptidyl peptidase 3 (DPP3) is released into the circulation upon profound cellular stress. In the bloodstream, circulating DPP3 (cDPP3) rapidly degrades several important mediators of vascular tone. The cDPP3-antagonizing antibody Procizumab (PCZ) improved outcome in animal models of shock. This study aimed to establish the safety and tolerability of PCZ across relevant animal species. In the first study, mice received vehicle (<i>n</i> = 72), 37.5 (<i>n</i> = 114), 75 (<i>n</i> = 114), or 150 (<i>n</i> = 126) mg/kg of PCZ intravenously on days 1, 2, 13, and 14. In the second study, cynomolgus monkeys received vehicle (<i>n</i> = 10), 40 (<i>n</i> = 6), 120 (<i>n</i> = 6), or 350 (<i>n</i> = 10) mg/kg of PCZ intravenously on days 1, 2, 13 and 14. Toxicokinetic analyses demonstrated instant and dose-dependent peak concentrations. PCZ was eliminated relatively fast compared to other monoclonal antibodies and administration resulted in an instant reduction of cDPP3 enzyme activity, confirming the intended pharmacodynamic mechanism-of-action. Apart from fully reversible, non-dose-dependent increases of enzymes aspartate aminotransferase, alanine aminotransferase, and creatinine kinase in monkeys, and decreased rarefaction of the cytoplasm of hepatocytes in treated mice compared to the control group, toxicologic analyses showed no test item-related effects. In both studies, no mortality, moribund condition or any other adverse histopathological findings were attributed to PCZ therapy. These findings demonstrate that intravenous, repeated administration of high doses of PCZ was well tolerated in mice and cynomolgus monkeys. Results of this study were followed by a Phase 1 safety assessment of PCZ in humans, with single-administration clinical doses of 3, 6, and 12 mg/kg (NCT06331884).</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2672800"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JMB2403, a potential best-in-class PD-1-dependent IL2Rβγ-activating tri-specific antibody for safe and potent immunotherapy.","authors":"Chunyin Gu, Deyi Wang, Yan Wang, Fangfang Jia, Fu Zhou, Shun Chang, Kedong Ouyang, Yu Zhao, Linlin Liu, Huawei Zhang, Peipei Liu, Haixiang Yu, Xiaodan Cao, Taylor B Guo, Huanzhang Xia","doi":"10.1080/19420862.2026.2709956","DOIUrl":"10.1080/19420862.2026.2709956","url":null,"abstract":"<p><p>PD-1-based immunocytokines, such as interleukin (IL)-2 fused with anti-PD-1, have been designed to increase efficacy, but their use is hampered by dose-limiting toxicity. To overcome this, substantial efforts have focused on engineering attenuated IL-2 variants, albeit with limited success to date. Taking an alternative approach, we screened a naïve alpaca library for weak agonistic nanobodies of IL-2/15Rβ and the common γ chain and attached a potent anti-PD-1 IgG to generate a tri-specific antibody JMB2403. JMB2403 did not bind IL2Rα (CD25), but activated STAT5 phosphorylation in an engineered Jurkat cell reporter assay albeit far less potently compared to wildtype IL-2. This translated to a JMB2403-induced pSTAT5 increase in natural killer (NK) cells, but minimal STAT5 phosphorylation in Treg cells. Notably, JMB2403 retained PD-1 blocking activity and concentration-dependently induced phospho-STAT5 only in activated (PD-1^high) but not in non-activated CD8⁺ T cells, indicating <i>cis</i>-action mediated by PD-1 engagement. In A375 (melanoma) and NCI-H292 (lung cancer) xenograft models, JMB2403 exhibited superior anti-tumor efficacy compared to its parental PD-1 antibody. In a cynomolgus monkey study, JMB2403 produced a dose-dependent increase in the proliferation of CD8⁺ T cells, PD-1⁺ CD8⁺ T cells, Treg cells, and NK cells after the first dose which returned to baseline before the second dose. No IL-2-related toxicities such as vascular leak syndrome or pulmonary edema were observed. In summary, JMB2403 can induce <i>cis</i>-activation of PD-1⁺ T cells and display enhanced anti-tumor efficacy with good tolerability. To our knowledge, this is the first tri-specific antibody of its kind that targets specifically IL2/15 receptor signaling subunits.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2709956"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody framework engineering enables augmented cytokine receptor signaling capacities of bispecific single domain antibody-based IL-21 mimetics.","authors":"Britta Lipinski, Laura Unmuth, Thi Hong Hue Tran, Jakob Harwood, Paul Arras, Stefan Becker, Julia Harwardt, Enrico Guarnera, Laura Helming, Rinat Zaynagetdinov, Davide Bertoldo, Arvind Rajpal, Desislava Elter, Lukas Pekar, Andreas Evers, Stefan Zielonka","doi":"10.1080/19420862.2026.2726042","DOIUrl":"10.1080/19420862.2026.2726042","url":null,"abstract":"<p><p>In this work, we developed bispecific antibody (bsAb)-derived surrogate agonists which mimic the function of IL-21 by targeting the IL-21 receptor composed of IL-21 R (CD360) and IL-2 Rγ (CD132). For this, antigen-specific VHHs (variable domains of the heavy chain of heavy-chain-only antibodies) were obtained by immunization of camelids and isolated using yeast surface display. Combinatorial reformatting of IL-21 R-specific single‑domain antibodies (sdAbs) and IL-2 Rγ-targeting paratopes into a monovalent bispecific antibody architecture enabled the identification of IL-21 mimetics displaying attenuated capacities in triggering STAT3 phosphorylation compared to the wild-type cytokine as demonstrated in NK-92 cells as well as peripheral blood mononuclear cells (PBMCs). Moreover, by applying different protein engineering strategies, we demonstrate that agonism capacities of the generated IL-21 mimetics, such as pSTAT3 induction or Granzyme B expression of cytotoxic T cells, can be significantly optimized. For this, framework mutations were introduced to engineer VHH:VHH interactions within the bispecific sdAb-Fc fusion geometry for a more rigid receptor targeting. Furthermore, we show that antibody format engineering, in which the VHHs were arranged in an IgG-like scaffold that replaces the conventional IgG VH and VL domains with the corresponding VHHs, combined with rigidifying mutations, enables IL-21 R agonism comparable to the wild-type cytokine. Taken together, these findings show that IL-21 receptor agonism can be substantially optimized by adapting the spatial orientation of paratopes targeting both receptor subunits via forced dimerization, without altering paratope valencies.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2726042"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of a highly versatile TCR bispecific scaffold optimized for targeting tumor-specific peptide-HLA antigens.","authors":"Martin Hofmann, Felix Unverdorben, M Gabriele Pszolla, Nadine Aschmoneit, Meike Hutt, Timo Manz, Heiko Schuster, Jens Hukelmann, Andreas Acs, Clara Tenkerian, Sarah Missel, Michael Mølhøj, Christoph Schräder, Claudia Wagner, Dominik Maurer, Sebastian Bunk, Carsten Reinhardt","doi":"10.1080/19420862.2026.2722707","DOIUrl":"10.1080/19420862.2026.2722707","url":null,"abstract":"<p><p>Redirection of T lymphocytes toward cancer cells has been one of the most promising treatment concepts in oncology developed over the past years and leading to multiple regulatory approvals for both adoptive cell therapy (ACT) and T-cell-engaging bispecific (TEB) molecules. However, progress has been achieved predominantly in hematological indications by aiming at so-called lineage antigens (i.e. CD19, CD20, BCMA). Targeting of peptide-HLA antigens (pHLA) has been proposed as a strategy to overcome the paucity of suitable surface antigens in solid cancers, yet the technical hurdle to specifically address this class of low copy and highly promiscuous antigens has so far hampered its use in a broader patient population. We here describe the successful development of TCER (T-Cell-Engaging Receptor), a novel and highly versatile class of T-cell receptor (TCR)-based TEB with optimized <i>in vivo</i> efficacy, tolerability, plasma half-life, and stability characteristics for a broad use targeting pHLA in oncology and beyond.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2722707"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and biochemical differences between non-catalytic and catalytic antibodies.","authors":"Taizo Uda, Ryuichi Kato, Yasuteru Shigeta, Shun Hirota, Jun Kobayashi, Hisashi Yoshida, Masato Tsuyuguchi, Kowit Hengphasatporn, Moe Tsujita, Hiroaki Taguchi, Emi Hifumi","doi":"10.1080/19420862.2025.2503978","DOIUrl":"10.1080/19420862.2025.2503978","url":null,"abstract":"<p><p>A conventional antibody can be converted into its catalytic counterparts by deleting Pro95 in the CDR-3 of human and mice antibody light chains, as previously reported. T99wt is a naturally occurring human antibody light chain that we transformed into its catalytic antibody using Pro95 deletion. In peptidase activity tests, T99wt exhibited a low catalytic activity against a synthetic peptide Arg-pNA and hardly cleaved amyloid-β peptide. In contrast, the engineered variant (T99-Pro95(-)) demonstrated significant catalytic activity, effectively cleaving both Arg-pNA substrate and amyloid-β peptides. In this study, the structural basis for the acquisition of enzymatic function through Pro95 deletion in the CDR-3 region of the light chain was elucidated using X-ray crystallography and molecular dynamics (MD) simulations. X-ray crystallography revealed that Pro95 deletion substantially reduces the distance between Asp1 and His93-key residues for catalytic activity - from 9.56 Å in T99wt to 3.84 Å in T99-Pro95(-). The observed decrease in distance indicates a strong interaction between Asp1(Oδ1) and His93(Nε2), contributing to the formation of an active site in T99-Pro95(-). MD simulations revealed that the entire structure exhibits slight fluctuations and adopts various configurations upon the removal of Pro95. In particular, when His residues in the catalytic region are fully deprotonated, Asp1, His93, and Ser27a transiently come into close proximity, enabling the formation of a functional catalytic triad. Catalytic antibodies can be made starting from just the amino acid sequence of a desired mAb, which may be available in databases such as OAS or IMGT. Therefore, our finding represents a significant technological advancement.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2503978"},"PeriodicalIF":7.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}