mAbs最新文献

{"title":"Discovery, development, and characterization of SPY002 and SPY072, two novel extended half-life monoclonal antibodies targeting TL1A: in vitro properties, in vivo pharmacology, pharmacokinetics, and preclinical safety.","authors":"Matthew Siegel, Eric Zhu, Daniel Rios, Byong H Kang, Justin McNally, Michael Kennedy, Kinjal Hew, Preeyam Patel, Olivia Ballew, David H Giles, Emily M A Lewis, Justin LaFountaine, Jason Oh, Joshua R Friedman, Mark J Rose, Hussam Shaheen, Andrew G Spencer","doi":"10.1080/19420862.2026.2670848","DOIUrl":"10.1080/19420862.2026.2670848","url":null,"abstract":"<p><p>TL1A is a proinflammatory cytokine in the tumor necrosis factor (TNF) superfamily that signals via DR3 on T helper cells, innate lymphoid cells, and fibroblasts. Dysregulated TL1A signaling has been hypothesized to affect multiple immune-mediated diseases, with clinical proof of concept demonstrated in ulcerative colitis and Crohn's disease. We characterized the binding affinity, specificity, structure, pharmacodynamics, pharmacokinetics, and toxicity profiles of SPY002 and SPY072, two novel extended half-life monoclonal antibodies that inhibit TL1A. SPY002 and SPY072 demonstrated selective, high-affinity binding to human TL1A (K_D ≈ 31-35 pM) and potent functional inhibition of DR3 signaling. Based on Fc modifications, SPY002 and SPY072 showed attenuated Fc effector function and increased FcRn binding at acidic pH (5.8). Both antibodies exhibited enhanced PK profiles in nonhuman primates, resulting in predicted human half-lives that support quarterly or biannual dosing. In toxicity studies, no drug-related adverse effects were observed with either antibody at exposures >10 times those anticipated in clinical trials. In a rat collagen-induced arthritis model, anti-TL1A antibody treatment effectively reduced arthritis severity, with similar efficacy to the TNF antagonist etanercept. In humanized mouse Imiquimod-induced psoriasis and 2,4,6‑trinitrobenzene sulfonic acid colitis models, anti-TL1A demonstrated similar efficacy to anti-IL-23 and anti-TNF antibodies. These findings characterize two novel extended half-life TL1A antibodies and support the ongoing Phase 2 clinical development of SPY002 and SPY072 for immune-mediated diseases such as inflammatory bowel disease and rheumatic diseases.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2670848"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13166218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147864311","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":"Conditional activation of IL-12 through a Fibronectin-EDB dependent switch gate.","authors":"Josephine D Kahn, Kothai Parthiban, Peter Slavny, Aaron Arvey, Marc Presler, Jamie Nosbisch, Adrienne Rothschilds, Allan Capili, Teresa Barata, Joana Martins, Jiang Zhu, Robert Kamen, Robert Tepper, Ton N Schumacher, Lioudmila Tchistiakova, Divya Mathur","doi":"10.1080/19420862.2026.2700812","DOIUrl":"10.1080/19420862.2026.2700812","url":null,"abstract":"<p><p>Potent immune-activators, such as interleukin-12 (IL-12) have been challenging to develop for the treatment of solid tumors due to high systemic toxicity. To expand the therapeutic window achievable with IL-12, we engineered a novel and reversible antibody format, comprising a switch arm and targeting arm, that permits conditional activation of IL12 only in the presence of the pan-tumor matrix antigen Fibronectin-EDB (FN-EDB). The switch arm is formed by a dual specificity Fab that binds to tethered IL-12 or FN-EDB in a competitive manner. The FN-EDB targeting arm promotes the avidity‑driven unveiling of IL-12 that is tethered to the switch arm. We employed a quantitative systems pharmacology (QSP) model to define binding parameters required for Switch-IL-12 activity and use a phage screening and rational library design process to generate switch binders with the desired binding profiles. We show that our <i>in vitro</i> functional data support FN-EDB dependent Switch-IL-12 activity and incorporate these data into our QSP model to further refine and expand the therapeutic index of Switch-IL-12.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2700812"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562333","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":"Glycan pairing in therapeutic IgG orchestrates Fcγ receptor engagement and ADCC: an integrated structure-function approach for thorough evaluation of Fc N-glycans as critical quality attributes.","authors":"Maximilian Meudt, Julia Baumeister, Antoinette Cassiopeia Russell, Lindsey Dzielak, Gale Hansen, Boris Mizaikoff, Sybille Ebert, Frank Rosenau, Michaela Blech, Fabian Higel","doi":"10.1080/19420862.2026.2652642","DOIUrl":"10.1080/19420862.2026.2652642","url":null,"abstract":"<p><p>Monoclonal antibodies (mAbs) can mediate their therapeutic activity through antigen binding and by engaging Fc receptors (FcRs) or the complement system. FcRs are expressed on immune cells and can initiate effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis. The conserved Fc N-glycans of immunoglobulin G (IgG) at N297 modulate the strength and stability of Fc-FcγR interactions and the resulting effector responses. Conventional analysis typically considers individual glycans in isolation and neglects the fact that each Fc part carries two N-glycans, that may be paired symmetrically or asymmetrically. Recent studies with IgG Fc regions have demonstrated that glycan pairing can significantly shape Fc-FcR interactions. Here, the effect of glycan pairing was evaluated with full-length IgG using rituximab as a model. A set of pure, homogeneous, symmetrical, and asymmetrical Fc glyco-pair variants was generated by controlled chemoenzymatic remodeling and purification. Surface plasmon resonance binding studies across a comprehensive panel of human FcγRs revealed receptor- and allotype-specific effects: FcγRI binding was essentially unaffected, FcγRIIa showed allotype dependence, with FcγRIIa-H131 predominantly modulated by galactosylation and FcγRIIa-R131 by afucosylation, whereas FcγRIIIa required only a single afucosylation to reach maximal binding. Galactosylation exerted modest and receptor-dependent effects, most pronounced for FcγRIIIb. High-mannose species reduced binding to FcγRI and FcγRII, but displayed intermediate affinity to FcγRIIIa, which was lower than afucosylated complex types yet higher than fully fucosylated variants. To evaluate the biological relevance, cell-based ADCC reporter gene assays confirmed that single afucosylation was sufficient to drive the increase in ADCC potency, with galactosylation and high-mannose contributing only modest or context-dependent effects. Together, these findings establish glycan pairing as a critical quality attribute of therapeutic antibodies and provide a framework for precise evaluation of Fc N-glycan criticality and for tailoring mAbs with defined effector function profiles.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2652642"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13048574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147593077","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":"A framework for evaluating unexpected reactions in antibody-drug conjugates during clinical development: a case study of a promiscuous payload.","authors":"Eef H C Dirksen, Marijn Buurman, Jeroen Kooistra, Benno Ingelse, Ruud Ubink","doi":"10.1080/19420862.2026.2732607","DOIUrl":"10.1080/19420862.2026.2732607","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs) are complex biotherapeutic molecules, comprising an antibody moiety and a small molecule linker-drug. The product quality of an ADC is controlled through monitoring of critical quality attributes to ensure safety and efficacy. During development, unexpected changes may occur in the product quality of an ADC, for example under stress or physiological conditions. This should prompt a systematic evaluation to determine the cause and impact on product quality. A structured approach for such an evaluation is not well established. Here, a strategy for the detection, identification, and assessment of unexpected reactions in an ADC during clinical development is presented encompassing physicochemical and functional analytical characterization, mechanistic confirmation, and evaluation of the relevance <i>in vivo</i>. The strategy is illustrated by a real-world example of an ADC in clinical development, SYD1875, exhibiting an unexpected decrease in biological activity following 3 months of storage at the stressed condition. Comprehensive analytical characterization revealed an intramolecular cross-link between the linker-drug and a glutamic acid in the light chain of the antibody. Mechanistic studies confirmed that this cross-link abolishes the cytotoxicity of the ADC. Subsequent bioanalytical and pharmacokinetic investigations demonstrated that, although the cross-link is also formed <i>in vivo</i>, its overall impact on systemic exposure was limited. The generalizable framework described in this report aims at facilitating the evaluation of anomalies in the product quality of an ADC and subsequent (clinical) risk assessment, thereby supporting decision making.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2732607"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975910","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":"Physics-based surface patch analysis for prediction of hydrophobic contribution to viscosity of mAbs.","authors":"Benjamin Knez, Miha Ravnik, Mitja Zidar","doi":"10.1080/19420862.2026.2614767","DOIUrl":"10.1080/19420862.2026.2614767","url":null,"abstract":"<p><p>The viscosity of monoclonal antibody solutions is critical in their biopharmaceutical application, as it directly influences the ease of subcutaneous injection. Although many descriptors have been developed to enable the <i>in silico</i> prediction of viscosity, they are typically based on electrostatic properties while neglecting hydrophobicity, or rely on AI-based approaches with limited generalizability, both rendering the models inadequate. Moreover, the scarcity of high-quality experimental datasets further limits the use of machine learning algorithms, necessitating interpretable analysis of protein-protein interactions. In this work, we combine computational modeling with experimental viscosity measurements for a set of monoclonal antibodies. We introduce an algorithm for surface patch analysis capable of quantifying the characteristics of hydrophobic patches. By calculating physically meaningful interaction energies, we can discern between the propensity for high and low viscosity due to the hydrophobic effect. Furthermore, by analyzing antibodies with problematic hydrophobic patches, we introduce a theory explaining their solubilization. This method is adaptable to any protein format and can be generalized for early <i>in silico</i> screening of viscosity in protein-based biopharmaceutical solutions.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2614767"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145944859","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":"Structure-guided design of antibody CDRs to reduce their reactivity to treatment-emergent anti-drug antibodies.","authors":"Maria U Johansson, Anne Kerschenmeyer, Alessandra Carella, Simon Carnal, Yannik Schmidt, Alessandra de Felice, Dana Mahler, Marc Thomas, Fabio Mario Spiga, Julia Tietz, Christopher Weinert, Christian Hess, David Urech, Stefan Warmuth","doi":"10.1080/19420862.2025.2604353","DOIUrl":"10.1080/19420862.2025.2604353","url":null,"abstract":"<p><p>Immunogenicity prediction is widely used in the developability assessment of antibodies, and many marketed and clinical-stage therapeutics have a predicted T-cell epitope in the second complementary-determining region of their light chain (CDR2L). To investigate such CDR2Ls in more detail, we identified an antibody with a CDR2L for which a patient had developed treatment-emergent (TE) anti-drug antibodies (ADAs) in a clinical setting. With this, we establish the importance of predicted T-cell epitopes in CDR2L. In the course of deleting the T-cell epitope, we decided to aim for a solution that can be applied broadly to facilitate larger high-throughput discovery campaigns. For this purpose, we have developed a double-mutation scheme that targets AHo67 (Kabat51) and AHo68 (Kabat52) in the CDR2L. This 67G-68G mutation scheme was applied to all light chain sequences of a tri-specific single-chain diabody fused to a single-chain variable fragment (scMATCH3™) antibody for which TE ADAs had been observed. Analyses of patient sera showed that introduction of 67 G-68 G in CDR2L in combination with our previously described T101S-T146K (Kabat: T87S-T110K) framework mutations led to a scMATCH3 antibody with significantly reduced levels of both preexisting and TE ADA reactivities. For a diverse collection of single-chain variable fragments, application of the 67 G-68 G mutation scheme was experimentally seen to not substantially affect the functional or biophysical properties of the molecules, suggesting that this mutation scheme may be applicable to the improvement of therapeutic safety of antibodies of many types, with CDR2L-associated immunogenicity.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2604353"},"PeriodicalIF":7.3,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12724142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804922","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":"Development and non-clinical characterization of Procizumab (invobenitug): a humanized antibody neutralizing circulating DPP3.","authors":"Magali Genest, Dirk Van Lier, Theo Ikenna Uba, Anika Schroeter, Adrien Picod, Hugo Nordin, Noma Assad, Gwendolyn Marguerit, Alexis Nguyen, Andreas Bergmann, Peter Pickkers, Alexandre Mebazaa, Karine Santos, Feriel Azibani","doi":"10.1080/19420862.2026.2675077","DOIUrl":"10.1080/19420862.2026.2675077","url":null,"abstract":"<p><p>Dipeptidyl peptidase 3 (DPP3) is an intracellular protein involved in cellular antioxidant responses. Upon acute stress and tissue damage, DPP3 is released into the circulation (circulating DPP3, cDPP3), where it induces vascular, cardiac, and immune dysregulation. Elevated cDPP3 levels have been implicated in multiple organ dysfunction during circulatory failure. Here, we describe the development and characterization of Procizumab (PCZ), a human immunoglobulin (Ig) G1 kappa monoclonal antibody targeting human cDPP3. The murine variant (mAb1967) was generated by immunizing BALB/c mice with a DPP3-derived peptide mimicking an exposed loop of human DPP3 and conjugated to bovine serum albumin. The humanized recombinant antibody was produced by complementarity-determining region grafting into a human framework, expressed in Chinese hamster ovary cells and purified. Binding kinetics and affinity of PCZ for human DPP3 were assessed by biolayer interferometry. The lack of Fc-mediated immune effector functions, including antibody-dependent cellular cytotoxicity, phagocytosis, and complement-dependent cytotoxicity, was demonstrated in human peripheral blood mononuclear cells. Potential cross-reactivity and specificity were evaluated using a human cell microarray assay. In vivo validation was performed in Dpp3 knock-out mice. Pharmacokinetics and tissue distribution of PCZ were assessed by quantitative whole-body autoradiography in male and female Wistar rats administered radio-labeled antibody. Finally, dose-range finding studies evaluating PCZ efficacy and safety were conducted in an acute cardiac dysfunction mouse model. Inhibition of circulating DPP3 activity represents a novel therapeutic approach for the treatment of shock, and PCZ is currently under investigation in clinical studies.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2675077"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982271","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":"Population-level analysis of glycoprotein glycoforms.","authors":"Alejandro Gomez Toledo, James T Sorrentino, Sanne Schoffelen, Bjørn Voldborg, Erika Velasquez, Aaron M Scott, Göran Larson, Nathan E Lewis, Johan Malmström","doi":"10.1080/19420862.2026.2665879","DOIUrl":"10.1080/19420862.2026.2665879","url":null,"abstract":"<p><p>The structure and function of many proteins are regulated post-translationally through glycan attachment. These glycans, assembled via competing enzymatic reactions, generate diverse glycoform populations - variants sharing a protein backbone but differing in glycan structures. While current analyses often focus on individual glycoforms, we demonstrate that population-level glycoform analysis - integrating spectral, biosynthetic, and physicochemical relationships - reveals new insights into glycoprotein regulation. Applied to immunoglobulin subclasses and antithrombin III (AT3), this approach provides comprehensive coverage of glycoform repertoires from human and murine plasma and biopharmaceuticals. It also enables sensitive quantification of glycosylation changes arising from in vitro manipulations or in vivo infections. Finally, we introduce a statistical framework adapted from ecological biodiversity studies, revealing that both IgG and AT3 exhibit skewed glycoform distributions shaped by biosynthetic constraints and degradation. Our findings demonstrate the added value of population-level glycoform analysis in understanding protein function and regulation through glycosylation.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2665879"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13134397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775785","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":"Near pan-alphavirus neutralization by an antibody-nanobody bispecific.","authors":"Sergei Pletnev, Christina L Gardner, Matthew S Sutton, Baoshan Zhang, Victoria Callahan, Courtney Green, Nicholas C Morano, Tatsiana Bylund, Megan M Dunagan, Yaroslav Tsybovsky, Ellen R Goldman, Lawrence Shapiro, Crystal W Burke, Julie M Fox, Mario Roederer, Peter D Kwong, Tongqing Zhou","doi":"10.1080/19420862.2026.2731281","DOIUrl":"10.1080/19420862.2026.2731281","url":null,"abstract":"<p><p>Alphaviruses represent a global concern, with some such as chikungunya virus currently infecting thousands in China and others such as Venezuelan equine encephalitis virus inducing neurological symptoms in 4-14% of infected individuals. A single antibody capable of protecting from all human-infecting alphaviruses, by achieving sufficient potency against each virus individually, may have high utility, as only a single therapeutic would then need to be stockpiled against this entire class of emerging pathogens. We previously identified an antibody, SKT05, with broad encephalitic alphavirus recognition, and we also identified nanobodies capable of neutralizing both arthritogenic and encephalitic alphaviruses. Here, we employ structure-based design to engineer a SKT05-nanobody bispecific, which has near pan-neutralization of alphaviruses that infect humans. Twenty-three designed SKT05-nanobody bispecifics broadly neutralized pseudotyped viruses expressing envelope proteins of encephalitic alphaviruses. With 10 of these bispecifics, we further assessed live arthritogenic alphavirus neutralization for Mayaro, O'nyong'nyong, Ross River, and Una viruses, observing potent neutralization for all of them with four bispecifics. The best of these four, V2C3-30-SKT05H, comprising the V2C3 nanobody genetically fused through a 30-amino acid linker to the heavy chain of SKT05, potently neutralized 9 of 11 tested alphaviruses that were phylogenetically proximal to all 26 alphaviruses that infect and cause symptoms in humans. Further, therapeutic administration of V2C3-30-SKT05H reduced viral loads in chikungunya virus-infected mice. Electron microscopy revealed that V2C3-30-SKT05H induced disorder of E1E2 spikes on the viral surface, suggesting E1E2 disassembly as a potential neutralization mechanism. Collectively, these results demonstrate near pan-neutralization of human-infecting alphaviruses by an antibody-nanobody bispecific.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2731281"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030817","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":"Dual agonism and selective T-cell depletion activity of a PD-1-directed antibody for treating autoimmune diseases.","authors":"Wenbo Jiang, Lingyun Li, Weili Xue, Xuzhi He, Xuebin Chu, Lei Song, Xue Li, Ranran Zhao, Xinghang Yuan, Xiaoliang Jin, Lishi Fan, Tian Sun, Aisi Zhu, Ling Zhou, Fei Gu, Qian Xu, Guangli Ma, Siqin Wang, Lei Jin, John L Xu","doi":"10.1080/19420862.2026.2624881","DOIUrl":"10.1080/19420862.2026.2624881","url":null,"abstract":"<p><p>Precise inhibition of autoreactivity without concomitant induction of general immunosuppression is an overarching goal that remains elusive for the treatment of autoimmune diseases. PD-1 is preferentially expressed on activated T cells that drive autoimmunity. These PD-1⁺ T cells could serve as a target for therapeutic intervention. Here, we report the discovery of a unique PD-1 agonist antibody, GenSci120, that exhibited potent and selective T-cell inhibition in vitro and T-cell depletion activity both in vitro and in vivo. Target engagement by GenSci120 directly promoted SHP2 recruitment into the PD-1 signaling pathway but also enhanced the binding of PD-1 to its natural ligands and augmented PD-L1-induced PD-1 signaling. Moreover, GenSci120 exhibited robust efficacy in several animal models of human autoimmune disease. Thus, GenSci120, by selectively depleting PD-1⁺ T cells and by directly (via PD-1 binding and SHP2 recruitment) or indirectly (via enhancing PD-1 and ligand interaction) stimulating PD-1 signaling, has the capability to restore immune balance in autoimmunity. In a first-in-human study in healthy adults (NCT06827457), GenSci120 demonstrated favorable safety/tolerability and pharmacokinetic profiles as well as robust pharmacodynamic effect. Together, these findings suggest the potential of GenSci120 as an innovative precision medicine for treating autoimmune diseases and support further evaluation of this investigational new drug in future clinical trials.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"18 1","pages":"2624881"},"PeriodicalIF":7.9,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12885395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119501","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}