mAbs最新文献

{"title":"Prediction of protein biophysical traits from limited data: a case study on nanobody thermostability through NanoMelt.","authors":"Aubin Ramon, Mingyang Ni, Olga Predeina, Rebecca Gaffey, Patrick Kunz, Shimobi Onuoha, Pietro Sormanni","doi":"10.1080/19420862.2024.2442750","DOIUrl":"10.1080/19420862.2024.2442750","url":null,"abstract":"<p><p>In-silico prediction of protein biophysical traits is often hindered by the limited availability of experimental data and their heterogeneity. Training on limited data can lead to overfitting and poor generalizability to sequences distant from those in the training set. Additionally, inadequate use of scarce and disparate data can introduce biases during evaluation, leading to unreliable model performances being reported. Here, we present a comprehensive study exploring various approaches for protein fitness prediction from limited data, leveraging pre-trained embeddings, repeated stratified nested cross-validation, and ensemble learning to ensure an unbiased assessment of the performances. We applied our framework to introduce NanoMelt, a predictor of nanobody thermostability trained with a dataset of 640 measurements of apparent melting temperature, obtained by integrating data from the literature with 129 new measurements from this study. We find that an ensemble model stacking multiple regression using diverse sequence embeddings achieves state-of-the-art accuracy in predicting nanobody thermostability. We further demonstrate NanoMelt's potential to streamline nanobody development by guiding the selection of highly stable nanobodies. We make the curated dataset of nanobody thermostability freely available and NanoMelt accessible as a downloadable software and webserver.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2442750"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142950964","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":"Biparatopic binding of ISB 1442 to CD38 in trans enables increased cell antibody density and increased avidity.","authors":"Jeremy Loyau, Thierry Monney, Marco Montefiori, Fedir Bokhovchuk, Jeremy Streuli, Matthew Blackburn, Arnaud Goepfert, Lydia N Caro, Samitabh Chakraborti, Stefania De Angelis, Camille Grandclément, Stanislas Blein, M Lamine Mbow, Ankita Srivastava, Mario Perro, Stefano Sammicheli, Eugene A Zhukovsky, Michael Dyson, Cyrille Dreyfus","doi":"10.1080/19420862.2025.2457471","DOIUrl":"10.1080/19420862.2025.2457471","url":null,"abstract":"<p><p>ISB 1442 is a bispecific biparatopic antibody in clinical development to treat hematological malignancies. It consists of two adjacent anti-CD38 arms targeting non-overlapping epitopes that preferentially drive binding to tumor cells and a low-affinity anti-CD47 arm to enable avidity-induced blocking of proximal CD47 receptors. We previously reported the pharmacology of ISB 1442, designed to reestablish synthetic immunity in CD38+ hematological malignancies. Here, we describe the discovery, optimization and characterization of the ISB 1442 antigen binding fragment (Fab) arms, their assembly to 2 + 1 format, and present the high-resolution co-crystal structures of the two anti-CD38 Fabs, in complex with CD38. This, with biophysical and functional assays, elucidated the underlying mechanism of action of ISB 1442. In solution phase, ISB 1442 forms a 2:2 complex with CD38 as determined by size-exclusion chromatography with multi-angle light scattering and electron microscopy. The predicted antibody-antigen stoichiometries at different CD38 surface densities were experimentally validated by surface plasmon resonance and cell binding assays. The specific design and structural features of ISB 1442 enable: 1) enhanced trans binding to adjacent CD38 molecules to increase Fc density at the cancer cell surface; 2) prevention of avid cis binding to monomeric CD38 to minimize blockade by soluble shed CD38; and 3) greater binding avidity, with a slower off-rate at high CD38 density, for increased specificity. The superior CD38 targeting of ISB 1442, at both high and low receptor densities, by its biparatopic design, will enhance proximal CD47 blockade and thus counteract a major tumor escape mechanism in multiple myeloma patients.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2457471"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066701","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":"YAbS: The Antibody Society's antibody therapeutics database.","authors":"Puneet Rawat, Silvia Crescioli, R Prabakaran, Divya Sharma, Victor Greiff, Janice M Reichert","doi":"10.1080/19420862.2025.2468845","DOIUrl":"10.1080/19420862.2025.2468845","url":null,"abstract":"<p><p>Therapeutic antibodies have gained prominence in recent years due to their precision in targeting specific diseases. As these molecules become increasingly essential in modern medicine, comprehensive data tracking and analysis are critical for advancing research and ensuring successful clinical outcomes. YAbS, The Antibody Society's Antibody Therapeutics Database, serves as a vital resource for monitoring the development and clinical progress of therapeutic antibodies. The database catalogs detailed information on over 2,900 commercially sponsored investigational antibody candidates that have entered clinical study since 2000, as well as all approved antibody therapeutics. Data for the late-stage clinical pipeline and antibody therapeutics in regulatory review or approved (over 450 molecules) are openly accessible (https://db.antibodysociety.org). Antibody-related information includes molecular format, targeted antigen, current development status, indications studied, and the clinical development timeline of the antibodies, as well as the geographical region of company sponsors. Furthermore, the database supports in-depth industry trends analysis, facilitating the identification of innovative developments and the assessment of success rates within the field. This resource is continually updated and refined, providing invaluable insights to researchers, clinicians, and industry professionals engaged in antibody therapeutics development.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2468845"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515965","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":"Maximizing activity and selectivity of antibody-mediated effector functions using antibody mixtures.","authors":"Tiexin Wang, Alec A Desai, Greg M Thurber, Peter M Tessier","doi":"10.1080/19420862.2025.2480666","DOIUrl":"https://doi.org/10.1080/19420862.2025.2480666","url":null,"abstract":"<p><p>Fc-mediated effector functions are key for conferring potent antibody-mediated killing of cancer cells. However, it is difficult to achieve highly selective targeting of cancer cells while minimizing toxicity on healthy tissue because of the expression of most receptors, albeit at lower levels, on non-cancer cells. Previous attempts to increase the selectivity of antibody-mediated effector functions have sought to reduce binding affinity and/or increase avidity, which typically results in modest improvements in selectivity. To overcome this limitation, we report the use of mixtures of antibody variants that achieve high selectivity based on receptor level while maintaining high activity for cells with high receptor levels. We have studied mixtures of two variants of an anti-HER2 antibody (trastuzumab), one that is affinity-reduced and effector-competent and a second high-affinity variant that is effectorless. Notably, we observe that the high-affinity, effectorless antibody reduces effector function for cells with low receptor levels, including reduced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), while the high-avidity, effector-competent antibody mediates significant effector function for cells with high receptor levels. Moreover, replacing the effector-competent Fc region of the affinity-reduced antibody with high-affinity Fc domains that enhance effector function drives high activity while maintaining high selectivity for the antibody mixtures. These findings outline a general strategy for maximizing the therapeutic window by selectively targeting cancer cells based on receptor levels that could be applied to a wide range of applications involving antibody-mediated synapse formation, including antibody-drug conjugates and bispecific antibodies, such as T cell engagers.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2480666"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1080/19420862.2025.2458393","DOIUrl":"10.1080/19420862.2025.2458393","url":null,"abstract":"","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2458393"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066706","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":"Combinatorial Fc modifications for complementary antibody functionality.","authors":"Yannic C Bartsch, Nicholas E Webb, Eleanor Burgess, Jaewon Kang, Douglas A Lauffenburger, Boris D Julg","doi":"10.1080/19420862.2025.2465391","DOIUrl":"10.1080/19420862.2025.2465391","url":null,"abstract":"<p><p>Therapeutic monoclonal antibodies (mAbs) can be functionally enhanced via Fc engineering. To determine whether pairs of mAbs with different Fc modifications can be combined for functional complementarity, we investigated the <i>in vitro</i> activity of two HIV-1 mAb libraries, each equipped with 60 engineered Fc variants. Our findings demonstrate that the impact of Fc engineering on Fc functionality is dependent on the specific Fab clone. Notably, combinations of Fc variants of the same Fab specificity exhibited limited enhancement in functional breadth compared to combinations involving two distinct Fabs. This suggests that the strategic selection of complementary Fc modifications can enhance both functional activity and breadth. Furthermore, while some combinations of Fc variants displayed additive functional effects, others were detrimental, suggesting that the functional outcome of Fc mutations is not easily predicted. Collectively, these results provide preliminary evidence supporting the potential of complementary Fc modifications in mAb combinations. Future studies will be essential to identify the optimal Fc modifications that maximize <i>in vivo</i> efficacy.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2465391"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414631","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":"PROPERMAB: an integrative framework for <i>in silico</i> prediction of antibody developability using machine learning.","authors":"Bian Li, Shukun Luo, Wenhua Wang, Jiahui Xu, Dingjiang Liu, Mohammed Shameem, John Mattila, Matthew C Franklin, Peter G Hawkins, Gurinder S Atwal","doi":"10.1080/19420862.2025.2474521","DOIUrl":"10.1080/19420862.2025.2474521","url":null,"abstract":"<p><p>Selection of lead therapeutic molecules is often driven predominantly by pharmacological efficacy and safety. Candidate developability, such as biophysical properties that affect the formulation of the molecule into a product, is usually evaluated only toward the end of the drug development pipeline. The ability to evaluate developability properties early in the process of antibody therapeutic development could accelerate the timeline from discovery to clinic and save considerable resources. <i>In silico</i> predictive approaches, such as machine learning models, which map molecular features to predictions of developability properties could offer a cost-effective and high-throughput alternative to experiments for antibody developability assessment. We developed a computational framework, PROPERMAB (PROPERties of Monoclonal AntiBodies), for large-scale and efficient <i>in silico</i> prediction of developability properties for monoclonal antibodies, using custom molecular features and machine learning modeling. We demonstrate the power of PROPERMAB by using it to develop models to predict antibody hydrophobic interaction chromatography retention time and high-concentration viscosity. We further show that structure-derived features can be rapidly and accurately predicted directly from sequences by pre-training simple models for molecular features, thus providing the ability to scale these approaches to repertoire-scale sequence datasets.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2474521"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11901398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557313","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":"Accelerating high-concentration monoclonal antibody development with large-scale viscosity data and ensemble deep learning.","authors":"Lateefat A Kalejaye, Jia-Min Chu, I-En Wu, Bismark Amofah, Amber Lee, Mark Hutchinson, Chacko Chakiath, Andrew Dippel, Gilad Kaplan, Melissa Damschroder, Valentin Stanev, Maryam Pouryahya, Mehdi Boroumand, Jenna Caldwell, Alison Hinton, Madison Kreitz, Mitali Shah, Austin Gallegos, Neil Mody, Pin-Kuang Lai","doi":"10.1080/19420862.2025.2483944","DOIUrl":"https://doi.org/10.1080/19420862.2025.2483944","url":null,"abstract":"<p><p>Highly concentrated antibody solutions are necessary for developing subcutaneous injections but often exhibit high viscosities, posing challenges in antibody-drug development, manufacturing, and administration. Previous computational models were only limited to a few dozen data points for training, a bottleneck for generalizability. In this study, we measured the viscosity of a panel of 229 monoclonal antibodies (mAbs) to develop predictive models for high concentration mAb screening. We developed DeepViscosity, consisting of 102 ensemble artificial neural network models to classify low-viscosity (≤20 cP) and high-viscosity (>20 cP) mAbs at 150 mg/mL, using 30 features from a sequence-based DeepSP model. Two independent test sets, comprising 16 and 38 mAbs with known experimental viscosity, were used to assess DeepViscosity's generalizability. The model exhibited an accuracy of 87.5% and 89.5% on both test sets, respectively, surpassing other predictive methods. DeepViscosity will facilitate early-stage antibody development to select low-viscosity antibodies for improved manufacturability and formulation properties, critical for subcutaneous drug delivery. The webserver-based application can be freely accessed via https://devpred.onrender.com/DeepViscosity.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2483944"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cell margination: investigating the detour of T cells following forimtamig treatment in humanized mice.","authors":"Nils O'Brien, Joerg P J Mueller, Ann-Marie E Bröske, Jan Attig, Franz Osl, Cylia Crisand, Ann-Katrin Wolf, Richard Rae, Stefanie Lechner, Thomas Pöschinger, Christian Klein, Pablo Umaña, Sara Colombetti, Andreas Beilhack, Jan Eckmann","doi":"10.1080/19420862.2024.2440578","DOIUrl":"10.1080/19420862.2024.2440578","url":null,"abstract":"<p><p>T cell bispecific antibodies (TCBs) are a promising new class of therapeutics for relapsed/refractory multiple myeloma. A frequently observed, yet incompletely understood effect of this treatment is the transient reduction of circulating T cell counts, also known as T cell margination (TCM). After administration of the GPRC5D-targeting TCB forimtamig (RG6234), TCM occurred in patients and correlated with cytokine release and soluble B cell maturation antigen decrease. We demonstrate that TCM is accurately represented in the humanized NSG mouse model and occurs at a lower threshold of target expression than systemic cytokine release. Application of whole-mouse tissue clearing and 3D imaging revealed that T cells accumulate in the bone marrow after treatment. We hypothesize that low amounts of targets are sufficient to rapidly redirect T cells upon TCB engagement. Therefore, we propose TCM as a beneficial, highly sensitive and early effect of forimtamig that leads T cells to likely sites of bone marrow tumor lesions.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2440578"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142837183","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":"Engineered ipilimumab variants that bind human and mouse CTLA-4.","authors":"Brett Robison, S J Diong, Anusha Kumar, Thomas M Moon, Olin Chang, Bryant Chau, Christine Bee, Ishita Barman, Arvind Rajpal, Alan J Korman, Sean West, Pavel Strop, Peter S Lee","doi":"10.1080/19420862.2025.2451296","DOIUrl":"10.1080/19420862.2025.2451296","url":null,"abstract":"<p><p>Testing of candidate monoclonal antibody therapeutics in preclinical models is an essential step in drug development. Identification of antibody therapeutic candidates that bind their human targets and cross-react to mouse orthologs is often challenging, especially for targets with low sequence homology. In such cases, surrogate antibodies that bind mouse orthologs must be used. The antibody 9D9, which binds mouse CTLA-4, is a commonly used surrogate for CTLA-4 checkpoint blockade studies in mouse cancer models. In this work, we reveal that 9D9 has significant biophysical dissimilarities to therapeutic CTLA-4 antibodies. The 9D9-mCTLA4 complex crystal structure was determined and shows that the surrogate antibody binds an epitope distinct from ipilimumab and tremelimumab. In addition, while ipilimumab has pH-independent binding to hCTLA-4, 9D9 loses binding to mCTLA-4 at physiologically relevant acidic pH ranges. We used phage and yeast display to engineer ipilimumab to bind mouse CTLA-4 with single-digit nM affinity from an initial state with no apparent binding. The engineered variants showed pH-independent and cross-reactive binding to both mouse and human CTLA-4. Crystal structures of a variant in complex with both mouse and human CTLA-4 confirmed that it targets an equivalent epitope as ipilimumab. These cross-reactive ipilimumab variants may facilitate improved translatability and future mechanism-of-action studies for anti-CTLA-4 targeting in murine models.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2451296"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029148","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}