IF 5.6 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-06-28 DOI: 10.1080/19420862.2025.2522838

Anna Damsbo, Melisa Benard-Valle, Tom Jansen, Nick J Burlet, Max D Overath, Alid Guadarrama-Martínez, Kim Boddum, Alejandro Alagon, Esperanza Rivera-de-Torre, Andreas H Laustsen

{"title":"Discovery of broadly neutralizing VHHs against short-chain α-neurotoxins using a consensus toxin as an antigen.","authors":"Anna Damsbo, Melisa Benard-Valle, Tom Jansen, Nick J Burlet, Max D Overath, Alid Guadarrama-Martínez, Kim Boddum, Alejandro Alagon, Esperanza Rivera-de-Torre, Andreas H Laustsen","doi":"10.1080/19420862.2025.2522838","DOIUrl":"10.1080/19420862.2025.2522838","url":null,"abstract":"Snakebite envenoming is a neglected tropical disease that afflicts millions of people globally, leading to substantial morbidity and mortality. Developing novel antivenoms, particularly recombinant antivenoms based on broadly neutralizing monoclonal antibodies, offers a promising strategy to address the challenge posed by venom variability. However, the extensive diversity of snake venom toxins across species and geographical regions makes this goal inherently complex. Consequently, there is a pressing need for robust discovery methodologies capable of identifying broadly neutralizing antibodies with high affinity and functional potency against a wide range of toxin families. In this study, we engineered a short-chain consensus (SCC) α-neurotoxin to serve as an antigen for a phage display - based antibody discovery campaign. The SCC was expressed using a yeast system, enabling the identification of seven variable domains of heavy-chain-only antibodies (VHHs) from immune libraries. These VHHs exhibited nanomolar-binding affinities and low dissociation rates across a panel of short-chain α-neurotoxins, which translated into in vitro neutralization, protecting the target receptor. The best two VHHs also conferred protection against lethality in a rodent model. These results highlight the unexpected value of consensus toxins in antibody discovery and offer a viable route for developing recombinant antivenoms with broad-spectrum efficacy.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2522838"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528634","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}

引用次数: 0

Trispecific SEED antibodies engineered for neutrophil-mediated cell killing. 用于中性粒细胞介导的细胞杀伤的三特异性SEED抗体。

IF 5.6 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-07-15 DOI: 10.1080/19420862.2025.2532851

Veronica Natale, Gergely Heves, Katharina Stadlbauer, Florian Rüker, Vanessa Siegmund, Lukas Pekar, Stefan Zielonka, Lars Toleikis, Stefan Becker, Gordana Wozniak-Knopp

{"title":"Trispecific SEED antibodies engineered for neutrophil-mediated cell killing.","authors":"Veronica Natale, Gergely Heves, Katharina Stadlbauer, Florian Rüker, Vanessa Siegmund, Lukas Pekar, Stefan Zielonka, Lars Toleikis, Stefan Becker, Gordana Wozniak-Knopp","doi":"10.1080/19420862.2025.2532851","DOIUrl":"10.1080/19420862.2025.2532851","url":null,"abstract":"Immunoglobulin (Ig) A has attracted interest as a proposed therapeutic agent due to its ability to engage cell groups differently compared to an IgG scaffold and elicit tumor eradication. Further, its multimeric forms enable increased flexibility in the design of available paratopes. The latter is particularly advantageous for bi- and multispecific antibody formats, which are unparalleled in their enhanced selectivity and unique biological functions. We engineered bispecific heterodimeric IgA-based antibodies using the strand-exchanged engineered domain (SEED) technology, which relies on intertwined segments of IgA and IgG in the CH3 domain, and applied mutagenesis to introduce two additional binding sites to enable the interaction of IgA-Fc with the myeloid cell-activating receptor CD89 (FcαR). These antibodies exhibited good biophysical properties and thermostability similar to the parental SEED molecule. Binding capacity to both antigens recognized by variable domains, epidermal growth factor receptor (EGFR) and receptor tyrosine kinase like orphan receptor 1 (ROR1), was not impaired, and in contrast to the original SEED-IgA, trispecific mutants could bind to CD89-expressing cells, mediate tumor cell-effector cell clustering, and induce neutrophil-mediated specific lysis of tumor cells. Trispecific design was applicable to both SEED-IgA1 and -IgA2 scaffolds. Interestingly, HEK-expressed mutants featured a CH2-linked N-glycan pattern more similar to wild-type IgA, with reduced core fucosylation in comparison with IgA-SEED. Collectively, the presented format combines the mobilization of CD89-positive effector cells with the flexibility of incorporating antigen specificities of choice into the variable domains, and thus is a promising basis for biochemically stable multispecific IgA with high therapeutic potential.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2532851"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637395","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}

引用次数: 0

A bispecific antibody-drug conjugate targeting CD7 and CD33 shows anti-tumor activity and improved tumor selectivity in an aggressive subtype of acute myeloid leukemia. 一种靶向CD7和CD33的双特异性抗体-药物偶联物在急性髓性白血病侵袭性亚型中显示出抗肿瘤活性和提高肿瘤选择性。

IF 7.3 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-09-01 DOI: 10.1080/19420862.2025.2551205

Hollie B S Griffiths, Nyle Jones, Mattia Vitale, Nikhil Faulkner, Edward W Masters, Naomi L A Nabi-Aldridge, Meera Mistry, Chloe Patterson, Adrian Blanco-Gomez, Emmanuel Griessinger, Oliver Schon, Tiffany J Daniels-Thorn

{"title":"A bispecific antibody-drug conjugate targeting CD7 and CD33 shows anti-tumor activity and improved tumor selectivity in an aggressive subtype of acute myeloid leukemia.","authors":"Hollie B S Griffiths, Nyle Jones, Mattia Vitale, Nikhil Faulkner, Edward W Masters, Naomi L A Nabi-Aldridge, Meera Mistry, Chloe Patterson, Adrian Blanco-Gomez, Emmanuel Griessinger, Oliver Schon, Tiffany J Daniels-Thorn","doi":"10.1080/19420862.2025.2551205","DOIUrl":"10.1080/19420862.2025.2551205","url":null,"abstract":"Acute myeloid leukemia (AML) is a heterogeneous malignancy with poor clinical outcome. Aberrant expression of CD7 in AML patients is linked to shorter overall survival and lack of response to standard of care therapy. CD33/CD7 co-expression on leukemic blasts occurs in approximately one-third of AML patients and is known to be absent in normal myeloid cells. We propose that CD33+CD7+ AML constitutes an aggressive subgroup characterized by poorer prognosis and enrichment in stem-cell associated gene signatures. To address the substantial unmet need in this patient cohort, we developed the antibody-drug conjugate BVX001, a CD33xCD7-targeted bispecific antibody-binding fragment linked to an auristatin payload. Importantly, BVX001 relies on simultaneous binding to CD33 and CD7 in cis through an 'AND-gated' design, for optimal delivery of its cytotoxic payload. Consequently, BVX001 did not affect healthy myeloid progenitors or T cells at concentrations at which its monospecific counterparts showed toxicity. BVX001 induced significant tumor regression in AML cell line and patient-derived xenografts and increased overall survival. Finally, BVX001 showed significant blast ablation and reduced leukemic stem cell frequency in AML patient samples with both high and low target co-expression. Together, our findings support BVX001 as a new and promising approach for the treatment of this aggressive CD33+CD7+ AML subtype, currently lacking targeted therapeutic options.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2551205"},"PeriodicalIF":7.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959272","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}

引用次数: 0

Combining deep mutational scanning and SPR binning approaches for large-scale epitope identification of anti-ricin antibodies. 结合深度突变扫描和SPR分组方法进行抗蓖麻毒素抗体大规模表位鉴定。

IF 7.3 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-08-29 DOI: 10.1080/19420862.2025.2544922

Ophélie Kot, Lois Lequesne, Hans Werner Mages, Steven Dubois, Paloma Piquet, François Becher, Bernard Maillère, Brigitte G Dorner, Stéphanie Simon, Daniel Stern, Hervé Nozach

{"title":"Combining deep mutational scanning and SPR binning approaches for large-scale epitope identification of anti-ricin antibodies.","authors":"Ophélie Kot, Lois Lequesne, Hans Werner Mages, Steven Dubois, Paloma Piquet, François Becher, Bernard Maillère, Brigitte G Dorner, Stéphanie Simon, Daniel Stern, Hervé Nozach","doi":"10.1080/19420862.2025.2544922","DOIUrl":"10.1080/19420862.2025.2544922","url":null,"abstract":"Ricin, a ribosome-inactivating lectin from Ricinus communis seeds, has been used as a bioterrorism agent in multiple cases. While passive immunotherapy with anti-ricin antibodies shows promise in preclinical studies, no approved countermeasure exists. Developing effective monoclonal antibodies (mAbs) is challenging, requiring epitope targeting that ensures neutralization of the two most dominant natural ricin isoforms (D and E). Moreover, high-affinity binding does not always correlate with toxin neutralization, highlighting the importance of epitope specificity in driving protection. Here, we characterized a panel of 17 anti-ricin antibodies, including VHH and IgG mAbs, to determine their affinities, selectivity, and epitopes. Using surface plasmon resonance (SPR) and biolayer interferometry (BLI), we evaluated antibody affinities for the two ricin isoforms (D and E), as well as for ricin agglutinin, a related lectin with markedly lower toxicity. Epitope determination was performed using (1) SPR-based epitope binning, enhanced by network analysis for streamlined bin visualization, and (2) deep mutational scanning with yeast surface display to identify key epitope residues. BLI effectively distinguished low- and high-affinity interactions, while SPR provided superior resolution for determining the highest affinities and lowest dissociation rates. Both epitope-mapping strategies yielded highly consistent results, allowing the identification of critical epitopes associated with potent neutralization and cross-reactivity between ricin isoforms. This study advances our understanding of ricin neutralization by this panel of antibodies, providing key insights into their affinity, epitope specificity, and cross-reactivity. These findings contribute to the rational design of antibody-based therapeutics for ricin intoxication.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2544922"},"PeriodicalIF":7.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144959376","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}

引用次数: 0

A pH-sensitive binding modality allows successful transferrin receptor-mediated transcytosis of a bivalent antibody across brain barriers. ph敏感的结合方式允许成功的转铁蛋白受体介导的二价抗体跨脑屏障的胞吞作用。

IF 7.3 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-09-22 DOI: 10.1080/19420862.2025.2563758

Philipp Kuhn, Sabrina Petralla, Fatemeh Dabbagh, Valentina Pegoretti, Walter Muranyi, Hiroshi Ishikawa, Horst Schroten, Roman Fischer, André Frenzel, Thomas Schirrmann, Markus Rehm, Christian Schwerk, Gert Fricker, Roland Kontermann, Gavin Fullstone

{"title":"A pH-sensitive binding modality allows successful transferrin receptor-mediated transcytosis of a bivalent antibody across brain barriers.","authors":"Philipp Kuhn, Sabrina Petralla, Fatemeh Dabbagh, Valentina Pegoretti, Walter Muranyi, Hiroshi Ishikawa, Horst Schroten, Roman Fischer, André Frenzel, Thomas Schirrmann, Markus Rehm, Christian Schwerk, Gert Fricker, Roland Kontermann, Gavin Fullstone","doi":"10.1080/19420862.2025.2563758","DOIUrl":"10.1080/19420862.2025.2563758","url":null,"abstract":"Efficient delivery of therapeutics to the central nervous system (CNS) is one of the major challenges in treating neurological diseases due to brain barriers, which prevent entry of almost all potential therapeutic agents into the CNS. Targeting receptors that induce receptor-mediated transcytosis (RMT) across brain barriers has long been heralded as a potential solution to this problem, but this approach has yet to deliver clinical improvements for patients. Here, we set out to identify and characterize bivalent antibodies against the transferrin receptor 1 (TfR) as mediators of RMT. We identified the antibody YU904-F06 (hereafter referred to as F06) that showed efficient transcytosis as a bivalent IgG in two independent in vitro models of brain barriers. Despite its high affinity at extracellular pH levels, we determined that F06's binding to TfR was greatly reduced at lower pH levels expected during endocytic acidification. We postulated, with the support of a validated predictive mathematical model of RMT, that the pH-sensitivity of F06 allowed it to overcome the lysosomal degradation that has been previously reported for high affinity bivalent binders of TfR. Finally, we demonstrated that F06 could mediate the transcytosis of scFvs that target TREM2 or EGFRvIII as potential therapeutic cargos. In conclusion, we present a proof-of-concept antibody and rationale for the design of high affinity bivalent anti-TfR antibodies that effectively induce RMT by exploiting pH-sensitivity in binding.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2563758"},"PeriodicalIF":7.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124032","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}

引用次数: 0

Accelerating antibody development: sequence and structure-based models for predicting developability properties via size exclusion chromatography. 加速抗体开发：基于序列和结构的模型，通过尺寸排斥色谱法预测可显影性。

IF 7.3 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-09-26 DOI: 10.1080/19420862.2025.2562997

A N M Nafiz Abeer, Mehdi Boroumand, Isabelle Sermadiras, Jenna G Caldwell, Valentin Stanev, Neil Mody, Gilad Kaplan, James Savery, Rebecca Croasdale-Wood, Maryam Pouryahya

{"title":"Accelerating antibody development: sequence and structure-based models for predicting developability properties via size exclusion chromatography.","authors":"A N M Nafiz Abeer, Mehdi Boroumand, Isabelle Sermadiras, Jenna G Caldwell, Valentin Stanev, Neil Mody, Gilad Kaplan, James Savery, Rebecca Croasdale-Wood, Maryam Pouryahya","doi":"10.1080/19420862.2025.2562997","DOIUrl":"10.1080/19420862.2025.2562997","url":null,"abstract":"Experimental screening for biopharmaceutical developability properties typically relies on resource-intensive, and time-consuming assays such as size exclusion chromatography (SEC). This study highlights the potential of in silico models to accelerate the screening process by exploring sequence and structure-based machine learning techniques. Specifically, we compared surrogate models based on pre-computed features extracted from sequence and predicted structure with sequence-based approaches using protein language models (PLMs) like ESM-2. In addition to different end-to-end fine-tuning strategies for PLM, we have also investigated the integration of the structural information of the antibodies into the prediction pipeline through graph neural networks (GNN). We applied these different methods for predicting protein aggregation propensity using a dataset of approximately 1200 Immunoglobulin G (IgG1) molecules. Through this empirical evaluation, our study identifies the most effective in silico approach for predicting developability properties for SEC assays, thereby adding insights to existing screening efforts for accelerating the antibody development process.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2562997"},"PeriodicalIF":7.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149524","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}

引用次数: 0

Machine learning-driven optimization of culture conditions and media components to mitigate charge heterogeneity in monoclonal antibody production: current advances and future perspectives. 机器学习驱动的培养条件和培养基成分优化，以减轻单克隆抗体生产中的电荷异质性：当前进展和未来展望。

IF 7.3 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-08-14 DOI: 10.1080/19420862.2025.2547084

Hossein Kavoni, Iman Shahidi Pour Savizi, Saratram Gopalakrishnan, Nathan E Lewis, Seyed Abbas Shojaosadati

{"title":"Machine learning-driven optimization of culture conditions and media components to mitigate charge heterogeneity in monoclonal antibody production: current advances and future perspectives.","authors":"Hossein Kavoni, Iman Shahidi Pour Savizi, Saratram Gopalakrishnan, Nathan E Lewis, Seyed Abbas Shojaosadati","doi":"10.1080/19420862.2025.2547084","DOIUrl":"10.1080/19420862.2025.2547084","url":null,"abstract":"Charge heterogeneity in monoclonal antibodies (mAbs), caused by post-translational modifications, remains a substantial obstacle to ensuring consistent, stable, and effective therapeutics. Conventional optimization techniques, such as one-factor-at-a-time and design of experiments, often fail to capture the complex, nonlinear interactions between culture parameters (e.g. pH, temperature, duration) and medium components (e.g. glucose, metal ions, amino acids). This review highlights machine learning (ML) as a powerful approach for modeling these relationships and forecasting charge variant profiles in CHO cell-based mAb process development. We summarize supervised learning and regression methods used to link process conditions with charge heterogeneity and present case studies showing ML's role in reducing acidic and basic variants. We also discuss challenges related to data quality, model interpretability, scalability, and regulatory compliance. Finally, we propose a roadmap for adaptive, ML-driven optimization strategies for bioprocess development, aligned with Quality-by-Design principles.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2547084"},"PeriodicalIF":7.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855725","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}

引用次数: 0

T cell margination: investigating the detour of T cells following forimtamig treatment in humanized mice. T细胞边缘化：在人源化小鼠中研究forimtaming治疗后T细胞的迂回。

IF 5.6 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2024-12-16 DOI: 10.1080/19420862.2024.2440578

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

{"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":"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.","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}

引用次数: 0

With great power, comes great responsibility: the importance of broadly measuring Fc-mediated effector function early in the antibody development process. 权力越大，责任越大：在抗体开发过程的早期广泛测量fc介导的效应物功能的重要性。

IF 5.6 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-01-16 DOI: 10.1080/19420862.2025.2453515

Silvia Crescioli, Shashi Jatiani, Lenny Moise

{"title":"With great power, comes great responsibility: the importance of broadly measuring Fc-mediated effector function early in the antibody development process.","authors":"Silvia Crescioli, Shashi Jatiani, Lenny Moise","doi":"10.1080/19420862.2025.2453515","DOIUrl":"10.1080/19420862.2025.2453515","url":null,"abstract":"The field of antibody therapeutics is rapidly growing, with over 210 antibodies currently approved or in regulatory review and ~ 1,250 antibodies in clinical development. Antibodies are highly versatile molecules that, with strategic design of their antigen-binding domain (Fab) and the domain responsible for mediating effector functions (Fc), can be used in a wide range of therapeutic indications. Building on many years of progress, the biopharmaceutical industry is now advancing innovative research and development by exploring new targets and new formats and using antibody engineering to fine-tune functions tailored to specific disease requirements. In addition to considering the target and the disease context, however, the unique features of each therapeutic antibody trigger a diverse set of Fc-mediated effector functions. To avoid unexpected results on safety and efficacy outcomes during the later stages of the development process, it is crucial to measure the impact of antibody design on Fc-mediated effector function early in the antibody development process. Given the breadth of effector functions antibodies can deploy and the close interplay between the antibody Fab and Fc functional domains, it is important to conduct a comprehensive evaluation of Fc-mediated functions using an array of antigen-specific biophysical and cell-mediated functional assays. Here, we review antibody and Fc receptor properties that influence Fc effector functions and discuss their implications on development of safe and efficacious antibody therapeutics.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"17 1","pages":"2453515"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11810086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007984","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}

引用次数: 0

Engineered ipilimumab variants that bind human and mouse CTLA-4. 结合人和小鼠CTLA-4的工程易普利姆单抗变体。

IF 5.6 2区医学

mAbs Pub Date : 2025-12-01 Epub Date: 2025-01-24 DOI: 10.1080/19420862.2025.2451296

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

{"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":"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.","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}

引用次数: 0

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