mAbs最新文献

{"title":"T and B cell epitope analysis for the immunogenicity evaluation and mitigation of antibody-based therapeutics.","authors":"Ruoxuan Sun, Mark G Qian, Xiaobin Zhang","doi":"10.1080/19420862.2024.2324836","DOIUrl":"10.1080/19420862.2024.2324836","url":null,"abstract":"<p><p>The surge in the clinical use of therapeutic antibodies has reshaped the landscape of pharmaceutical therapy for many diseases, including rare and challenging conditions. However, the administration of exogenous biologics could potentially trigger unwanted immune responses such as generation of anti-drug antibodies (ADAs). Real-world experiences have illuminated the clear correlation between the ADA occurrence and unsatisfactory therapeutic outcomes as well as immune-related adverse events. By retrospectively examining research involving immunogenicity analysis, we noticed the growing emphasis on elucidating the immunogenic epitope profiles of antibody-based therapeutics aiming for mechanistic understanding the immunogenicity generation and, ideally, mitigating the risks. As such, we have comprehensively summarized here the progress in both experimental and computational methodologies for the characterization of T and B cell epitopes of therapeutics. Furthermore, the successful practice of epitope-driven deimmunization of biotherapeutics is exceptionally highlighted in this article.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2324836"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10962608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184822","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":"In silico methods for immunogenicity risk assessment and human homology screening for therapeutic antibodies.","authors":"Aimee E Mattei, Andres H Gutierrez, Soorya Seshadri, Jacob Tivin, Matt Ardito, Amy S Rosenberg, William D Martin, Anne S De Groot","doi":"10.1080/19420862.2024.2333729","DOIUrl":"10.1080/19420862.2024.2333729","url":null,"abstract":"<p><p>In silico immunogenicity risk assessment has been an important step in the development path for many biologic therapeutics, including monoclonal antibodies. Even if the source of a given biologic is 'fully human', T cell epitopes that are contained in the sequences of the biologic may activate the immune system, enabling the development of anti-drug antibodies that can reduce drug efficacy and may contribute to adverse events. Computational tools that identify T cell epitopes from primary amino acid sequences have been used to assess the immunogenic potential of therapeutic candidates for several decades. To facilitate larger scale analyses and accelerate preclinical immunogenicity risk assessment, our group developed an integrated web-based platform called ISPRI, (Immunogenicity Screening and Protein Re-engineering Interface) that provides hands-on access through a secure web-based interface for scientists working in large and mid-sized biotech companies in the US, Europe, and Japan. This toolkit has evolved and now contains an array of algorithms that can be used individually and/or consecutively for immunogenicity assessment and protein engineering. Most analyses start with the advanced epitope mapping tool (EpiMatrix), then proceed to identify epitope clusters using ClustiMer, and then use a tool called JanusMatrix to define whether any of the T cell epitope clusters may generate a regulatory T cell response which may diminish or eliminate anti-drug antibody formation. Candidates can be compared to similar products on a normalized immunogenicity scale. Should modifications to the biologic sequence be an option, a tool for moderating putative immunogenicity by editing T cell epitopes out of the sequence is available (OptiMatrix). Although this perspective discusses the in-silico immunogenicity risk assessment for monoclonal antibodies, bi-specifics, multi-specifics, and antibody-drug conjugates, the analysis of additional therapeutic modalities such as enzyme replacement proteins, blood factor proteins, CAR-T, gene therapy products, and peptide drugs is also made available on the ISPRI platform.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2333729"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10978032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306147","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":"Decoding the mannose receptor-mAb interaction: the importance of high-mannose N-glycans and glycan-pairing.","authors":"Julia Baumeister, Maximilian Meudt, Sybille Ebert, Frank Rosenau, Boris Mizaikoff, Michaela Blech, Kristina M J Aertker, Fabian Higel","doi":"10.1080/19420862.2024.2400414","DOIUrl":"10.1080/19420862.2024.2400414","url":null,"abstract":"<p><p>During the development process of therapeutic monoclonal antibodies (mAbs), it is crucial to control (critical) quality attributes such as N-glycosylation influencing pharmacokinetics (PK) and Fc effector functions. Previous reports have shown that mAbs containing high-mannose N-glycans are cleared faster from blood circulation, leading to reduced half-lives. The high-mannose N-glycan content of mAbs can be influenced during the cell culture process by factors such as cell lines, process conditions, and media. Furthermore, mAbs have either one high mannose N-glycan (asymmetrical high-mannose glyco-pair) or two high mannose N-glycans (symmetrical high-mannose glyco-pair). The hypothesis that the mannose receptor (MR, CD206) accelerates clearance by facilitating their internalization and subsequent lysosomal degradation is widespread. However, the interaction between MR and mAbs has not been explicitly demonstrated. This study aimed to investigate this interaction, providing the first systematic demonstration of MR binding to the Fc region of mAbs with high-mannose N-glycans. Two novel analytical methods, MR surface plasmon resonance and MR affinity chromatography, were developed and applied to investigate the MR-mAb interaction. The interaction is found to be dependent on high-mannose content, but is independent of the mAb format or sequence. However, different glyco-pairs exhibited varying binding affinities to the MR, with the symmetrical high-mannose glyco-pair showing the strongest binding properties. These findings strengthen the hypothesis for the MR-mediated mAb interaction and contribute to a deeper understanding of the MR-mAb interaction, which could affect the criticality of high-mannose containing mAbs development strategies of IgG-based molecules and improve their PK profiles.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2400414"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11385167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154495","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":"RUBY® - a tetravalent (2+2) bispecific antibody format with excellent functionality and IgG-like stability, pharmacology and developability properties.","authors":"Barnabas Nyesiga, Mattias Levin, Anna Säll, Anna Rosén, Kim Jansson, Sara Fritzell, Karin Hägerbrand, Dietmar Weilguny, Laura von Schantz","doi":"10.1080/19420862.2024.2330113","DOIUrl":"10.1080/19420862.2024.2330113","url":null,"abstract":"<p><p>Despite the large number of existing bispecific antibody (bsAb) formats, the generation of novel bsAbs is still associated with development and bioprocessing challenges. Here, we present RUBY, a novel bispecific antibody format that allows rapid generation of bsAbs that fulfill key development criteria. The RUBY^TM format has a 2 + 2 geometry, where two Fab fragments are linked via their light chains to the C-termini of an IgG, and carries mutations for optimal chain pairing. The unique design enables generation of bsAbs with mAb-like attributes. Our data demonstrate that RUBY bsAbs are compatible with small-scale production systems for screening purposes and can be produced at high yields (>3 g/L) from stable cell lines. The bsAbs produced are shown to, in general, contain low amounts of aggregates and display favorable solubility and stress endurance profiles. Further, compatibility with various IgG isotypes is shown and tailored Fc gamma receptor binding confirmed. Also, retained interaction with FcRn is demonstrated to translate into a pharmacokinetic profile in mice and non-human primates that is comparable to mAb controls. Functionality of conditional active RUBY bsAbs is confirmed in vitro. Anti-tumor effects in vivo have previously been demonstrated, and shown to be superior to a comparable mAb, and here it is further shown that RUBY bsAbs penetrate and localize to tumor tissue in vivo. In all, the RUBY format has attractive mAb-like attributes and offers the possibility to mitigate many of the development challenges linked to other bsAb formats, facilitating both high functionality and developability.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2330113"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10965115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288478","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":"Discovery of potent allosteric antibodies inhibiting EGFR.","authors":"Léxane Fournier, Lukas Pekar, Birgitta Leuthner, Harald Kolmar, Lars Toleikis, Stefan Becker","doi":"10.1080/19420862.2024.2406548","DOIUrl":"10.1080/19420862.2024.2406548","url":null,"abstract":"<p><p>In this work, we report the discovery of potent anti-epidermal growth factor receptor (EGFR) allosteric heavy-chain antibodies by combining camelid immunization and fluorescence-activated cell sorting (FACS). After immunization and yeast surface display library construction, allosteric clones were obtained by introducing the labeled EGF Fc fusion protein as an additional criterion for FACS. This sorting method enabled the identification of 11 heavy-chain antibodies that did not compete with the orthosteric ligand EGF for the binding to EGFR. These antibodies bind to a triple-negative breast cancer cell line expressing EGFR with affinities in the picomolar to nanomolar range. Those camelid-derived antibodies also exhibit interesting properties by modulating EGFR affinity for EGF. Moreover, they are also able to inhibit EGF-induced downstream signaling pathways. In particular, we identified one clone that is more potent than the approved blocking antibody cetuximab in inhibiting both PI3K/AKT and MAPK/ERK pathways. Our results suggest that allosteric antibodies may be potential new modalities for therapeutics.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2406548"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290470","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":"CD200R1 immune checkpoint blockade by the first-in-human anti-CD200R1 antibody 23ME-00610: molecular mechanism and engineering of a surrogate antibody.","authors":"Cristina Melero, S Jimmy Budiardjo, Anahita Daruwalla, Lance Larrabee, Oleg Ganichkin, Alexander J Heiler, Jill Fenaux, Ben Chung, Germaine Fuh, Yao-Ming Huang","doi":"10.1080/19420862.2024.2410316","DOIUrl":"https://doi.org/10.1080/19420862.2024.2410316","url":null,"abstract":"<p><p>Human CD200R1 (hCD200R1), an immune inhibitory receptor expressed predominantly on T cells and myeloid cells, was identified as a promising immuno-oncology target by the 23andMe database. Blockade of CD200R1-dependent signaling enhances T cell-mediated antitumor activity in vitro and in vivo. 23ME-00610 is a potential first-in-class, humanized IgG1 investigational antibody that binds hCD200R1 with high affinity. We have previously shown that 23ME-00610 inhibits the hCD200R1 immune checkpoint function. Herein, we dissect the molecular mechanism of 23ME-00610 blockade of hCD200R1 by solving the crystal structure of 23ME-00610 Fab in complex with hCD200R1 and performing mutational studies, which show 23ME-00610 blocks the interaction between hCD200 and hCD200R1 through steric hindrance. However, 23ME-00610 does not bind CD200R1 of preclinical species such as cynomolgus monkey MfCD200R1. To enable preclinical toxicology studies of CD200R1 blockade in a pharmacologically relevant non-clinical species, we engineered a surrogate antibody with high affinity toward MfCD200R1. We used phage display libraries of 23ME-00610 variants with individual CDR residues randomized to all 20 amino acids, from which we identified mutations that switched on MfCD200R1 binding. Structural analysis suggests how the surrogate, named 23ME-00611, acquires the ortholog binding ability at the equivalent epitope of 23ME-00610. This engineering approach does not require <i>a priori</i> knowledge of structural and functional mapping of antibody-antigen interaction and thus is generally applicable for therapeutic antibody development when desired ortholog binding is lacking. These findings provide foundational insights as 23ME-00610 advances in clinical studies to gain understanding of the hCD200R1 immune checkpoint as a target in immuno-oncology.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2410316"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469140","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":"Heavy chain-only antibodies with a stabilized human VH in transgenic chickens for therapeutic antibody discovery.","authors":"Christine N Vuong, Kevin M Reynolds, Gerry S Rivera, Baisen Zeng, Zahra Karimpourkalou, Manith Norng, Yulei Zhang, Robayet Chowdhury, Darlene Pedersen, Melissa Pantoja, Ellen Collarini, Swetha Garimalla, Shelley Izquierdo, Eric G Vajda, Brett Antonio, Devendra B Srivastava, Marie-Cecile van de Lavoir, Yasmina Abdiche, William Harriman, Philip A Leighton","doi":"10.1080/19420862.2024.2435476","DOIUrl":"10.1080/19420862.2024.2435476","url":null,"abstract":"<p><p>Heavy chain-only antibodies have found many applications where conventional heavy-light heterodimeric antibodies are not favorable. Heavy chain-only antibodies with their single antigen-binding domain offer the advantage of a smaller size and higher stability relative to conventional antibodies, and thus, the potential for novel targeting modalities. Domain antibodies have commonly been sourced from camelids with <i>ex-vivo</i> humanization or transgenic rodents expressing heavy chains without light chains, but these host species are all mammalian, limiting their capacity to elicit robust immune responses to conserved mammalian targets. We have developed transgenic chickens expressing heavy chain-only antibodies with a human variable region to combine the superior target recognition advantages of a divergent, non-mammalian host with the ability to discover single-domain binders. These birds produce robust immune responses, consisting of antigen-specific antibodies targeting diverse epitopes with a range of affinities. Biophysical attributes are favorable, with good developability profiles and low predicted immunogenicity.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2435476"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739880","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":"Humatch - fast, gene-specific joint humanisation of antibody heavy and light chains.","authors":"Lewis Chinery, Jeliazko R Jeliazkov, Charlotte M Deane","doi":"10.1080/19420862.2024.2434121","DOIUrl":"10.1080/19420862.2024.2434121","url":null,"abstract":"<p><p>Antibodies are a popular and powerful class of therapeutic due to their ability to exhibit high affinity and specificity to target proteins. However, the majority of antibody therapeutics are not genetically human, with initial therapeutic designs typically obtained from animal models. Humanization of these precursors is essential to reduce immunogenic risks when administered to humans.Here, we present Humatch, a computational tool designed to offer experimental-like joint humanization of heavy and light chains in seconds. Humatch consists of three lightweight Convolutional Neural Networks (CNNs) trained to identify human heavy V-genes, light V-genes, and well-paired antibody sequences with near-perfect accuracy. We show that these CNNs, alongside germline similarity, can be used for fast humanization that aligns well with known experimental data. Throughout the humanization process, a sequence is guided toward a specific target gene and away from others via multiclass CNN outputs and gene-specific germline data. This guidance ensures final humanized designs do not sit 'between' genes, a trait that is not naturally observed. Humatch's optimization toward specific genes and good VH/VL pairing increases the chances that final designs will be stable and express well and reduces the chances of immunogenic epitopes forming between the two chains. Humatch's training data and source code are provided open-source.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2434121"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751334","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 TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer.","authors":"Peter Jung, Stefan P Glaser, Jing Han, Alexandra Popa, Laura Pisarsky, Ningping Feng, Antonia Geyer, Franziska Haderk, Donat Alpar, Christopher Bristow, Susanne Schmittner, Paula-Elena Traexler, Mikhila Mahendra, Birgit Poehn, Poojabahen Gandhi, Roberto Fiorelli, Sanket Awate, Nicole Budano, Florian Martin, Christoph Albrecht, Barbara Drobits-Handl, Sathanandam S Anand, Srinath Kasturirangan, Francesca Trapani, Norbert Schweifer, Joseph R Marszalek, Ulrike Tontsch-Grunt, Mark Pearson, Timothy P Heffernan, Norbert Kraut, Christopher P Vellano, Juan Manuel García-Martínez","doi":"10.1080/19420862.2024.2438173","DOIUrl":"10.1080/19420862.2024.2438173","url":null,"abstract":"<p><p>Exploitation of extrinsic apoptosis signaling via TRAILR2 activation represents a promising therapeutic concept in cancer treatment. The limited clinical success of previous TRAILR2 agonistic agents, to date, has been ascribed to either poor efficacy or hepatotoxicity. TR2/CDH3 BAB is a human bispecific antibody that relies on binding both CDH3 and TRAILR2 on cell surfaces to achieve TRAILR2 hyperclustering and efficient apoptosis induction by TRAILR2 signaling selectively in CDH3-expressing tumor cells. We demonstrate target-dependent TR2/CDH3 BAB anti-tumor activity in CRISPR/Cas9-engineered <i>TRAILR2</i> or <i>CDH3</i> knock-out cells. By utilizing the cell line screening platform PRISM, we found selective TR2/CDH3 BAB efficacy in various cancer types, such as pancreatic, gastric, colorectal, and triple negative breast cancer. The efficacy of TR2/CDH3 BAB correlated with caspase activation in cancer cell lines and in xenograft tumor tissues. In pancreatic ductal adenocarcinoma (PDAC), where patient benefit from current cytotoxic therapy options is unsatisfactory, a close to uniform cell surface expression of CDH3 and TRAILR2 was observed, which will qualify the majority of PDAC patients for TR2/CDH3 BAB-based treatment. TR2/CDH3 BAB demonstrated anti-tumor activity in a panel of PDAC patient-derived xenograft models, including tumor regressions. By combining TR2/CDH3 BAB with chemotherapeutic agents, deeper and more sustained anti-tumor responses were observed when compared to monotherapy. Together with the potential to deliver a favorable safety profile, these data support clinical testing of TR2/CDH3 BAB in patients with PDAC.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2438173"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11633135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801457","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":"Interactions of the anti-FcRn monoclonal antibody, rozanolixizumab, with Fcγ receptors and functional impact on immune cells <i>in vitro</i>.","authors":"Omar S Qureshi, Emma J Sutton, Rosemary F Bithell, Shauna M West, Rona M Cutler, Gillian McCluskey, Graham Craggs, Asher Maroof, Nicholas M Barnes, David P Humphreys, Stephen Rapecki, Bryan J Smith, Anthony Shock","doi":"10.1080/19420862.2023.2300155","DOIUrl":"10.1080/19420862.2023.2300155","url":null,"abstract":"<p><p>Rozanolixizumab is a humanized anti-neonatal Fc receptor (FcRn) monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) sub-class, currently in clinical development for the treatment of IgG autoantibody-driven diseases. This format is frequently used for therapeutic mAbs due to its intrinsic lower affinity for Fc gamma receptors (FcγR) and lack of C1q engagement. However, with growing evidence suggesting that no Fc-containing agent is truly \"silent\" in this respect, we explored the engagement of FcγRs and potential functional consequences with rozanolixizumab. In the study presented here, rozanolixizumab was shown to bind to FcγRs in both protein-protein and cell-based assays, and the kinetic data were broadly as expected based on published data for an IgG4 mAb. Rozanolixizumab was also able to mediate antibody bipolar bridging (ABB), a phenomenon that led to a reduction of labeled FcγRI from the surface of human macrophages in an FcRn-dependent manner. However, the presence of exogenous human IgG, even at low concentrations, was able to prevent both binding and ABB events. Furthermore, data from <i>in vitro</i> experiments using relevant human cell types that express both FcRn and FcγRI indicated no evidence for functional sequelae in relation to cellular activation events (e.g., intracellular signaling, cytokine production) upon either FcRn or FcγR binding of rozanolixizumab. These data raise important questions about whether therapeutic antagonistic mAbs like rozanolixizumab would necessarily engage FcγRs at doses typically administered to patients in the clinic, and hence challenge the relevance and interpretation of <i>in vitro</i> assays performed in the absence of competing IgG.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2300155"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10802195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139502657","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}