IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-03-18 DOI: 10.1080/19420862.2024.2329321

W van der Wulp, W Luu, M E Ressing, J Schuurman, S I van Kasteren, L Guelen, R C Hoeben, B Bleijlevens, M H M Heemskerk

{"title":"Antibody-epitope conjugates deliver immunogenic T-cell epitopes more efficiently when close to cell surfaces.","authors":"W van der Wulp, W Luu, M E Ressing, J Schuurman, S I van Kasteren, L Guelen, R C Hoeben, B Bleijlevens, M H M Heemskerk","doi":"10.1080/19420862.2024.2329321","DOIUrl":"10.1080/19420862.2024.2329321","url":null,"abstract":"Antibody-mediated delivery of immunogenic viral CD8+ T-cell epitopes to redirect virus-specific T cells toward cancer cells is a promising new therapeutic avenue to increase the immunogenicity of tumors. Multiple strategies for viral epitope delivery have been shown to be effective. So far, most of these have relied on a free C-terminus of the immunogenic epitope for extracellular delivery. Here, we demonstrate that antibody-epitope conjugates (AECs) with genetically fused epitopes to the N-terminus of the antibody can also sensitize tumors for attack by virus-specific CD8+ T cells. AECs carrying epitopes genetically fused at the N-terminus of the light chains of cetuximab and trastuzumab demonstrate an even more efficient delivery of the T-cell epitopes compared to AECs with the epitope fused to the C-terminus of the heavy chain. We demonstrate that this increased efficiency is not caused by the shift in location of the cleavage site from the N- to the C-terminus, but by its increased proximity to the cell surface. We hypothesize that this facilitates more efficient epitope delivery. These findings not only provide additional insights into the mechanism of action of AECs but also broaden the possibilities for genetically fused AECs as an avenue for the redirection of multiple virus-specific T cells toward tumors.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2329321"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10950288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140143825","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

Predicting deamidation and isomerization sites in therapeutic antibodies using structure-based in silico approaches. 利用基于结构的硅学方法预测治疗性抗体中的去酰胺化和异构化位点。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-03-28 DOI: 10.1080/19420862.2024.2333436

David Hoffmann, Joschka Bauer, Markus Kossner, Andrew Henry, Anne R Karow-Zwick, Giuseppe Licari

{"title":"Predicting deamidation and isomerization sites in therapeutic antibodies using structure-based in silico approaches.","authors":"David Hoffmann, Joschka Bauer, Markus Kossner, Andrew Henry, Anne R Karow-Zwick, Giuseppe Licari","doi":"10.1080/19420862.2024.2333436","DOIUrl":"10.1080/19420862.2024.2333436","url":null,"abstract":"Asparagine (Asn) deamidation and aspartic acid (Asp) isomerization are common degradation pathways that affect the stability of therapeutic antibodies. These modifications can pose a significant challenge in the development of biopharmaceuticals. As such, the early engineering and selection of chemically stable monoclonal antibodies (mAbs) can substantially mitigate the risk of subsequent failure. In this study, we introduce a novel in silico approach for predicting deamidation and isomerization sites in therapeutic antibodies by analyzing the structural environment surrounding asparagine and aspartate residues. The resulting quantitative structure-activity relationship (QSAR) model was trained using previously published forced degradation data from 57 clinical-stage mAbs. The predictive accuracy of the model was evaluated for four different states of the protein structure: (1) static homology models, (2) enhancing low-frequency vibrational modes during short molecular dynamics (MD) runs, (3) a combination of (2) with a protonation state reassignment, and (4) conventional full-atomistic MD simulations. The most effective QSAR model considered the accessible surface area (ASA) of the residue, the pKa value of the backbone amide, and the root mean square deviations of both the alpha carbon and the side chain. The accuracy was further enhanced by incorporating the QSAR model into a decision tree, which also includes empirical information about the sequential successor and the position in the protein. The resulting model has been implemented as a plugin named \"Forecasting Reactivity of Isomerization and Deamidation in Antibodies\" in MOE software, completed with a user-friendly graphical interface to facilitate its use.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2333436"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318621","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

Large-scale data mining of four billion human antibody variable regions reveals convergence between therapeutic and natural antibodies that constrains search space for biologics drug discovery. 对 40 亿个人类抗体可变区的大规模数据挖掘揭示了治疗性抗体与天然抗体之间的趋同性，这限制了生物制剂药物发现的搜索空间。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-06-06 DOI: 10.1080/19420862.2024.2361928

Pawel Dudzic, Dawid Chomicz, Jarosław Kończak, Tadeusz Satława, Bartosz Janusz, Sonia Wrobel, Tomasz Gawłowski, Igor Jaszczyszyn, Weronika Bielska, Samuel Demharter, Roberto Spreafico, Lukas Schulte, Kyle Martin, Stephen R Comeau, Konrad Krawczyk

{"title":"Large-scale data mining of four billion human antibody variable regions reveals convergence between therapeutic and natural antibodies that constrains search space for biologics drug discovery.","authors":"Pawel Dudzic, Dawid Chomicz, Jarosław Kończak, Tadeusz Satława, Bartosz Janusz, Sonia Wrobel, Tomasz Gawłowski, Igor Jaszczyszyn, Weronika Bielska, Samuel Demharter, Roberto Spreafico, Lukas Schulte, Kyle Martin, Stephen R Comeau, Konrad Krawczyk","doi":"10.1080/19420862.2024.2361928","DOIUrl":"10.1080/19420862.2024.2361928","url":null,"abstract":"The naïve human antibody repertoire has theoretical access to an estimated > 1015 antibodies. Identifying subsets of this prohibitively large space where therapeutically relevant antibodies may be found is useful for development of these agents. It was previously demonstrated that, despite the immense sequence space, different individuals can produce the same antibodies. It was also shown that therapeutic antibodies, which typically follow seemingly unnatural development processes, can arise independently naturally. To check for biases in how the sequence space is explored, we data mined public repositories to identify 220 bioprojects with a combined seven billion reads. Of these, we created a subset of human bioprojects that we make available as the AbNGS database (https://naturalantibody.com/ngs/). AbNGS contains 135 bioprojects with four billion productive human heavy variable region sequences and 385 million unique complementarity-determining region (CDR)-H3s. We find that 270,000 (0.07% of 385 million) unique CDR-H3s are highly public in that they occur in at least five of 135 bioprojects. Of 700 unique therapeutic CDR-H3, a total of 6% has direct matches in the small set of 270,000. This observation extends to a match between CDR-H3 and V-gene call as well. Thus, the subspace of shared ('public') CDR-H3s shows utility for serving as a starting point for therapeutic antibody design.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2361928"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284137","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

The history and potential future of monoclonal antibody therapeutics development and manufacturing in four eras. 四个时代的单克隆抗体疗法开发和生产的历史与潜在未来。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-07-01 DOI: 10.1080/19420862.2024.2373330

Brian Kelley

引用次数: 0

Early determination of potential critical quality attributes of therapeutic antibodies in developability studies through surface plasmon resonance-based relative binding activity assessment. 通过基于表面等离子共振的相对结合活性评估，在可开发性研究中及早确定治疗性抗体的潜在关键质量属性。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-07-02 DOI: 10.1080/19420862.2024.2374607

Shuai Wang, Yanqiu Wang, Zhenzhen Li, Ye Hong, Zhaohui Wang, Jiteng Fan, Qiong Wang, Yuanjie Ge, Xiaofeng Zhao, Guangcun Cheng, Changyan Chen, Yadan Wu, Yayuan Fu

{"title":"Early determination of potential critical quality attributes of therapeutic antibodies in developability studies through surface plasmon resonance-based relative binding activity assessment.","authors":"Shuai Wang, Yanqiu Wang, Zhenzhen Li, Ye Hong, Zhaohui Wang, Jiteng Fan, Qiong Wang, Yuanjie Ge, Xiaofeng Zhao, Guangcun Cheng, Changyan Chen, Yadan Wu, Yayuan Fu","doi":"10.1080/19420862.2024.2374607","DOIUrl":"10.1080/19420862.2024.2374607","url":null,"abstract":"Precise measurement of the binding activity changes of therapeutic antibodies is important to determine the potential critical quality attributes (CQAs) in developability assessment at the early stage of antibody development. Here, we report a surface plasmon resonance (SPR)-based relative binding activity method, which incorporates both binding affinity and binding response and allows us to determine relative binding activity of antibodies with high accuracy and precision. We applied the SPR-based relative binding activity method in multiple forced degradation studies of antibody developability assessment. The current developability assessment strategy provided comprehensive, precise characterization of antibody binding activity in the stability studies, enabling us to perform correlation analysis and establish the structure-function relationship between relative binding activity and quality attributes. The impact of a given quality attribute on binding activity could be confidently determined without isolating antibody variants. We identified several potential CQAs, including Asp isomerization, Asn deamidation, and fragmentation. Some potential CQAs affected binding affinity of antibody and resulted in a reduction of binding activity. Certain potential CQAs impaired antibody binding to antigen and led to a loss of binding activity. A few potential CQAs could influence both binding affinity and binding response and cause a substantial decrease in antibody binding activity. Specifically, we identified low abundance Asn33 deamidation in the light chain complementarity-determining region as a potential CQA, in which all the stressed antibody samples showed Asn33 deamidation abundances ranging from 4.2% to 27.5% and a mild binding affinity change from 1.76 nM to 2.16 nM.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2374607"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492486","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

Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows. 评估体外相关药代动力学结果并将其纳入抗体可开发性工作流程。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-07-31 DOI: 10.1080/19420862.2024.2384104

Tushar Jain, Bianka Prinz, Alexander Marker, Alexander Michel, Katrin Reichel, Valerie Czepczor, Sylvie Klieber, Wei Sun, Sagar Kathuria, Sevim Oezguer Bruederle, Christian Lange, Lena Wahl, Charles Starr, Alessandro Masiero, Lindsay Avery

{"title":"Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows.","authors":"Tushar Jain, Bianka Prinz, Alexander Marker, Alexander Michel, Katrin Reichel, Valerie Czepczor, Sylvie Klieber, Wei Sun, Sagar Kathuria, Sevim Oezguer Bruederle, Christian Lange, Lena Wahl, Charles Starr, Alessandro Masiero, Lindsay Avery","doi":"10.1080/19420862.2024.2384104","DOIUrl":"10.1080/19420862.2024.2384104","url":null,"abstract":"In vitro assessments for the prediction of pharmacokinetic (PK) behavior of biotherapeutics can help identify corresponding liabilities significantly earlier in the discovery timeline. This can minimize the need for extensive early in vivo PK characterization, thereby reducing animal usage and optimizing resources. In this study, we recommend bolstering classical developability workflows with in vitro measures correlated with PK. In agreement with current literature, in vitro measures assessing nonspecific interactions, self-interaction, and FcRn interaction are demonstrated to have the highest correlations to clearance in hFcRn Tg32 mice. Crucially, the dataset used in this study has broad sequence diversity and a range of physicochemical properties, adding robustness to our recommendations. Finally, we demonstrate a computational approach that combines multiple in vitro measurements with a multivariate regression model to improve the correlation to PK compared to any individual assessment. Our work demonstrates that a judicious choice of high throughput in vitro measurements and computational predictions enables the prioritization of candidate molecules with desired PK properties.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2384104"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11296533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855914","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

Engineering hydrophobicity and manufacturability for optimized biparatopic antibody-drug conjugates targeting c-MET. 针对 c-MET 的优化双位抗体-药物共轭物的疏水性和可制造性工程。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-01-12 DOI: 10.1080/19420862.2024.2302386

Andreas Evers, Simon Krah, Deniz Demir, Ramona Gaa, Desislava Elter, Christian Schroeter, Stefan Zielonka, Nicolas Rasche, Julia Dotterweich, Christine Knuehl, Achim Doerner

{"title":"Engineering hydrophobicity and manufacturability for optimized biparatopic antibody-drug conjugates targeting c-MET.","authors":"Andreas Evers, Simon Krah, Deniz Demir, Ramona Gaa, Desislava Elter, Christian Schroeter, Stefan Zielonka, Nicolas Rasche, Julia Dotterweich, Christine Knuehl, Achim Doerner","doi":"10.1080/19420862.2024.2302386","DOIUrl":"10.1080/19420862.2024.2302386","url":null,"abstract":"Optimal combinations of paratopes assembled into a biparatopic antibody have the capacity to mediate high-grade target cross-linking on cell membranes, leading to degradation of the target, as well as antibody and payload delivery in the case of an antibody-drug conjugate (ADC). In the work presented here, molecular docking suggested a suitable paratope combination targeting c-MET, but hydrophobic patches in essential binding regions of one moiety necessitated engineering. In addition to rational design of HCDR2 and HCDR3 mutations, site-specific spiking libraries were generated and screened in yeast and mammalian surface display approaches. Comparative analyses revealed similar positions amendable for hydrophobicity reduction, with a broad combinatorial diversity obtained from library outputs. Optimized variants showed high stability, strongly reduced hydrophobicity, retained affinities supporting the desired functionality and enhanced producibility. The resulting biparatopic anti-c-MET ADCs were comparably active on c-MET expressing tumor cell lines as REGN5093 exatecan DAR6 ADC. Structural molecular modeling of paratope combinations for preferential inter-target binding combined with protein engineering for manufacturability yielded deep insights into the capabilities of rational and library approaches. The methodologies of in silico hydrophobicity identification and sequence optimization could serve as a blueprint for rapid development of optimal biparatopic ADCs targeting further tumor-associated antigens in the future.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2302386"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10793681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139425064","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

Evaluation of the impact of antibody fragments on aggregation of intact molecules via size exclusion chromatography coupled with native mass spectrometry. 通过尺寸排阻色谱法和原生质谱法评估抗体片段对完整分子聚集的影响。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-03-27 DOI: 10.1080/19420862.2024.2334783

Jing Xu, John E Coughlin, Malgorzata Szyjka, Serene Jabary, Sonal Saluja, Zoran Sosic, Yunqiu Chen, Chong-Feng Xu

{"title":"Evaluation of the impact of antibody fragments on aggregation of intact molecules via size exclusion chromatography coupled with native mass spectrometry.","authors":"Jing Xu, John E Coughlin, Malgorzata Szyjka, Serene Jabary, Sonal Saluja, Zoran Sosic, Yunqiu Chen, Chong-Feng Xu","doi":"10.1080/19420862.2024.2334783","DOIUrl":"10.1080/19420862.2024.2334783","url":null,"abstract":"Aggregates are recognized as one of the most critical product-related impurities in monoclonal antibody (mAb)-based therapeutics due to their negative impact on the stability and safety of the drugs. So far, investigational efforts have primarily focused on understanding the causes and effects of mAb self-aggregation, including both internal and external factors. In this study, we focused on understanding mAb stability in the presence of its monovalent fragment, formed through hinge cleavage and loss of one Fab unit (referred to as \"Fab/c\"), a commonly observed impurity during manufacturing and stability. The Fab/c fragments were generated using a limited IgdE digestion that specifically cleaves above the IgG1 mAb hinge region, followed by hydrophobic interaction chromatographic (HIC) enrichment. Two IgG1 mAbs containing different levels of Fab/c fragments were incubated under thermally accelerated conditions. A method based on size exclusion chromatography coupled with native mass spectrometry (SEC-UV-native MS) was developed and used to characterize the stability samples and identified the formation of heterogeneous dimers, including intact dimer, mAb-Fab/c dimer, Fab/c-Fab/c dimer, and mAb-Fab dimer. Quantitative analyses on the aggregation kinetics suggested that the impact of Fab/c fragment on the aggregation rate of individual dimer differs between a glycosylated mAb (mAb1) and a non-glycosylated mAb (mAb2). An additional study of deglycosylated mAb1 under 25°C accelerated stability conditions suggests no significant impact of the N-glycan on mAb1 total aggregation rate. This study also highlighted the power of SEC-UV-native MS method in the characterization of mAb samples with regard to separating, identifying, and quantifying mAb aggregates and fragments.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2334783"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10978026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306146","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

Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration. 针对 properdin 的特异性双特异性 VHH 抗体 tarperprumig（ALXN1820）的特性分析，该抗体专为小剂量给药而设计。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-10-13 DOI: 10.1080/19420862.2024.2415060

Paul Tamburini, Dennis Vestergaard Pedersen, Denise Devore, Josh Cone, Rekha Patel, Todd Hunter, Fang Sun, Gregers Rom Andersen, Jeffrey Hunter

{"title":"Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration.","authors":"Paul Tamburini, Dennis Vestergaard Pedersen, Denise Devore, Josh Cone, Rekha Patel, Todd Hunter, Fang Sun, Gregers Rom Andersen, Jeffrey Hunter","doi":"10.1080/19420862.2024.2415060","DOIUrl":"https://doi.org/10.1080/19420862.2024.2415060","url":null,"abstract":"The bispecific antibody tarperprumig (ALXN1820) was developed as a treatment option for diseases involving dysregulated complement alternative pathway (AP) activity that could be administered in small volumes, either subcutaneously or intravenously. Tarperprumig incorporates a C-terminal variable domain of a heavy chain only antibody (VHH) that binds properdin (FP) connected via a flexible linker to an N-terminal VHH that binds human serum albumin (HSA). The purified bispecific VHH antibody exhibits an experimental molecular weight average of 27.4 kDa and can be formulated at > 100 mg/mL. Tarperprumig binds tightly to FP and HSA with sub-nanomolar affinity at pH 7.4 and can associate simultaneously with FP and HSA to form a ternary complex. Tarperprumig potently and dose-dependently inhibits to completion in vitro AP-dependent complement C5b-9 formation, AP-dependent hemolysis, and the AP deposition of C3, FP and C9. X-ray crystallography revealed that the isolated FP-binding VHH recognizes the thrombospondin repeat 5 domain of FP, thereby preventing FP from binding to the AP convertase owing to severe steric hindrance. Tarperprumig cross-reacts with cynomolgus monkey FP and serum albumin. In summary, tarperprumig exhibits properties tailored for subcutaneous administration and is currently in clinical development for the treatment of complement AP-related disorders.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2415060"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469141","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

The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics. 基于细胞的蛋白质阵列用于检测抗体疗法的多特异性脱靶结合。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-08-24 DOI: 10.1080/19420862.2024.2393785

Diana M Norden, Carmen T Navia, Jonathan T Sullivan, Benjamin J Doranz

{"title":"The emergence of cell-based protein arrays to test for polyspecific off-target binding of antibody therapeutics.","authors":"Diana M Norden, Carmen T Navia, Jonathan T Sullivan, Benjamin J Doranz","doi":"10.1080/19420862.2024.2393785","DOIUrl":"10.1080/19420862.2024.2393785","url":null,"abstract":"Specificity profiling is a requirement for monoclonal antibodies (mAbs) and antibody-directed biotherapeutics such as CAR-T cells prior to initiating human trials. However, traditional approaches to assess the specificity of mAbs, primarily tissue cross-reactivity studies, have been unreliable, leading to off-target binding going undetected. Here, we review the emergence of cell-based protein arrays as an alternative and improved assessment of mAb specificity. Cell-based protein arrays assess binding across the full human membrane proteome, ~6,000 membrane proteins each individually expressed in their native structural configuration within live or unfixed cells. Our own profiling indicates a surprisingly high off-target rate across the industry, with 33% of lead candidates displaying off-target binding. Moreover, about 20% of therapeutic mAbs in clinical development and currently on the market display off-target binding. Case studies and off-target rates at different phases of biotherapeutic drug approval suggest that off-target binding is likely a major cause of adverse events and drug attrition.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2393785"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046861","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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