IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-02-01 DOI: 10.1080/19420862.2024.2304624

Jing Song, Marc Taraban, Y Bruce Yu, Lynn Lu, Pallavi Guha Biswas, Wei Xu, Hanmi Xi, Akhilesh Bhambhani, Guangli Hu, Yongchao Su

{"title":"In-situ biophysical characterization of high-concentration protein formulations using wNMR.","authors":"Jing Song, Marc Taraban, Y Bruce Yu, Lynn Lu, Pallavi Guha Biswas, Wei Xu, Hanmi Xi, Akhilesh Bhambhani, Guangli Hu, Yongchao Su","doi":"10.1080/19420862.2024.2304624","DOIUrl":"10.1080/19420862.2024.2304624","url":null,"abstract":"High-concentration protein formulation is of paramount importance in patient-centric drug product development, but it also presents challenges due to the potential for enhanced aggregation and increased viscosity. The analysis of critical quality attributes often necessitates the transfer of samples from their primary containers together with sample dilution. Therefore, there is a demand for noninvasive, in situ biophysical methods to assess protein drug products directly in primary sterile containers, such as prefilled syringes, without dilution. In this study, we introduce a novel application of water proton nuclear magnetic resonance (wNMR) to evaluate the aggregation propensity of a high-concentration drug product, Dupixent® (dupilumab), under stress conditions. wNMR results demonstrate a concentration-dependent, reversible association of dupilumab in the commercial formulation, as well as irreversible aggregation when exposed to accelerated thermal stress, but gradually reversible aggregation when exposed to freeze and thaw cycles. Importantly, these results show a strong correlation with data obtained from established biophysical analytical tools widely used in the pharmaceutical industry. The application of wNMR represents a promising approach for in situ noninvasive analysis of high-concentration protein formulations directly in their primary containers, providing valuable insights for drug development and quality assessment.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2304624"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139651047","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 the clinical subcutaneous absorption rate constant of monoclonal antibodies using only the primary sequence: a machine learning approach. 仅使用主序列预测单克隆抗体的临床皮下吸收率常数：一种机器学习方法。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-05-14 DOI: 10.1080/19420862.2024.2352887

Ronghua Bei, Justin Thomas, Shiven Kapur, Mahlet Woldeyes, Adam Rauk, Jason Robarge, Jiangyan Feng, Kaoutar Abbou Oucherif

{"title":"Predicting the clinical subcutaneous absorption rate constant of monoclonal antibodies using only the primary sequence: a machine learning approach.","authors":"Ronghua Bei, Justin Thomas, Shiven Kapur, Mahlet Woldeyes, Adam Rauk, Jason Robarge, Jiangyan Feng, Kaoutar Abbou Oucherif","doi":"10.1080/19420862.2024.2352887","DOIUrl":"10.1080/19420862.2024.2352887","url":null,"abstract":"Subcutaneous injections are an increasingly prevalent route of administration for delivering biological therapies including monoclonal antibodies (mAbs). Compared with intravenous delivery, subcutaneous injections reduce administration costs, shorten the administration time, and are strongly preferred from a patient experience point of view. An understanding of the absorption process of a mAb from the injection site to the systemic circulation is critical to the process of subcutaneous mAb formulation development. In this study, we built a model to predict the absorption rate constant (ka), which denotes how fast a mAb is absorbed from the site of administration. Once trained, our model (enabled by the XGBoost algorithm in machine learning) can predict the ka of a mAb following a subcutaneous injection using in silico molecular properties alone (generated from the primary sequence). Our model does not need clinically observed plasma concentration-time data; this is a novel capability not previously achieved in predictive pharmacokinetic models. The model also showed improved performance when benchmarked against a recently reported mechanistic model that relied on clinical data to predict subcutaneous absorption of mAbs. We further interpreted the model to understand which molecular properties affect the absorption rate and showed that our findings are consistent with previous studies evaluating subcutaneous absorption through direct experimentation. Taken altogether, this study reports the development, validation, benchmarking, and interpretation of a model that can predict the clinical ka of a mAb using its primary sequence as the only input.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2352887"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922717","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

Proceedings of the 14th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals. 第 14 届欧洲免疫原性平台生物制药免疫原性公开研讨会论文集》。

IF 5.3 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-03-05 DOI: 10.1080/19420862.2024.2324801

Sophie Tourdot, Daniel Baltrunkonis, Sofie Denies, Viswanath Devanarayan, Joanna Grudzinska-Goebel, Arno Kromminga, Gregor P Lotz, Laurent Malherbe, Lydia Michaut, Karin N Weldingh, Joao A Pedras-Vasconcelos, Laura I Salazar-Fontana, Sebastian Spindeldreher, Zuben Sauna, Veerle Snoeck, Daniela Verthelyi, Daniel Kramer

{"title":"Proceedings of the 14th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals.","authors":"Sophie Tourdot, Daniel Baltrunkonis, Sofie Denies, Viswanath Devanarayan, Joanna Grudzinska-Goebel, Arno Kromminga, Gregor P Lotz, Laurent Malherbe, Lydia Michaut, Karin N Weldingh, Joao A Pedras-Vasconcelos, Laura I Salazar-Fontana, Sebastian Spindeldreher, Zuben Sauna, Veerle Snoeck, Daniela Verthelyi, Daniel Kramer","doi":"10.1080/19420862.2024.2324801","DOIUrl":"10.1080/19420862.2024.2324801","url":null,"abstract":"Biologics have revolutionized disease management in many therapeutic areas by addressing unmet medical needs and overcoming resistance to standard-of-care treatment in numerous patients. However, the development of unwanted immune responses directed against these drugs, humoral and/or cellular, can hinder their efficacy and have safety consequences with various degrees of severity. Health authorities ask that a thorough immunogenicity risk assessment be conducted during drug development to incorporate an appropriate monitoring and mitigation plan in clinical studies. With the rapid diversification and complexification of biologics, which today include modalities such as multi-domain antibodies, cell-based products, AAV delivery vectors, and nucleic acids, developers are faced with the challenge of establishing a risk assessment strategy sometimes in the absence of specific regulatory guidelines. The European Immunogenicity Platform (EIP) Open Symposium on Immunogenicity of Biopharmaceuticals and its one-day training course gives experts and newcomers across academia, industry, and regulatory agencies an opportunity to share experience and knowledge to overcome these challenges. Here, we report the discussions that took place at the EIP's 14th Symposium, held in April 2023. The topics covered included immunogenicity monitoring and clinical relevance, non-clinical immunogenicity risk assessment, regulatory aspects of immunogenicity assessment and reporting, and the challenges associated with new modalities, which were discussed in a dedicated session.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2324801"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10936655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028390","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

Understanding the impacts of dual methionine oxidations in complementarity-determining regions on the structure of monoclonal antibodies. 了解互补性决定区的双蛋氨酸氧化对单克隆抗体结构的影响。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-11-02 DOI: 10.1080/19420862.2024.2422898

Bo Zhao, Joy Yoon, Bojie Zhang, Youmi Moon, Yue Fu, Yinyin Li, Yunlong Zhao, Hui Xiao, Ning Li

{"title":"Understanding the impacts of dual methionine oxidations in complementarity-determining regions on the structure of monoclonal antibodies.","authors":"Bo Zhao, Joy Yoon, Bojie Zhang, Youmi Moon, Yue Fu, Yinyin Li, Yunlong Zhao, Hui Xiao, Ning Li","doi":"10.1080/19420862.2024.2422898","DOIUrl":"10.1080/19420862.2024.2422898","url":null,"abstract":"Methionine oxidation can substantially alter the structure and functionality of monoclonal antibodies (mAbs), especially when it occurs in the complementarity-determining regions (CDRs). It is imperative to fully understand the effects of methionine oxidation because these modifications can affect the binding affinity, stability, and immunogenicity of mAbs. Moreover, the presence of multiple methionines in close proximity within the amino acid sequence increases the complexity of accurate characterization, and sophisticated analytical methods are required to detect these modifications. In this study, we used hydrogen deuterium exchange mass spectrometry (HDX-MS) and homology modeling to investigate the effects of dual methionine oxidations (heavy chain (HC) Met111 and Met115) within a single CDR on the structure of a mAb. Our findings reveal that the solvent-accessible methionine (HC Met111) is more prone to oxidation, but such a modification does not result in conformational changes in the mAb. In contrast, the methionine (HC Met115) at the VH-VL interface, when subjected to different oxidative stresses, can undergo oxidation with selective stereochemistry. This can lead to predominant formation of either the S- or R-form of methionine sulfoxide diastereomer, each of which can induce distinct local conformational changes. A mechanism is proposed to elucidate these observations in this particular antibody. Furthermore, binding assays confirm that both CDR methionine oxidations do not compromise antigen binding, which alleviates concerns about potential loss of therapeutic efficacy.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2422898"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564678","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

Developability considerations for bispecific and multispecific antibodies. 双特异性和多特异性抗体的可开发性考虑因素。

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-08-27 DOI: 10.1080/19420862.2024.2394229

Alaa Amash, Gesa Volkers, Patrick Farber, Daniel Griffin, K Shawn Davison, Allison Goodman, Raffi Tonikian, Aaron Yamniuk, Bryan Barnhart, Tim Jacobs

{"title":"Developability considerations for bispecific and multispecific antibodies.","authors":"Alaa Amash, Gesa Volkers, Patrick Farber, Daniel Griffin, K Shawn Davison, Allison Goodman, Raffi Tonikian, Aaron Yamniuk, Bryan Barnhart, Tim Jacobs","doi":"10.1080/19420862.2024.2394229","DOIUrl":"10.1080/19420862.2024.2394229","url":null,"abstract":"Bispecific antibodies (bsAb) and multispecific antibodies (msAb) encompass a diverse variety of formats that can concurrently bind multiple epitopes, unlocking mechanisms to address previously difficult-to-treat or incurable diseases. Early assessment of candidate developability enables demotion of antibodies with low potential and promotion of the most promising candidates for further development. Protein-based therapies have a stringent set of developability requirements in order to be competitive (e.g. high-concentration formulation, and long half-life) and their assessment requires a robust toolkit of methods, few of which are validated for interrogating bsAbs/msAbs. Important considerations when assessing the developability of bsAbs/msAbs include their molecular format, likelihood for immunogenicity, specificity, stability, and potential for high-volume production. Here, we summarize the critical aspects of developability assessment, and provide guidance on how to develop a comprehensive plan tailored to a given bsAb/msAb.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2394229"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073235","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

Multivariate quantitative analysis of glycan impact on IgG1 effector functions. 聚糖对 IgG1 效应功能影响的多元定量分析

IF 5.6 2区医学

mAbs Pub Date : 2024-01-01 Epub Date: 2024-11-21 DOI: 10.1080/19420862.2024.2430295

Tamara Cvijić, Matej Horvat, Jakob Plahutnik, Ana Golob, Jaka Marušič

{"title":"Multivariate quantitative analysis of glycan impact on IgG1 effector functions.","authors":"Tamara Cvijić, Matej Horvat, Jakob Plahutnik, Ana Golob, Jaka Marušič","doi":"10.1080/19420862.2024.2430295","DOIUrl":"10.1080/19420862.2024.2430295","url":null,"abstract":"Development of novel therapeutic proteins and biosimilars requires a thorough understanding of the relationship between their structure and function. Particularly, how IgG glycosylation affects its effector functions is a point increasingly underscored in guidelines by the World Health Organization and regulatory agencies. Our results show that just a 1% decrease in Fc fucosylation can lead to a more than 25% increase in antibody-dependent cell-mediated cytotoxicity. The intercorrelated nature of glycan patterns, combined with the low variability and lack of well-defined glycan patterns in process development and manufacture samples, makes studying the effects of individual glycan structures challenging. The conventional approach to structure-function studies often relies on a suboptimal set of tools, such as the one-factor-at-a-time method for experimental planning and univariate data analysis. Here, we introduce a systematic approach to understanding and prediction of the impact of Fc glycans on effector functions, using a combination of the design of experiment, multivariate data analysis, and in-vitro glycoengineering. This approach adheres to quality-by-design principles and aligns with regulatory agency guidelines. A variety of analytical assays, including binding and cell-based assays, were applied to investigate the effect of individual glycans of the IgG1 molecule. The regression models developed here provide a quantitative explanation and prediction of the impact of individual glycan features on the binding to FcγRs and bioactivity of the therapeutic protein. To the best of our knowledge, this is the first report of a systematic approach to quantitatively understand the multivariate impact of glycosylation on the effector functionality of therapeutic monoclonal antibodies, providing valuable tools for advancing therapeutic protein development.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2430295"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687439","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 the speed of innovative anti-tumor drugs to first-in-human trials incorporating key de-risk strategies 采用关键的降低风险策略，加快创新抗肿瘤药物进行首次人体试验的速度

IF 5.3 2区医学

mAbs Pub Date : 2023-12-14 DOI: 10.1080/19420862.2023.2292305

Yuqi Wang, Quan Quan, Camille Gleason, Helin Yu, Lujia Peng, Yanshen Kang, Ling Jiang, Kailun Wu, Jie Pan, Moxiyele Bao, Qing Zhu, Meiqi Yi, Ming Fang, Yue Zheng, Ling Qiu, Bin Xu, Xiang Li, Jinfeng Song, Jiamu Sun, Zheng Zhang, Zijun Su, Jara Lin, Yuanyuan Xie, April Xu, Xiling Song, Chichi Huang, Zhirong Shen, Lai Wang, Jing Song

引用次数: 0

Determining the affinities of high-affinity antibodies using KinExA and surface plasmon resonance 利用 KinExA 和表面等离子体共振确定高亲和力抗体的亲和力

IF 5.3 2区医学

mAbs Pub Date : 2023-12-13 DOI: 10.1080/19420862.2023.2291209

M. Frank Erasmus, Molly Dovner, Fortunato Ferrara, Sara D’Angelo, André A. Teixeira, Camila Leal-Lopes, Laura Spector, Elizabeth Hopkins, Andrew R. M. Bradbury

引用次数: 0

Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer 发现吉尼索坦单抗--一种用于治疗癌症的临床开发中的强效新型抗格雷姆林-1 抗体

IF 5.3 2区医学

mAbs Pub Date : 2023-12-12 DOI: 10.1080/19420862.2023.2289681

Gareth C. G. Davies, Neesha Dedi, Paul S. Jones, Lara Kevorkian, David McMillan, Cristina Ottone, Monika-Sarah E. D. Schulze, Anthony Scott-Tucker, Roohi Tewari, Shauna West, Michael Wright, Tania F. Rowley

引用次数: 0

Ascending-Price Mechanism for General Multi-sided Markets 一般多边市场的价格上涨机制

IF 5.3 2区医学

mAbs Pub Date : 2023-10-01 DOI: 10.1007/978-3-030-82254-5_1

Dvir Gilor, Rica Gonen, Erel Segal-Halevi

引用次数: 0

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