Pub Date : 2024-09-17DOI: 10.1080/19420862.2024.2404064
Wanlei Wei,Traian Sulea
The engineering of pH-sensitive therapeutic antibodies, particularly for improving effectiveness and specificity in acidic solid-tumor microenvironments, has recently gained traction. While there is a justified need for pH-dependent immunotherapies, current engineering techniques are tedious and laborious, requiring repeated rounds of experiments under different pH conditions. Inexpensive computational techniques to predict the effectiveness of His pH-switches require antibody-antigen complex structures, but these are lacking in most cases. To circumvent these requirements, we introduce a sequence-based in silico method for predicting His mutations in the variable region of antibodies, which could lead to pH-biased antigen binding. This method, called Sequence-based Identification of pH-sensitive Antibody Binding (SIpHAB), was trained on 3D-structure-based calculations of 3,490 antibody-antigen complexes with solved experimental structures. SIpHAB was parametrized to enhance preferential binding either toward or against the acidic pH, for selective targeting of solid tumors or for antigen release in the endosome, respectively. Applications to nine antibody-antigen systems with previously reported binding preferences at different pHs demonstrated the utility and enrichment capabilities of this high-throughput computational tool. SIpHAB, which only requires knowledge of the antibody primary amino-acid sequence, could enable a more efficient triage of pH-sensitive antibody candidates than could be achieved conventionally. An online webserver for running SipHAB is available freely at https://mm.nrc-cnrc.gc.ca/software/siphab/runner/.
{"title":"Sequence-based engineering of pH-sensitive antibodies for tumor targeting or endosomal recycling applications.","authors":"Wanlei Wei,Traian Sulea","doi":"10.1080/19420862.2024.2404064","DOIUrl":"https://doi.org/10.1080/19420862.2024.2404064","url":null,"abstract":"The engineering of pH-sensitive therapeutic antibodies, particularly for improving effectiveness and specificity in acidic solid-tumor microenvironments, has recently gained traction. While there is a justified need for pH-dependent immunotherapies, current engineering techniques are tedious and laborious, requiring repeated rounds of experiments under different pH conditions. Inexpensive computational techniques to predict the effectiveness of His pH-switches require antibody-antigen complex structures, but these are lacking in most cases. To circumvent these requirements, we introduce a sequence-based in silico method for predicting His mutations in the variable region of antibodies, which could lead to pH-biased antigen binding. This method, called Sequence-based Identification of pH-sensitive Antibody Binding (SIpHAB), was trained on 3D-structure-based calculations of 3,490 antibody-antigen complexes with solved experimental structures. SIpHAB was parametrized to enhance preferential binding either toward or against the acidic pH, for selective targeting of solid tumors or for antigen release in the endosome, respectively. Applications to nine antibody-antigen systems with previously reported binding preferences at different pHs demonstrated the utility and enrichment capabilities of this high-throughput computational tool. SIpHAB, which only requires knowledge of the antibody primary amino-acid sequence, could enable a more efficient triage of pH-sensitive antibody candidates than could be achieved conventionally. An online webserver for running SipHAB is available freely at https://mm.nrc-cnrc.gc.ca/software/siphab/runner/.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"4 1","pages":"2404064"},"PeriodicalIF":5.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-15DOI: 10.1080/19420862.2024.2402701
Geoff Hale, Jelle De Vos, Alastair Douglas Davy, Koen Sandra, Ian Wilkinson
Elimination of the binding of immunoglobulin Fc to Fc gamma receptors is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many di...
消除免疫球蛋白 Fc 与 Fc γ 受体的结合对于避免治疗性抗体和融合蛋白引起不必要的炎症反应是非常理想的。许多二...
{"title":"Systematic analysis of Fc mutations designed to reduce binding to Fc-gamma receptors","authors":"Geoff Hale, Jelle De Vos, Alastair Douglas Davy, Koen Sandra, Ian Wilkinson","doi":"10.1080/19420862.2024.2402701","DOIUrl":"https://doi.org/10.1080/19420862.2024.2402701","url":null,"abstract":"Elimination of the binding of immunoglobulin Fc to Fc gamma receptors is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many di...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"1 1","pages":"2402701"},"PeriodicalIF":5.3,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-15DOI: 10.1080/19420862.2024.2402713
Philip Green, Andreas Schneider, Jakob Lange
Subcutaneous (SC) administration is transforming the delivery of biopharmaceuticals, facilitating care in a variety of healthcare settings, including home self-treatment. Large-volume single SC dos...
{"title":"Navigating large-volume subcutaneous injections of biopharmaceuticals: a systematic review of clinical pipelines and approved products","authors":"Philip Green, Andreas Schneider, Jakob Lange","doi":"10.1080/19420862.2024.2402713","DOIUrl":"https://doi.org/10.1080/19420862.2024.2402713","url":null,"abstract":"Subcutaneous (SC) administration is transforming the delivery of biopharmaceuticals, facilitating care in a variety of healthcare settings, including home self-treatment. Large-volume single SC dos...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"4 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142251298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26DOI: 10.1080/19420862.2024.2339582
Sandi Brudar, Leonid Breydo, Elisha Chung, Ken A. Dill, Nasim Ehterami, Ketan Phadnis, Samir Senapati, Mohammed Shameem, Xiaolin Tang, Muhammmad Tayyab, Barbara Hribar-Lee
Understanding factors that affect the clustering and association of antibodies molecules in solution is critical to their development as therapeutics. For 19 different monoclonal antibody (mAb) sol...
{"title":"Antibody association in solution: cluster distributions and mechanisms","authors":"Sandi Brudar, Leonid Breydo, Elisha Chung, Ken A. Dill, Nasim Ehterami, Ketan Phadnis, Samir Senapati, Mohammed Shameem, Xiaolin Tang, Muhammmad Tayyab, Barbara Hribar-Lee","doi":"10.1080/19420862.2024.2339582","DOIUrl":"https://doi.org/10.1080/19420862.2024.2339582","url":null,"abstract":"Understanding factors that affect the clustering and association of antibodies molecules in solution is critical to their development as therapeutics. For 19 different monoclonal antibody (mAb) sol...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"100 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140798638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.1080/19420862.2024.2339337
Eva Schlein, Ken G. Andersson, Tiffany Dallas, Stina Syvänen, Dag Sehlin
Recent development of amyloid-β (Aβ)-targeted immunotherapies for Alzheimer’s disease (AD) have highlighted the need for accurate diagnostic methods. Antibody-based positron emission tomography (PE...
{"title":"Reducing neonatal Fc receptor binding enhances clearance and brain-to-blood ratio of TfR-delivered bispecific amyloid-β antibody","authors":"Eva Schlein, Ken G. Andersson, Tiffany Dallas, Stina Syvänen, Dag Sehlin","doi":"10.1080/19420862.2024.2339337","DOIUrl":"https://doi.org/10.1080/19420862.2024.2339337","url":null,"abstract":"Recent development of amyloid-β (Aβ)-targeted immunotherapies for Alzheimer’s disease (AD) have highlighted the need for accurate diagnostic methods. Antibody-based positron emission tomography (PE...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"1 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140613518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.1080/19420862.2024.2343499
Stefan Dübel
There is no doubt that today’s life sciences would look very different without the availability of millions of research antibody products. Nevertheless, the use of antibody reagents that are poorly...
{"title":"Can antibodies be “vegan”? A guide through the maze of today’s antibody generation methods","authors":"Stefan Dübel","doi":"10.1080/19420862.2024.2343499","DOIUrl":"https://doi.org/10.1080/19420862.2024.2343499","url":null,"abstract":"There is no doubt that today’s life sciences would look very different without the availability of millions of research antibody products. Nevertheless, the use of antibody reagents that are poorly...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"15 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140613752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1080/19420862.2024.2338301
Sophia Liu, Yuetian Yan, Cody M. Secor, Zachary R. Oberholtzer, Donna J. Skow, Mushhood Sheikh, Youmi Moon, Yue Fu, Cristinel Sandu, Shunhai Wang, Ning Li, Jennifer B. Nguyen, Michael P. Rosconi, Erica A. Pyles
Co-formulation of multiple drug products is an efficient and convenient approach to simultaneously deliver multiple biotherapeutics with the potentially added benefit of a synergistic therapeutic e...
{"title":"Enrichment strategy and initial characterization of heterodimers enriched from a co-formulated cocktail of therapeutic antibodies against SARS-COV-2","authors":"Sophia Liu, Yuetian Yan, Cody M. Secor, Zachary R. Oberholtzer, Donna J. Skow, Mushhood Sheikh, Youmi Moon, Yue Fu, Cristinel Sandu, Shunhai Wang, Ning Li, Jennifer B. Nguyen, Michael P. Rosconi, Erica A. Pyles","doi":"10.1080/19420862.2024.2338301","DOIUrl":"https://doi.org/10.1080/19420862.2024.2338301","url":null,"abstract":"Co-formulation of multiple drug products is an efficient and convenient approach to simultaneously deliver multiple biotherapeutics with the potentially added benefit of a synergistic therapeutic e...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"42 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140583470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-04DOI: 10.1080/19420862.2024.2324485
Armin Sepp, Morris Muliaditan
Model-informed drug discovery advocates the use of mathematical modeling and simulation for improved efficacy in drug discovery. In the case of monoclonal antibodies (mAbs) against cell membrane an...
{"title":"Application of quantitative protein mass spectrometric data in the early predictive analysis of membrane-bound target engagement by monoclonal antibodies","authors":"Armin Sepp, Morris Muliaditan","doi":"10.1080/19420862.2024.2324485","DOIUrl":"https://doi.org/10.1080/19420862.2024.2324485","url":null,"abstract":"Model-informed drug discovery advocates the use of mathematical modeling and simulation for improved efficacy in drug discovery. In the case of monoclonal antibodies (mAbs) against cell membrane an...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"45 3","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140034896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-21DOI: 10.1080/19420862.2024.2311992
Caitlin Fawcett, Joseph. R. Tickle, Charlotte. H. Coles
A major driver for the recent investment surge in bispecific antibody (bsAb) platforms and products is the multitude of distinct mechanisms of action that bsAbs offer compared to a combination of t...
{"title":"Facilitating high throughput bispecific antibody production and potential applications within biopharmaceutical discovery workflows","authors":"Caitlin Fawcett, Joseph. R. Tickle, Charlotte. H. Coles","doi":"10.1080/19420862.2024.2311992","DOIUrl":"https://doi.org/10.1080/19420862.2024.2311992","url":null,"abstract":"A major driver for the recent investment surge in bispecific antibody (bsAb) platforms and products is the multitude of distinct mechanisms of action that bsAbs offer compared to a combination of t...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"6 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139947437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01Epub Date: 2024-02-21DOI: 10.1080/19420862.2024.2316872
Jacquelyn Blake-Hedges, Dan Groff, Wilson Foo, Jeffrey Hanson, Elenor Castillo, Miao Wen, Diana Cheung, Mary Rose Masikat, Jian Lu, Young Park, Nina Abi Carlos, Hans Usman, Kevin Fong, Abigail Yu, Sihong Zhou, Joyce Kwong, Cuong Tran, Xiaofan Li, Dawei Yuan, Trevor Hallam, Gang Yin
Therapeutic bioconjugates are emerging as an essential tool to combat human disease. Site-specific conjugation technologies are widely recognized as the optimal approach for producing homogeneous drug products. Non-natural amino acid (nnAA) incorporation allows the introduction of bioconjugation handles at genetically defined locations. Escherichia coli (E. coli) is a facile host for therapeutic nnAA protein synthesis because it can stably replicate plasmids encoding genes for product and nnAA incorporation. Here, we demonstrate that by engineering E. coli to incorporate high levels of nnAAs, it is feasible to produce nnAA-containing antibody fragments and full-length immunoglobulin Gs (IgGs) in the cytoplasm of E. coli. Using high-density fermentation, it was possible to produce both of these types of molecules with site-specifically incorporated nnAAs at titers > 1 g/L. We anticipate this strategy will help simplify the production and manufacture of promising antibody therapeutics.
{"title":"Production of antibodies and antibody fragments containing non-natural amino acids in <i>Escherichia coli</i>.","authors":"Jacquelyn Blake-Hedges, Dan Groff, Wilson Foo, Jeffrey Hanson, Elenor Castillo, Miao Wen, Diana Cheung, Mary Rose Masikat, Jian Lu, Young Park, Nina Abi Carlos, Hans Usman, Kevin Fong, Abigail Yu, Sihong Zhou, Joyce Kwong, Cuong Tran, Xiaofan Li, Dawei Yuan, Trevor Hallam, Gang Yin","doi":"10.1080/19420862.2024.2316872","DOIUrl":"10.1080/19420862.2024.2316872","url":null,"abstract":"<p><p>Therapeutic bioconjugates are emerging as an essential tool to combat human disease. Site-specific conjugation technologies are widely recognized as the optimal approach for producing homogeneous drug products. Non-natural amino acid (nnAA) incorporation allows the introduction of bioconjugation handles at genetically defined locations. <i>Escherichia coli</i> (<i>E. coli</i>) is a facile host for therapeutic nnAA protein synthesis because it can stably replicate plasmids encoding genes for product and nnAA incorporation. Here, we demonstrate that by engineering <i>E. coli</i> to incorporate high levels of nnAAs, it is feasible to produce nnAA-containing antibody fragments and full-length immunoglobulin Gs (IgGs) in the cytoplasm of <i>E. coli</i>. Using high-density fermentation, it was possible to produce both of these types of molecules with site-specifically incorporated nnAAs at titers > 1 g/L. We anticipate this strategy will help simplify the production and manufacture of promising antibody therapeutics.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2316872"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912940","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}
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