mAbs最新文献

{"title":"Correction.","authors":"","doi":"10.1080/19420862.2024.2335597","DOIUrl":"10.1080/19420862.2024.2335597","url":null,"abstract":"","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2335597"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318620","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":"Systematic analysis of Fc mutations designed to enhance binding to Fc-gamma receptors.","authors":"Geoff Hale, Alastair Douglas Davy, Ian Wilkinson","doi":"10.1080/19420862.2024.2406539","DOIUrl":"10.1080/19420862.2024.2406539","url":null,"abstract":"<p><p>A critical attribute of therapeutic antibodies is their ability to engage with humoral or cellular effector mechanisms, and this depends on the ability of the Fc region to bind to complement (C1q) or Fc receptors. Investigators have sought to optimize these effects by engineering the Fc region to bind to a greater or lesser extent to individual receptors. Different approaches have been used in the clinic, but they have not been systematically compared. We have now produced a matched set of anti-CD20 antibodies representing a range of variants and compared their activity in cell-based assays for complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent phagocytosis using a range of individual Fc receptors. We have also compared the thermal stability of the variants by differential scanning fluorimetry (DSF). The results reveal a spectrum of activities which may be appropriate for different applications.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2406539"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290483","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":"Molecular surface descriptors to predict antibody developability: sensitivity to parameters, structure models, and conformational sampling.","authors":"Eliott Park, Saeed Izadi","doi":"10.1080/19420862.2024.2362788","DOIUrl":"10.1080/19420862.2024.2362788","url":null,"abstract":"<p><p><i>In silico</i> assessment of antibody developability during early lead candidate selection and optimization is of paramount importance, offering a rapid and material-free screening approach. However, the predictive power and reproducibility of such methods depend heavily on the selection of molecular descriptors, model parameters, accuracy of predicted structure models, and conformational sampling techniques. Here, we present a set of molecular surface descriptors specifically designed for predicting antibody developability. We assess the performance of these descriptors by benchmarking their correlations with an extensive array of experimentally determined biophysical properties, including viscosity, aggregation, hydrophobic interaction chromatography, human pharmacokinetic clearance, heparin retention time, and polyspecificity. Further, we investigate the sensitivity of these surface descriptors to methodological nuances, such as the choice of interior dielectric constant, hydrophobicity scales, structure prediction methods, and the impact of conformational sampling. Notably, we observe systematic shifts in the distribution of surface descriptors depending on the structure prediction method used, driving weak correlations of surface descriptors across structure models. Averaging the descriptor values over conformational distributions from molecular dynamics mitigates the systematic shifts and improves the consistency across different structure prediction methods, albeit with inconsistent improvements in correlations with biophysical data. Based on our benchmarking analysis, we propose six <i>in silico</i> developability risk flags and assess their effectiveness in predicting potential developability issues for a set of case study molecules.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2362788"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11168226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296308","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":"Electrostatic properties of human germlines and biodistribution of small biologics.","authors":"Leticia Maria De Souza Cordeiro, Kelley Christine Atkinson, Argin Aivazian, Patrick Frank Joyce, Fang Jia, Alessandro Mascioni","doi":"10.1080/19420862.2024.2311991","DOIUrl":"10.1080/19420862.2024.2311991","url":null,"abstract":"<p><p>Off-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicities. Renal and hepatic uptakes are known to be affected by protein electrostatics, which promote protein internalization through pinocytosis. Using minibodies as a model of an antibody fragment lacking FcRn recycling, we compared the biodistributions of leads with different degrees of accumulation at the kidney and liver. We identified a positive electrostatic patch highly conserved in a germline family very commonly used in the humanization of approved biologics. Neutralization of this patch led to a drastic reduction in the kidney uptake, leading to a biodistribution more favorable to the delivery of highly cytotoxic payloads. Next, we conducted a high throughput study of the electrostatic properties for all combinations of VH and VL germlines. This analysis shows how different VH/VL combinations exhibit varying tendencies to create electrostatic patches, resulting in Fv variants with different isoelectric points. Our work emphasizes the importance of carefully selecting germlines for humanization with optimal electrostatic properties in order to control the unspecific tissue uptake of low molecular weight biologics.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2311991"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139707135","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 novel conditional active biologic anti-EpCAM x anti-CD3 bispecific antibody with synergistic tumor selectivity for cancer immunotherapy.","authors":"Gerhard Frey, Ana Paula G Cugnetti, Haizhen Liu, Charles Xing, Christina Wheeler, Hwai Wen Chang, William J Boyle, Jay M Short","doi":"10.1080/19420862.2024.2322562","DOIUrl":"10.1080/19420862.2024.2322562","url":null,"abstract":"<p><p>Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues. Initial attempts to develop EpCAM-specific T-cell engagers were unsuccessful due to severe cytokine release effects, as well as serious on-target, off-tumor drug-related toxicities. We developed novel, conditionally active biological (CAB) bispecific antibodies that bind to both EpCAM and CD3 in an acidic tumor microenvironment. In healthy tissues, binding to EpCAM and CD3 is greatly reduced by a novel, dual CAB selection, where each binding domain is independently blocked by the presence of physiological chemicals known as Protein-associated Chemical Switches (PaCS). The CAB anti-EpCAM T-cell engagers displayed the anticipated bispecific binding properties and mediated the potent lysis of EpCAM-positive cancer cell lines through the recruitment of T cells in the tumor microenvironment. Xenograft studies showed that the efficacy of CAB bispecific antibodies is similar to that of a non-CAB anti-EpCAM bispecific antibody, but they have markedly reduced toxicity in non-human primates, indicating an unprecedentedly widened therapeutic index of over 100-fold. These preclinical results indicate that the dual CAB bispecific antibody is potentially both a powerful and safe therapeutic platform and a promising T cell-engaging treatment for patients with EpCAM-expressing tumors.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2322562"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10936661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039791","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":"Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the <i>MAPT</i> 10+16 mutation.","authors":"Dale O Starkie, Charles Arber, Terry Baker, Daniel J Lightwood, Selina Wray","doi":"10.1080/19420862.2024.2436102","DOIUrl":"10.1080/19420862.2024.2436102","url":null,"abstract":"<p><p>Microtubule-associated protein tau is inextricably linked to a group of clinically diverse neurodegenerative diseases termed tauopathies. The ratio balance of the major tau splicing isoform groups (3 R- and 4 R-tau) is critical in maintaining healthy neurons. An imbalance causing excess 4 R tau is associated with diseases such as progressive supranuclear palsy and frontotemporal dementia. The mechanisms by which increased 4 R results in neuronal dysfunction and neurodegeneration are not fully understood, and progress has been limited partly by a lack of suitable tools to investigate tau isoform imbalance. This work generated novel 3 R- and 4 R-specific antibody tools and 4 R-tau degrading intracellular antibody fragment \"degrabodies\". These were used to probe the molecular mechanisms of excess 4 R-tau in disease-mutant induced pluripotent stem cell-derived neurons. For the first time, we demonstrate a causative link between excess 4 R-tau and mitochondrial membrane hyperpolarization with wide-ranging potential for elucidating novel therapeutic approaches to treat neurodegenerative disease.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2436102"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813684","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":"Reconciling predicted and measured viscosity parameters in high concentration therapeutic antibody solutions.","authors":"Georgina Bethany Armstrong, Aisling Roche, William Lewis, Zahra Rattray","doi":"10.1080/19420862.2024.2438172","DOIUrl":"10.1080/19420862.2024.2438172","url":null,"abstract":"<p><p>Monoclonal antibody (mAb) solution viscosity in ultra-high concentration formulations is a key developability consideration in mAb development risk mitigation strategies that has implications for downstream processing and patient safety. Predicting viscosity at therapeutically relevant concentrations remains critical, despite the need for large mAb quantities for viscosity measurement being prohibitive. Using a panel of IgG1s, we examined the suitability of viscosity prediction and fitting models at different mAb test concentration regimes. Our findings caution against extrapolation from low concentration measurements, as they lack predictive ability for ultra-high concentration regimes. For the first time, we demonstrate the importance of analyte concentration range selection, and the need for bespoke viscosity model development.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2438172"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813686","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":"CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin's lymphoma.","authors":"Dan Zhu, Haralambos Hadjivassiliou, Catherine Jennings, David Mikolon, Massimo Ammirante, Sharmistha Acharya, Jon Lloyd, Mahan Abbasian, Rama Krishna Narla, Joseph R Piccotti, Katie Stamp, Ho Cho, Kandasamy Hariharan","doi":"10.1080/19420862.2024.2310248","DOIUrl":"10.1080/19420862.2024.2310248","url":null,"abstract":"<p><p>Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a \"don't eat me\" signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20⁺ cells, while sparing CD47⁺CD20^- normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20⁺ cancer cells via enhanced phagocytosis and other effector functions.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2310248"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10865928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139723151","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":"Do antibody CDR loops change conformation upon binding?","authors":"Chu'nan Liu, Lilian M Denzler, Oliver E C Hood, Andrew C R Martin","doi":"10.1080/19420862.2024.2322533","DOIUrl":"10.1080/19420862.2024.2322533","url":null,"abstract":"<p><p>Antibodies have increasingly been developed as drugs with over 100 now licensed in the US or EU. During development, it is often necessary to increase or reduce the affinity of an antibody and rational attempts to do so rely on having a structure of the antibody-antigen complex often obtained by modeling. The antigen-binding site consists primarily of six loops known as complementarity-determining regions (CDRs), and an open question has been whether these loops change their conformation when they bind to an antigen. Existing surveys of antibody-antigen complex structures have only examined CDR conformational change in case studies or small-scale surveys. With an increasing number of antibodies where both free and complexed structures have been deposited in the Protein Data Bank, a large-scale survey of CDR conformational change during binding is now possible. To this end, we built a dataset, AbAgDb, that currently includes 177 antibodies with high-quality CDRs, each of which has at least one bound and one unbound structure. We analyzed the conformational change of the C<i>α</i> backbone of each CDR upon binding and found that, in most cases, the CDRs (other than CDR-H3) show minimal movement, while 70.6% and 87% of CDR-H3s showed global C<i>α</i> RMSD ≤ 1.0Å and ≤ 2.0Å, respectively. We also compared bound CDR conformations with the conformational space of unbound CDRs and found most of the bound conformations are included in the unbound conformational space. In future, our results will contribute to developing insights into antibodies and new methods for modeling and docking.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2322533"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110600","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":"Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG₁ antibodies.","authors":"Wen-Ting K Tsai, Yinyin Li, Zhaojun Yin, Peter Tran, Qui Phung, Zhenru Zhou, Kun Peng, Dan Qin, Sien Tam, Christoph Spiess, Jochen Brumm, Manda Wong, Zhengmao Ye, Patrick Wu, Sivan Cohen, Paul J Carter","doi":"10.1080/19420862.2024.2362789","DOIUrl":"10.1080/19420862.2024.2362789","url":null,"abstract":"<p><p>Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient <i>in vivo</i> assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG₁ antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by <i>in silico</i> prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. <i>In toto</i>, these data suggest that the KIH mutations and <i>in vitro</i> assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG₁, nor do the Fab mutations used for efficient <i>in vivo</i> assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG₁ as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2362789"},"PeriodicalIF":5.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11164226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284152","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}