mAbs最新文献

{"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":"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":"https://doi.org/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":"","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":"","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":"https://doi.org/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":"","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":"","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}

{"title":"Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy.","authors":"Amelia C McCue, Stephen J Demarest, Karen J Froning, Michael J Hickey, Stephen Antonysamy, Brian Kuhlman","doi":"10.1080/19420862.2024.2373325","DOIUrl":"10.1080/19420862.2024.2373325","url":null,"abstract":"<p><p>T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and <i>in vitro</i> T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2373325"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498394","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":"FcRn-enhancing mutations lead to increased and prolonged levels of the HIV CCR5-blocking monoclonal antibody leronlimab in the fetuses and newborns of pregnant rhesus macaques.","authors":"Joanna Zikos, Gabriela M Webb, Helen L Wu, Jason S Reed, Jennifer Watanabe, Jodie L Usachenko, Ala M Shaqra, Celia A Schiffer, Koen K A Van Rompay, Jonah B Sacha, Diogo M Magnani","doi":"10.1080/19420862.2024.2406788","DOIUrl":"10.1080/19420862.2024.2406788","url":null,"abstract":"<p><p>Prenatal administration of monoclonal antibodies (mAbs) is a strategy that could be exploited to prevent viral infections during pregnancy and early life. To reach protective levels in fetuses, mAbs must be transported across the placenta, a selective barrier that actively and specifically promotes the transfer of antibodies (Abs) into the fetus through the neonatal Fc receptor (FcRn). Because FcRn also regulates Ab half-life, Fc mutations like the M428L/N434S, commonly known as LS mutations, and others have been developed to enhance binding affinity to FcRn and improve drug pharmacokinetics. We hypothesized that these FcRn-enhancing mutations could similarly affect the delivery of therapeutic Abs to the fetus. To test this hypothesis, we measured the transplacental transfer of leronlimab, an anti-CCR5 mAb, in clinical development for preventing HIV infections, using pregnant rhesus macaques to model <i>in utero</i> mAb transfer. We also generated a stabilized and FcRn-enhanced form of leronlimab, termed leronlimab-PLS. Leronlimab-PLS maintained higher levels within the maternal compartment while also reaching higher mAb levels in the fetus and newborn circulation. Further, a single dose of leronlimab-PLS led to complete CCR5 receptor occupancy in mothers and newborns for almost a month after birth. These findings support the optimization of FcRn interactions in mAb therapies designed for administration during pregnancy.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2406788"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11441024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349520","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":"GB18-06, a nanobody targeting GDF15, effectively alleviates weight loss and restores physical function in cachexia models.","authors":"Yu Huang, Jinyong Wang, Xiling Wei, Hui Zhang, Wei Shang, Xiangling Zhang, Lanjiao Zhai, Xi Chen, Huiming Li, Suofu Qin","doi":"10.1080/19420862.2024.2416453","DOIUrl":"https://doi.org/10.1080/19420862.2024.2416453","url":null,"abstract":"<p><p>Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18-06, that was able to bind GDF15 with high affinity. <i>In vitro</i>, GB18-06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; <i>in vivo</i>, GB18-06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18-06-treated group also increased 77%. Furthermore, GB18-06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":"16 1","pages":"2416453"},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469143","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}