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991.
Alexandre Ambrogelly Stephen Gozo Amit Katiyar Shara Dellatore Yune Kune Ram Bhat 《MABS-AUSTIN》2018,10(4):513-538
Process changes are inevitable in the life cycle of recombinant monoclonal antibody therapeutics. Products made using pre- and post-change processes are required to be comparable as demonstrated by comparability studies to qualify for continuous development and commercial supply. Establishment of comparability is a systematic process of gathering and evaluating data based on scientific understanding and clinical experience of the relationship between product quality attributes and their impact on safety and efficacy. This review summarizes the current understanding of various modifications of recombinant monoclonal antibodies. It further outlines the critical steps in designing and executing successful comparability studies to support process changes at different stages of a product's lifecycle. 相似文献
992.
Rina Fong Kimberly Kajihara Matthew Chen Isidro Hotzel Sanjeev Mariathasan Wouter L.W. Hazenbos 《MABS-AUSTIN》2018,10(7):979-991
Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a growing health threat worldwide. Efforts to identify novel antibodies that target S. aureus cell surface antigens are a promising direction in the development of antibiotics that can halt MRSA infection. We biochemically and structurally characterized three patient-derived MRSA-targeting antibodies that bind to wall teichoic acid (WTA), which is a polyanionic surface glycopolymer. In S. aureus, WTA exists in both α- and β-forms, based on the stereochemistry of attachment of a N-acetylglucosamine residue to the repeating phosphoribitol sugar unit. We identified a panel of antibodies cloned from human patients that specifically recognize the α or β form of WTA, and can bind with high affinity to pathogenic wild-type strains of S. aureus bacteria. To investigate how the β-WTA specific antibodies interact with their target epitope, we determined the X-ray crystal structures of the three β-WTA specific antibodies, 4462, 4497, and 6078 (Protein Data Bank IDs 6DWI, 6DWA, and 6DW2, respectively), bound to a synthetic WTA epitope. These structures reveal that all three of these antibodies, while utilizing distinct antibody complementarity-determining region sequences and conformations to interact with β-WTA, fulfill two recognition principles: binding to the β-GlcNAc pyranose core and triangulation of WTA phosphate residues with polar contacts. These studies reveal the molecular basis for targeting a unique S. aureus cell surface epitope and highlight the power of human patient-based antibody discovery techniques for finding novel pathogen-targeting therapeutics. 相似文献
993.
Xiling Jiang Xi Chen Thomas J. Carpenter Jun Wang Rebecca Zhou Hugh M. Davis 《MABS-AUSTIN》2018,10(6):876-889
T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs. 相似文献
994.
995.
Liu Yi Xia Jun Ma Dongling Faber Donald S. Fischer Itzhak 《Neurochemical research》1997,22(12):1511-1516
This report describes the presence of a group of tau-like proteins (TLPs) in goldfish central nervous system. The TLPs were immunoreactive with antibodies that recognized the carboxy-terminal domain of mammalian tau, but not with antibodies that recognized the amino-terminus. The TLPs of goldfish exhibited the basic properties of tau proteins including neuronal specificity, structural heterogeneity, heat stability and the ability to co-assemble with tubulin. We propose that TLPs may represent a precursor of tau, that share the microtubule binding domain and the carboxy-terminal domain with mammalian tau proteins. In contrast the amino-terminus of the TLPs is much shorter and may represent a more variable domain of tau proteins. 相似文献
996.
Loeffler David A. Juneau Paul L. Nguyen Hanh-Uyen Najman Dina Pomara Nunzio LeWitt Peter A. 《Neurochemical research》1997,22(2):209-214
Immunocytochemical staining was performed to investigate the presence of anti-hippocampal antibodies in cerebrospinal fluid (CSF) from patients with probable Alzheimer's disease (AD) (n = 19), aged normal controls (n = 9), and young normal controls (n = 10). Marked staining of neurons in the granule cell layer of the dentate gyrus and in pyramidal neurons in CA1-3 of the rat hippocampus was observed in 5 AD CSF samples (26%), 1 aged control sample (11%), and 1 young control sample (10%). These differences were not statistically significant. One of the immunoreactive AD CSF specimens also contained high concentrations of C5b-9, the membrane attack complex. The infrequent occurrence of anti-hippocampal antibodies in AD CSF, and the detection of similar immunoreactivity in control CSF specimens, suggest that these antibodies are unlikely to play a role in the neurodegenerative process in most individuals with AD. However, elevated C5b-9 concentration in an AD CSF specimen with marked immunoreactivity to hippocampal neurons suggests the possibility that anti-neuronal antibodies may contribute to complement activation in some AD patients. 相似文献
997.
Frank B. van Gog Ruud H. Brakenhoff Gordon B. Snow G. A. M. S. van Dongen 《Cancer immunology, immunotherapy : CII》1997,44(2):103-111
At our laboratory we are currently evaluating the suitability of mouse/human chimeric monoclonal antibodies (cmAb) for use
in radioimmunotherapy of patients with head and neck squamous cell carcinoma (HNSCC). We have developed cmAb containing the
human constant IgG1 domain and the variable domains of murine mAb (mmAb) E48 and U36 respectively. We considered the tumour-bearing
nude mouse to be a well-validated model for a first testing of the targeting capabilities of these cmAb in comparison with
the mmAb. Therefore, 3 μg cmAb E48 (labelled with 125I) and 3 μg mmAb E48 (labelled with 131I) were simultaneously injected into HNSCC-bearing nude mice and, at various assay times, mAb uptake in blood and other tissues
was assessed. Remarkably, while in roughly 50% of the animals the biodistribution of the conjugates was similar, in the other
animals cmAb E48 showed a much higher blood clearance than mmAb E48. This resulted in a lower tumour uptake of cmAb E48 in
comparison with mmAb E48. To determine whether this phenomenon was related to mAb E48 or to the animal model, other cmAb-mmAb
combinations were evaluated in the same way: cmAbs SF-25, 17-1A and U36 (all IgG1) were tested and all showed a rapid elimination
in about 50% of the animals. Besides a decrease in blood concentration, an increase of cmAb levels in liver and spleen was
observed within 24 h after injection. Isotype-specific enzyme-linked immunosorbent assays showed that mice that demonstrated
a rapid elimination of cmAb from the blood had much lower endogenous IgG1, IgG2b and IgG3 titres than mice showing normal
clearance. IgG2a levels were low in all mice. Biodistribution experiments with 3 μg chimeric 17-1A isoforms showed high blood
clearance in a proportion of the mice for IgG1, IgG3 and IgG4, but not for IgG2. Increase of the cmAb dose to 100 μg resulted
in a similar cmAb and mmAb biodistribution in all mice. Moreover, the biodistribution of the F(ab′)2 fragment of an IgG1 cmAb was similar for all mice in contrast to that of coinjected whole IgG. On the basis of these results
it can be hypothesized that, in mice with low endogenous IgG titres, cmAb with specific isotypes are rapidly removed from
the blood (and ultimately from the body) by mediation of Fc-binding receptors. Apparently, in mice with high endogenous IgG
titres or in mice receiving a high cmAb dose, these receptors are saturated. Furthermore, the rapid elimination of cmAb from
nude mice, which may occur after injection at a low dose, is a phenomenon related to the nude mouse model.
Received: 26 July 1996 / Accepted: 16 January 1997 相似文献
998.
用基因重组人IL-6免疫Balb/c小鼠,采用小鼠杂交瘤技术,筛选克隆到分泌抗人重组IL-6单克隆抗体的杂交瘤细胞株,并对其中2H2、 1D2 和4B4瘤细胞株进行了鉴定.其抗体类别均为IgG,亚类分别为IgG1和IgG2a.用多种细胞因子和无关蛋白的鉴别试验结果证实它们均特异地识别rhIL-6.免疫转染结果显示,该单抗识别分子质量为21 ku的IL-6单一条带.IL-6单克隆抗体的亲和常数Kaff= 1.62×109 (mol/L)-1. 相似文献
999.
表达轮状病毒SA11株Vp4的抗原表位诱导病毒中和抗体生成 总被引:5,自引:0,他引:5
以昆虫病毒Flockhousevirus(FHV)外壳蛋白为载体的外源抗原表位表达系统(FHV-RNA2载体系统).在重组杆状病毒和重组pET系统中构建和表达了SA11Vp4胰酶切割位点两侧和重叠切割位点3个抗原表位氨基酸序列(抗原表位A,aa223~242;抗原表位B,aa243~262;抗原表位C,aa234~251),并对其免疫原性进行了研究。结果表明:这3个抗原表位能诱导动物产生抗同源氨基酸序列的抗体和抗同源病毒(SA11)感染性的血清中和抗体。研究结果提示:RVVp4胰酶切割位点区氨基酸序列除了具有胰酶切割增强病毒感染力外,还具有诱导动物机体产生血清中和抗体的能力,是RV重组抗原表位亚单位疫苗研究中重要的抗原表位氨基酸序列。 相似文献
1000.
Expression of chalcone synthase and chalcone isomerase proteins in Arabidopsis seedlings 总被引:4,自引:0,他引:4
Cain Cody C. Saslowsky David E. Walker Richard A. Shirley Brenda W. 《Plant molecular biology》1997,35(3):377-381
Antibodies have been developed against the first two enzymes of flavonoid biosynthesis in Arabidopsis thaliana. Chalcone synthase (CHS) and chalcone isomerase (CHI) were overexpressed and purified from Escherichia coli as fusion proteins with glutathione S-transferase from Schistosoma japonicum. The recombinant proteins were then used to immunize chickens and the resulting IgY fraction was purified from egg yolks. Immunoblots of crude protein extracts from Arabidopsis seedlings carrying wild-type and null alleles for CHS and CHI showed that the resulting antibody preparations provide useful tools for characterizing expression of the flavonoid pathway at the protein level. An initial analysis of expression patterns in seedlings shows that CHS and CHI proteins are present at high levels during a brief period of early seedling germination that just precedes the transient accumulation of flavonoid end-products. 相似文献