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31.
Different Glycosylation in Acetylcholinesterases from Mammalian Brain and Erythrocytes 总被引:1,自引:0,他引:1
Acetylcholinesterases (EC 3.1.1.7, AChE) have varying amounts of carbohydrates attached to the core protein. Sequence analysis of the known primary structures gives evidence for several asparagine-linked carbohydrates. From the differences in molecular mass determined on sodium dodecyl sulfate-polyacrylamide gel before and after deglycosylation with N-glycosidase F (EC 3.2.2.18), it is seen that dimeric AChE from red cell membranes is more heavily glycosylated than the tetrameric brain enzyme. Furthermore, dimeric and tetrameric forms of bovine AChE are more heavily glycosylated than the corresponding human enzymes. Monoclonal antibodies 2E6, 1H11, and 2G8 raised against detergent-soluble AChE from electric organs of Torpedo nacline timilei as well as Elec-39 raised against AChE from Electrophorus electricus cross-reacted with AChE from bovine and human brain but not with AChE from erythrocytes. Treatment of the enzyme with N-glycosidase F abolished binding of monoclonal antibodies, suggesting that the epitope, or part of it, consists of N-linked carbohydrates. Analysis of N-acetylglucosamine sugars revealed the presence of N-acetylglucosamine in all forms of cholinesterases investigated, giving evidence for N-linked glycosylation. On the other hand, N-acetylgalactosamine was not found in AChE from human and bovine brain or in butyrylcholinesterase (EC 3.1.1.8) from human serum, indicating that these forms of cholinesterase did not contain O-linked carbohydrates. Despite the notion that within one species, the different forms of AChE arise from one gene by different splicing, our present results show that dimeric erythrocyte and tetrameric brain AChE must undergo different postsynthetic modifications leading to differences in their glycosylation patterns. 相似文献
32.
Abstract Murine monoclonal antibodies (mAbs) were selected against a cell wall glycoprotein of Saccharomyces cerevisiae . One of the mAbs (92-276/018) specifically identified S. cerevisiae and the sibling species S. paradoxus, S. pastorianus and S. bayanus in immunofluorescence studies and immunoblot analyses, while no other yeast genera except Saccharomyces were recognized. Further analysis indicated that the mAb 92-276/018 reacts with an epitope in the carbohydrate chain of the cell wall glycoproteins. 相似文献
33.
John H. Pazur Michael E. Tay Beverly A. Pazur Frank J. Miskiel 《Journal of Protein Chemistry》1987,6(5):387-399
Sets of isomeric anti-lactose antibodies with specificity for the lactose units of a cell wall polysaccharide fromStreptococcus faecalis strain N were induced in rabbits immunized with a vaccine of nonviable cells of the organism. Such sets of anti-lactose antibodies
were isolated from the serum of immunized animals by affinity chromatography on lactosyl-Sepharose. Gel electrofocusing experiments
showed that the preparations consisted of multiprotein components. One preparation of antibodies of 13 isomers was separated
into homogeneous components by liquid isoelectrofocusing. The individual isomeric antibodies exhibit specificity for the lactose
units of the antigenic polysaccharide, possess isoelectric points in the range of 5.9–8.0, and belong to the IgG class of
immunoglobulins, and each member yields one light chain and one heavy chain on dissociation in sodium dodecyl sulfate (SDS)
and mercaptoethanol. These results have been interpreted as evidence for the assembly of the chains of isomeric antibodies
by a single-chain pairing mechanism. 相似文献
34.
Historically, potency testing of bacterins containing Leptospira involved a hamster vaccination-challenge assay. The United States Department of Agriculture (USDA) has long recognized that an in vitro system has several inherent advantages over the animal model. This is a review of the work performed at the USDA to replace the hamster vaccination-challenge model used to test Leptospira bacterins. The work covered a span of approximately 20 years and resulted in the development of USDA monoclonal antibody based enzyme-linked immunosorbent assays (ELISAs) for the quantitation of antigen in bacterins containing Leptospira serogroups canicola, icterohaemorrhagiae, pomona, and grippotyphosa. The monoclonal antibodies used in the assay a) recognize lipopolysaccharide-like epitopes on the surface of the whole cell, b) agglutinate the homologous leptospiral serovars but do not agglutinate heterologous leptospiral serovars or heterologous bacterial species, and c) passively protect hamsters against a homologous challenge but fail to protect hamsters against heterologous challenges. Once developed, the performance of each ELISA was evaluated at the USDA followed by industry evaluation. Serials that passed the hamster vaccination-challenge assay yielded ELISA relative potency values of 1.0 or greater. These ELISAs have been shown to be a reproducible, sensitive, specific, and inexpensive alternative to the current Codified hamster potency assay. 相似文献
35.
《Cell communication & adhesion》2013,20(4):325-333
Rhenium (Re)-188 is a generator (W-188/Re-188) produced high energy β-emitter suitable for radionuclide therapy (T1/2 is 16.9 hrs and Emax 2.1 MeV (range 11 mm)). We have labelled monoclonal antibody (MAb) raised against vascular cell adhesion molecule-1 (VCAM-1) with Re-188 using glucoheptonate chelation technique and SnCl2 as reducing agent. The labelling efficiency, free perrhenate and reduced Re were controlled with thin layer chromatography and the purification of Re-188-MoAbs was performed using gel filtration. Our results indicate that Re-188-labelled antibodies remain in vitro stable and the labelling purity is >90%. We also have applied these Re-188-MoAbs for detection of inflammatory disease in a mouse. The effective half-lives of organs of interest after an injection of Re-188-anti-VCAM1 were as follows: blood 5.2 hr, kidney 4.7 hr, and liver 9.6 hr. Re-188-anti-VCAM-1 was found to accumulate mainly in kidney and liver. One hour after the injection, the kidney contained in average as high as 12.5% and the liver 2.8 ID/g tissue. After 6 hr, the kidney contained 5.5% ID/g and the liver 2.6% ID/g. At 24 hr, the kidney uptake was 0.5% ID/g and the liver uptake 0.8 % ID/g, respectively. The inflamed foci, subcutaneous lesions in the footpad skin, were visualized using gamma camera. From the distribution data the upakes in the inflamed foci as follows: at 1 hr 2.18 (inflammation) and 1.72% ID/g (control), at 6 hr 1.42 (inflammation) and 0.85% ID/g (control), and at 24 hr 0.17 (inflammation) and 0.084% ID/g (control), respectively. Anti-VCAM-1 MAb showed better targeting as compared to control MoAbs in inflammation (caused by E. coli lipoplysaccaride). In conclusion, Re-188 is suitable for MAb labelling, and MAb against VCAM-1 may be used for detection of local inflammatory disease. 相似文献
36.
Fabien Dépis Eric Hatterer Romain Ballet Bruno Daubeuf Laura Cons Sophie Glatt Walter Reith Marie Kosco-Vilbois Yann Dean 《MABS-AUSTIN》2013,5(4):555-564
Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration. 相似文献
37.
《MABS-AUSTIN》2013,5(4):799-802
The commercial pipeline of monoclonal antibodies is highly dynamic, with a multitude of transitions occurring during the year as product candidates advance through the clinical phases and onto the market. The data presented here add to that provided in the extensive “Antibodies to watch in 2014” report published in the January/February 2014 issue of mAbs. Recent phase transition data suggest that 2014 may be a banner year for first approvals of antibody therapeutics. As of May 2014, three products, ramucirumab (Cyramza®), siltuximab (Sylvant®) and vedolizumab (EntyvioTM), had been granted first approvals in the United States, and four additional antibody therapeutics (secukinumab, dinutuximab, nivolumab, pembrolizumab) are undergoing regulatory review in either the US or the European Union. Other notable events include the start of first Phase 3 studies for seven antibody therapeutics (dupilumab, SA237, etrolizumab, MPDL3280A, bavituximab, clivatuzumab tetraxetan, blinatumomab). Relevant data for these product candidates are summarized, and metrics for antibody therapeutics development are discussed. 相似文献
38.
《MABS-AUSTIN》2013,5(2):153-160
Monoclonal antibodies (mAbs) are used with increasing success against many tumors but, for brain tumors, the blood-brain barrier (BBB) is a special concern. The BBB prevents antibody entry to the normal brain; however, its role in brain tumor therapy is more complex. The BBB is closest to normal at micro-tumor sites; its properties and importance change as the tumor grows. In this review, evolving insight into the role of the BBB is balanced against other factors that affect efficacy or interpretation when mAbs are used against brain tumor targets. As specific examples, glioblastoma multiforme (GBM), primary central nervous system lymphoma (PCNSL) and blood-borne metastases from breast cancer are discussed in the context of treatment, respectively, with the mAbs bevacizumab, rituximab, and trastuzumab, each of which is already widely used against tumor outside the brain. It is suggested that success against brain tumors will require getting past the BBB in two senses: physically, to better attack brain tumor targets and conceptually, to give equal attention to problems that are shared with other tumor sites. 相似文献
39.
Alzheimer's disease is one of the most common causes of dementia. It is believed that the aggregation of short Aβ -peptides to form oligomeric and protofibrillar amyloid assemblies plays a central role for disease-relevant neurotoxicity. In recent years, passive immunotherapy has been introduced as a potential treatment strategy with anti-amyloid antibodies binding to Aβ -amyloids and inducing their subsequent degradation by the immune system. Although so far mostly unsuccessful in clinical studies, the high-dosed application of the monoclonal antibody Aducanumab has shown therapeutic potential that might be attributed to its much greater affinity to Aβ -aggregates vs monomeric Aβ -peptides. In order to better understand how Aducanumab interacts with aggregated Aβ -forms compared to monomers, we have generated structural model complexes based on the known structure of Aducanumab in complex with an Aβ2 − 7 -eptitope. Structural models of Aducanumab bound to full-sequence Aβ1 − 40 -monomers, oligomers, protofilaments and mature fibrils were generated and investigated using extensive molecular dynamics simulations to characterize the flexibility and possible additional interactions. Indeed, an aggregate-specific N-terminal binding motif was found in case of Aducanumab binding to oligomers, protofilaments and fibrils that is located next to but not overlapping with the epitope binding site found in the crystal structure with Aβ2 − 7 . Analysis of binding energetics indicates that this motif binds weaker than the epitope but likely contributes to Aducanumab's preference for aggregated Aβ -species. The predicted aggregate-specific binding motif could potentially serve as a basis to reengineer Aducanumab for further enhanced preference to bind Aβ -aggregates vs monomers. 相似文献
40.
Damilola D. Phillips David N. Garboczi Kavita Singh Zonglin Hu Stephen H. Leppla Clinton E. Leysath 《Journal of molecular recognition : JMR》2013,26(8):376-381
The monoclonal antibody S9.6 binds DNA–RNA hybrids with high affinity, making it useful in research and diagnostic applications, such as in microarrays and in the detection of R‐loops. A single‐chain variable fragment (scFv) of S9.6 was produced, and its affinities for various synthetic nucleic acid hybrids were measured by surface plasmon resonance (SPR). S9.6 exhibits dissociation constants of approximately 0.6 nM for DNA–RNA and, surprisingly, 2.7 nM for RNA–RNA hybrids that are AU‐rich. The affinity of the S9.6 scFv did not appear to be strongly influenced by various buffer conditions or by ionic strength below 500 mM NaCl. The smallest epitope that was strongly bound by the S9.6 scFv contained six base pairs of DNA–RNA hybrid. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. 相似文献