WO2013092951A2 - Standard zur quantifizierung von pathogenen aggregaten aus körpereigenen proteinen - Google Patents
Standard zur quantifizierung von pathogenen aggregaten aus körpereigenen proteinen Download PDFInfo
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- WO2013092951A2 WO2013092951A2 PCT/EP2012/076551 EP2012076551W WO2013092951A2 WO 2013092951 A2 WO2013092951 A2 WO 2013092951A2 EP 2012076551 W EP2012076551 W EP 2012076551W WO 2013092951 A2 WO2013092951 A2 WO 2013092951A2
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- proteins
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- disease
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/002—Dendritic macromolecules
- C08G83/003—Dendrimers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2821—Alzheimer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2828—Prion diseases
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette
Definitions
- the invention relates to standards for the quantification of pathogenic aggregates or oligomers from endogenous proteins which characterize a protein aggregation disease, an amyloid degeneration or protein misfolding diseases and the use of these standards for the quantification of these pathogenic aggregates or oligomers.
- Protein misfolding diseases or protein aggregation diseases or amyloid degeneration are a heterogeneous group of clinical conditions whose common criterion in many cases (but not exclusively) is the extracellular systemic or local deposition of a specific protein in the ordered conformation of a beta-sheet structure.
- AD Alzheimer's disease
- Latin Alzheimer's disease
- Parkinson's disease age-related dementia is becoming an ever greater problem in today's society, as more life expectancy is affecting more and more people, and the disease is affecting social security systems and their affordability.
- amyloid-beta-peptide deposits are found in the brain and synuclein deposits in Parkinson's disease.
- the amyloid-beta-peptide deposits or plaques consisting of peptide fibrils
- APP amyloid precursor protein
- the main pathological feature of AD is the formation of senile or amyloid plaques, consisting of the A-beta peptide. Furthermore Emerge neurofibrillary deposits from the tau protein.
- the precursor protein of the A beta peptide, the APP is located in the cell wall of the neurons.
- A-beta fragments of different lengths and types such as A-beta 1 -40, A-beta 11 -40, A-beta 1 -42, A-beta 11 -42 or pyroGluA -Beta 3-42, pyroGluA-Beta 3- 40.
- Monomeric A-beta peptides are also produced in the healthy organism throughout life.
- the plaque A-beta deposits are the cause of the disease symptoms.
- various studies indicate that especially the small, freely diffusing A-beta oligomers have the highest toxicity, and are responsible for the development and progress of AD.
- aggregates of the A-beta peptide are directly linked to AD pathogenesis.
- Aggregation of peptides is governed by a variety of factors, e.g. Temperature, salt content of the sample, protein manufacturer, purity, etc. This makes the preparation of polymers as standards difficult to reproduce by aggregation of monomer peptides for test development and validation.
- prepared A-beta oligomers are not stable enough, i. it could not be guaranteed that the same A-Beta aggregate species were always present at the time of removal of A-beta oligomers from one preparation.
- the previously known oligomer preparations generally consist of various intermediate forms which are of uneven size and are therefore insufficiently reproducible.
- A-beta oligomers prepared from synthetically prepared A-beta monomers by various protocols have hitherto been used as comparison values. There was no assurance that only one oligomer size was present in the oligomer preparations and that the preparations contained no A-beta monomers or fibrils.
- the object of the present invention was to provide standards which make possible an exact and quantitative determination of pathogenic aggregates or oligomers from endogenous proteins.
- the standards should be usable as internal or external standards.
- oligomers or pathogenic aggregates which characterize a protein aggregation disease or an amyloid degeneration or protein misfolding disease, characterized in that a polymer is constructed from polypeptide sequences which are identical in their sequence with the body's own proteins in terms of their sequence or have a homology of at least 50% over the corresponding portion of the body's own proteins that characterize a protein aggregation disease or amyloid degeneration or protein misfolding disease, where the polymers do not aggregate.
- a generally valid and accepted fixed reference is used, which is for comparing and Determining properties and / or amount is used, in particular for determining the size and amount of pathogenic aggregates of endogenous proteins.
- the standard in the sense of the present invention can be used for calibrating devices and / or measurements.
- protein aggregation disease may also include amyloid degenerations and protein misfolding diseases
- diseases and the associated endogenous proteins are: A beta and tau protein for AD, alpha synuclein for Parkinson or prion Protein for Phon disorders, such as human Creutzfeldt-Jakob disease (CJD), sheep disease scrapie and bovine spongiform encephalopathy (BSE).
- CJD human Creutzfeldt-Jakob disease
- BSE bovine spongiform encephalopathy
- “Homologous sequences” in the sense of the invention means that an amino acid sequence has an identity with an amino acid sequence from an endogenous pathogenic aggregate or oligomer which causes a protein aggregation disease of at least 50, 55, 60, 65, 70, 71, 72, 73, 74 , 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99
- the term “homologous” or “homology” is used to be equivalent to the term "identity.”
- the identity between two nucleic acid sequences or polypeptide sequences is determined by comparison with the aid of the program BESTFIT based on the algorithm of Smith, TF and Waterman, MS (Adv.
- the identity between two nucleic acid sequences or polypeptide sequences is defined by the identity of the nucleic acid sequence / polypeptide sequence over the entire sequence length, as determined by comparison using the GAP program based on the Needleman, SB and Wunsch, CD. (J. Mol. Biol. 48: 443-453) is calculated by setting the following parameters for amino acids: gap creation penalty: 8 and gap extension penalty: 2; and the following parameters for nucleic acid gap creation penalty: 50 and gap extension penalty: 3.
- Two amino acid sequences are identical for the purposes of the present invention if they have the same amino acid sequence.
- corresponding subregion of the body's own proteins is to be understood as meaning those peptide sequences which, according to the definitions according to the invention, have an identical or with the stated percentage homologous peptide sequence of a monomer from which the standards according to the invention are built up.
- the standards do not aggregate, preferably by using monomeric sequences which do not aggregate, since the "corresponding subrange" of endogenous proteins is not responsible for the aggregation, or by blocking the groups responsible for the aggregation do not aggregate.
- the standards have a well-defined number of epitopes covalently linked (directly or via amino acids, spacers, and / or functional groups) for binding of the corresponding probes.
- Probes according to the invention are selected from the group consisting of: antibody, nanobody and affibody. Probes are also all molecules that have sufficient binding specificity for the aggregate to be detected, e.g. Dyes (thioflavin T, Congo red, etc.).
- the number of epitopes is determined by using a polypeptide sequence which is identical in its sequence to that part of the body's own proteins which forms an epitope or a homology of at least 50% with this subregion, thereby possessing the biological activity of the epitope.
- a polypeptide sequence which is identical in its sequence to that part of the body's own proteins which forms an epitope or a homology of at least 50% with this subregion, thereby possessing the biological activity of the epitope.
- Such a selected polypeptide sequence is incorporated in the desired number in the structure of the standards of the invention and / or linked together according to the invention.
- the standards according to the invention are polymers which are composed of the above-described polypeptide sequences, preferably epitopes, optionally containing further elements.
- above-described polypeptide sequences preferably epitopes, and / or their homologs having the biological activity of the corresponding epitope, the same or largest number of monomers based on the number of each one of the remaining monomer species of the standard and / or based on the number of all other monomers.
- the epitopes are epitopes of the A-beta peptide selected from subregions A-beta 1-8 (SEQ ID NO: 2), A-beta 1-11 (SEQ ID NO 3), A-Beta 1-16 (SEQ ID NO: 4), A-Beta 3-11 (SEQ ID NO: 5), and pyroGluA-Beta 3-11 (SEQ ID NO: 6), A-beta 11 - 16 (SEQ ID NO: 7) and pyroGluA-Beta 11 -16 (SEQ ID NO: 8), for example, the human N-terminal epitope (with the following sequence: DAEFRHDSGYE (1-11, corresponds to SEQ ID NO: 3) ,
- PyroGlu is the abbreviation for a pyroglutamate that can be formed from the glutamate residue at position 3 or 11 of the A-beta peptide after the N-terminal residues have been cleaved off.
- the standard molecule according to the invention is a polymer of the above-defined polypeptide sequences.
- an oligomer is a polymer composed of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 monomers (cf. Monomer is the above polypeptide sequence to understand), or multiples thereof, preferably 2-16, 4-16, 8-16, particularly preferably 8 or 16, or multiples thereof.
- the standards according to the invention are therefore oligomers or polymers according to the invention.
- the standards are water-soluble.
- the standards of the invention are constructed from the same polypeptide sequences.
- the standards of the invention are constructed from different polypeptide sequences.
- such above-defined polypeptide sequences are aligned in a linear conformation.
- such above-defined polypeptide sequences are strung together to form a branched oligomer of the invention.
- such above-defined polypeptide sequences are strung together to form a cross-linked oligomer of the invention.
- Branched or cross-linked oligomers according to the invention can be prepared by linking individual building blocks by means of lysine or by click chemistry.
- the standards according to the invention ie the oligomers or polymers according to the invention, in addition to the polypeptide sequences present in a precisely defined number, preferably epitopes, may additionally contain additional amino acids, spacers and / or functional groups via which the polypeptide sequences, preferably epitopes are covalently linked together.
- the direct linkage of the polypeptide sequences, preferably epitopes with cysteine, in particular by means of disulfide bridging by cysteine is excluded (to avoid that reducing agents solve the bridging).
- an immediate linkage of the spacer with the polypeptide sequence on the one hand and with cysteine on the other hand excluded.
- the invention relates to a standard molecule containing or constructed from copies of the amino-terminal part of the A-beta peptide selected from the subregions A-beta 1 - 8 (SEQ ID NO: 2), A-beta 1 - 11 (SEQ ID NO: 3), A-beta 1 - 16 (SEQ ID NO: 4), A-Beta 3-11 (SEQ ID NO: 5) and pyroGluA Beta 3-11 (SEQ ID NO: 6), A-Beta 11-16 (SEQ ID NO: 7) and pyroGluA-Beta 11 -16 (SEQ ID NO: 8), for example, the human N-terminal epitope (with the following sequence: DAEFRHDSGYE (1-11).
- the amplification of the epitopes by functional groups can be carried out before or after the synthesis of the individual building blocks.
- Characteristic of the standards according to the invention is the covalent linkage of the polypeptide sequences.
- polypeptide sequences to be used according to the invention may be identical to the sequence of the A-beta full-length peptide or show a homology of 50, 55, 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78 , 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% having the sequence of A Beta full-length peptide.
- polypeptide sequences which are identical to a partial region of the A-beta full-length peptide or a homology of 50, 60, 65, 70, 71, 72, 73, 74 are also used to construct the standard molecules of the invention , 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 , 100% with a portion of the A-beta full-length peptide.
- Essential for the sequences used according to the invention is their property not to aggregate (or controlled only in accordance with the conditions) and / or their activity as an epitope.
- the standards are constructed as dendrimers.
- the dendrimers according to the invention are composed of the above-described polypeptide sequences to be used according to the invention and may contain a central scaffold molecule.
- the scaffold molecule is a streptavidin monomer, more preferably a polymer, especially tetramer.
- the dendrimers of the invention contain in a variant polypeptide sequences which have a sequence which is identical to a portion of the A-beta peptide, or exhibits at least 50% homology to the corresponding subregion.
- the term at least 50% homology is also understood to mean a higher homology selected from the group consisting of 50, 55, 60, 65, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 , 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100%.
- Standards advantageously with higher aqueous solubility than pathogenic aggregates or oligomers from endogenous proteins, in one embodiment of the invention are formed from polypeptide sequences that are identical to the N-terminal region of the A beta peptide or at least 50% homology have to.
- the amino acid sequence A-beta 1 - 8 (SEQ ID NO: 2), A-beta 1 - 11 (SEQ ID NO: 3), A-beta 1 - is below the N-terminal region of an A-beta polypeptide.
- a standard molecule according to the invention may contain epitopes for at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different probes.
- Epitopes characteristic of various probes can be incorporated into the standards of the invention by using polypeptide sequences that are identical to, or have at least 50% homology to, different regions of the A beta peptide, but the activity of the corresponding epitope.
- polypeptide sequences that are identical or have 50% homology with the N-terminal region of the A-beta polypeptide, as well as polypeptide sequences that are identical or have at least 50% homology with the C-terminus are used for this purpose of the A beta polypeptide.
- the standard molecules contain so-called spacers.
- a spacer is understood to mean a molecule which is incorporated into the standard molecule via covalent bonds and has certain physical and / or chemical properties which alter the properties of the standard molecule.
- hydrophilic or hydrophobic, preferably hydrophilic, spacers are used. Hydrophilic spacers are selected from the group of molecules formed from polyethylene glycol, sugar, glycerol, poly-L-lysine or beta-alanine.
- the standards according to the invention contain (further) functional groups in an alternative of the present invention.
- functional groups molecules that are covalently bound to the standard molecules.
- the functional groups contain biotin groups. This allows strong covalent attachment to streptavidin. Standard molecules containing biotin groups can thus be bound to molecules containing streptavidin groups. If the standard molecules of the invention contain biotin and / or streptavidin groups, then larger standards can be assembled or several, optionally different standard molecules, can be bound to a scaffold.
- the standard molecules contain dyes for spectrophotometric determination and / or aromatic amino acids.
- Aromatic amino acids are, for example, tryptophan, tyrosine, phenylalanine or histidine, or selected from this group. The incorporation of tryptophan allows a spectrophotometric determination of the concentration of standards in solution.
- Another object of the present invention are dendrimers containing polypeptides which are identical in terms of their sequence in the corresponding subregion with the body's own proteins or have a homology of at least 50% over the corresponding portion with the body's own proteins, the Characterize protein aggregation disease.
- the dendomers of the invention may contain any of the above-described features of the standards or any combination thereof.
- An alternative of the present invention is:
- Dendrimer characterized in that it has a higher solubility in aqueous than the pathogenic aggregates of endogenous proteins, the one
- Dendrimer containing at least one spacer molecule and / or
- Dendrimer containing dyes for spectrophotometric determination and / or aromatic amino acids Dendrimer containing dyes for spectrophotometric determination and / or aromatic amino acids.
- the dendrimers have a radial symmetry.
- the branching of the first generation of the dendrimer is via lysine, in particular three Lys in amino acids.
- the polypeptide sequences in particular dendrimers, the polypeptide sequences, preferably epitopes, not via a bond to a sulfur atom, not via a thioether bond and / or not via cysteine (optionally by disulfide bridging Cysteine) with each other or with other elements of the standards such as amino acids, spacers and / or functional groups and / or other elements described above, in particular covalently bonded.
- the polypeptide sequences, preferably epitopes, and a spacer attached to the spacer are not linked to a sulfur atom, not via a thioether bond and / or via cysteine with each other or with other elements of the standards such as amino acids , further spacers and / or functional groups and / or other elements described above, especially covalently bound.
- the present invention further relates to a method for the preparation of a standard as described above.
- the standard of the invention is prepared by peptide synthesis or recombinant methods known to those skilled in the art.
- Another object of the present invention is the use of a standard or a dendrimer described above for the quantification of pathogenic aggregates or oligomers from the body's own proteins that characterize a protein aggregation disease.
- the standard is used to quantify A-beta oligomers.
- the present invention thus also provides a method for the quantification of pathogenic aggregates or oligomers from endogenous proteins which characterize a protein aggregation disease or an amyloid degeneration or protein misfolding disease in which the oligomers or polymers according to the invention are used as standard.
- the standards according to the invention are used in an embodiment of the present invention for calibration in the surface FIDA method, Elisa (sandwich Elisa) or FACS.
- the present invention relates to a kit comprising standard of the invention.
- the compounds and / or components of the kit of the present invention may be packaged in containers, optionally with / in buffers and / or solution. Alternatively, some components may be packaged in the same container. Additionally or alternatively, one or more of the components could be absorbed on a solid support such as a glass plate, a chip or a nylon membrane, or the well of a microtiter plate. Further, the kit may provide instructions for using the kit for one Any of the embodiments include.
- the standards are used to quantify pathogenic aggregates or oligomers from endogenous proteins by:
- the standards or the dendrimers are labeled with probes and the number of probes bound to the standards or dendrimers is determined
- pathogenic aggregates or oligomers from endogenous proteins which characterize a protein aggregation disease are labeled with probes, the number of probes binding to a respective pathogenic aggregate or oligomer is determined,
- step 2 the number of probes from step 1 binding to a standard or dendrimer is compared with that from step 2, and
- this determines the number and size of the oligomers from the body fluid.
- the standards according to the invention are used for the calibration of the surface FIDA method.
- the body's own pathogenic aggregates of body fluids e.g. A beta aggregates
- a capture molecule e.g. Capture antibody
- an N-terminal binding capture antibody can be used for this purpose.
- the aggregates are labeled by two different probes.
- a beta aggregates e.g. A beta antibodies are used, both of which are bound via N-terminal binding epitopes.
- the detection probes are labeled with, preferably different, fluorescent dyes. Thereby they are examined under the microscope, e.g. Laser scanning microscope visible.
- monomer detection of endogenous polypeptides is ruled out by using three different or three differently labeled probes which bind to a similar or identical epitope in the test system.
- the detection of monomers may be precluded by passing signals of lower intensity through the Definition of an intensity threshold can not be evaluated. Since larger aggregates have multiple binding sites for the two with different labeled dyes, monomer detection can alternatively or additionally be precluded by cross-correlation of these signals.
- the standards of the invention can be used as internal or external standards in the measurement.
- an A ⁇ oligomer standard was constructed having 16 epitopes for N-terminal A ⁇ binding antibody (epitope corresponds to A ⁇ i.n, sequence: DAEFRHDSGYE, SEQ ID NO: 3).
- MAP multiple antigen antigen peptide
- MAP-16 was serially diluted in PBS and used in the sFIDA assay for the detection of A ⁇ oligomers.
- Glass microtiter plates were cleaned in an ultrasonic bath for 15 minutes and then treated with a plasma cleaner for 10 minutes.
- the wells were incubated in 5 M NaOH for at least 3 hours, rinsed with water and then dried in a nitrogen gas stream.
- the glass surface was hydroxylated and then activated with amino groups.
- the glass plates were incubated in a solution of 5 M ethanolamine in DMSO overnight. Subsequently, the glass plates were rinsed with water and dried in a nitrogen gas stream.
- Carboxymethyl-dextran was dissolved in water at a concentration of 20 mg to ml and treated with N-ethyl-N- (3-dimethylaminopropyl) carbodiimide (EDC), (200 mM) and N-hydroxysuccinimide (NHS), (50 mM). After a pre-incubation of 10 minutes, the solution was incubated for a further 2 hours at room temperature. Subsequently, the glass plates were washed with water.
- EDC N-ethyl-N- (3-dimethylaminopropyl) carbodiimide
- NHS N-hydroxysuccinimide
- Alexa 488 antibodies and IC-16 antibodies were used.
- the IC16 antibodies were labeled with a kit (fluorescence labeling KIT Alexa-647, Molecular Probes, Düsseldorf, Germany) according to the manufacturer's instructions.
- the labeled antibodies were stored in PBS with 2 mM sodium azide at 4 ° C in the dark. e. Mark the aggregates with the probes
- the measurement was carried out using a confocal laser scanning microscope LSM 710 (Carl Zeiss, Jena, Germany). The microscope was equipped with an argon ion laser and three helium neon lasers. The measurements were made in the tile scan mode, where adjacent areas in a well are measured and put together to form an image. Each tile scan contained 3 x 2 frames, each image had an area of 213 x 213 ⁇ .
- TIRF total internal reflection
- Figure 2 shows the results of the measurements. It can be clearly seen that the sFIDA signal, ie the amount of colocalized pixels, correlates with the concentration of MAP-16 molecules. figure description
- Figure 1 Construction of an A ⁇ oligomer standard with 16 epitopes for N-terminal A ⁇ binding antibodies corresponding to the first 11 amino acids of A ⁇ (sequence: DAEFRHDSGYE).
- B and C To generate 16-MAP, four 4-MAPs were coupled via a streptavidin teramer. MAP-16 was separated from other components of the incubation approach by size exclusion chromatography.
- Figure 2 sFIDA measurements of MAP-16 at various concentrations diluted in PBS buffer.
- PBS buffer without MAP-16 served as a negative control.
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Abstract
Description
Claims
Priority Applications (8)
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BR112014015397A BR112014015397A2 (pt) | 2011-12-23 | 2012-12-21 | padrão para quantificar agregados patogênicos ou oligômeros de proteínas endógenas que definem uma doença de agregação de proteína ou degeneração amiloide ou doença de desenovelamento de proteína, dendrímeros contendo polipeptídeos, método para a produção de um padrão, uso de um padrão, kit contendo pelo menos um padrão e método para quantificar agregados patogênicos ou oligômeros de proteínas endógenas que definem uma doença de agregação de proteína ou degeneração amiloide ou doença de desenovelamento de proteína |
CN201280064164.XA CN104067129A (zh) | 2011-12-23 | 2012-12-21 | 用于量化内源蛋白质致病聚集体的标准物 |
EP18206804.9A EP3470847A3 (de) | 2011-12-23 | 2012-12-21 | Standard zur quantifizierung von pathogenen aggregaten aus körpereigenen proteinen |
CA2858210A CA2858210A1 (en) | 2011-12-23 | 2012-12-21 | Standard for quantifying pathogenic aggregates from proteins produced naturally in the body |
JP2014548050A JP2015502968A (ja) | 2011-12-23 | 2012-12-21 | 生体固有のタンパク質からの病原性の凝集体を定量化するための標準物質 |
US14/366,941 US20150037826A1 (en) | 2011-12-23 | 2012-12-21 | Standard for quantifying pathogenic aggregates from proteins produced naturally in the body |
EP12816051.2A EP2795336A2 (de) | 2011-12-23 | 2012-12-21 | Standard zur quantifizierung von pathogenen aggregaten aus körpereigenen proteinen |
IL232871A IL232871B (en) | 2011-12-23 | 2014-05-29 | A standard for the quantification of pathogenic aggregates from proteins produced naturally in the body |
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DE102011057019A DE102011057019A1 (de) | 2011-12-23 | 2011-12-23 | Standard zur Quantifizierung von pathogenen Aggregaten aus körpereigenen Proteinen |
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US (1) | US20150037826A1 (de) |
EP (2) | EP2795336A2 (de) |
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WO2015003674A3 (de) * | 2013-07-12 | 2015-09-03 | Forschungszentrum Jülich GmbH | Verfahren zur quantitativen charakterisierung amyloider und/oder aggregierender peptide und/oder proteine in einer probe |
CN105358978A (zh) * | 2013-06-26 | 2016-02-24 | 于利希研究中心有限公司 | 用于查明确定疾病的指示物的方法 |
DE102015003404A1 (de) | 2015-03-18 | 2016-09-22 | Forschungszentrum Jülich GmbH | Verfahren zur Herstellung eines Standards für den Nachweis von Proteinaggregaten einer Proteinfehlfaltungserkrankung sowie Standard und dessen Verwendung |
JP2017535517A (ja) * | 2014-09-16 | 2017-11-30 | エスアールアイ インターナショナルSRI International | 光ファイバーアレイ走査技術による親和性試薬および触媒の発見 本発明は、Space and Naval Warfare Systems Command Systems Center Pacificから授与された契約番号N66001−14−C−4059に基づく国庫補助でなされたものである。政府は、本発明に関してある権利を有する。 |
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JP7473398B2 (ja) | 2020-05-28 | 2024-04-23 | シスメックス株式会社 | キャリブレータ、複合体、及びIgA凝集体を測定する方法 |
CN116574271B (zh) * | 2023-06-06 | 2023-12-19 | 苏州谱迪生物科技有限公司 | 一种用于免疫检测低丰度生物标志物信号级联放大的荧光树状大分子的制备方法及其应用 |
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CN105358978A (zh) * | 2013-06-26 | 2016-02-24 | 于利希研究中心有限公司 | 用于查明确定疾病的指示物的方法 |
US11175288B2 (en) | 2013-06-26 | 2021-11-16 | Forschungszentrum Juelich Gmbh | Method for detecting indicators for determining diseases |
WO2015003674A3 (de) * | 2013-07-12 | 2015-09-03 | Forschungszentrum Jülich GmbH | Verfahren zur quantitativen charakterisierung amyloider und/oder aggregierender peptide und/oder proteine in einer probe |
US10088487B2 (en) | 2013-07-12 | 2018-10-02 | Forschungszentrum Juelich Gmbh | Method for the quantitative characterization of amyloid and/or aggregating peptides and/or proteins in a sample |
JP2017535517A (ja) * | 2014-09-16 | 2017-11-30 | エスアールアイ インターナショナルSRI International | 光ファイバーアレイ走査技術による親和性試薬および触媒の発見 本発明は、Space and Naval Warfare Systems Command Systems Center Pacificから授与された契約番号N66001−14−C−4059に基づく国庫補助でなされたものである。政府は、本発明に関してある権利を有する。 |
DE102015003404A1 (de) | 2015-03-18 | 2016-09-22 | Forschungszentrum Jülich GmbH | Verfahren zur Herstellung eines Standards für den Nachweis von Proteinaggregaten einer Proteinfehlfaltungserkrankung sowie Standard und dessen Verwendung |
WO2016146093A1 (de) | 2015-03-18 | 2016-09-22 | Forschungszentrum Jülich GmbH | Verfahren zur herstellung eines standards für den nachweis von proteinaggregaten einer proteinfehlfaltungserkrankung sowie standard und dessen verwendung - |
US10948499B2 (en) | 2015-03-18 | 2021-03-16 | Forschungszentrum Juelich Gmbh | Method for producing a standard for detecting protein aggregates of a protein misfolding disease, standard and use thereof |
DE102015003404B4 (de) | 2015-03-18 | 2021-10-07 | Forschungszentrum Jülich GmbH | Verfahren zur Herstellung eines Standards für den Nachweis von Proteinaggregaten einer Proteinfehlfaltungserkrankung sowie Standard und dessen Verwendung |
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Publication number | Publication date |
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DE102011057019A1 (de) | 2013-06-27 |
CN104067129A (zh) | 2014-09-24 |
BR112014015397A2 (pt) | 2019-09-24 |
JP2015502968A (ja) | 2015-01-29 |
EP3470847A2 (de) | 2019-04-17 |
IL232871B (en) | 2019-06-30 |
IL232871A0 (en) | 2014-07-31 |
US20150037826A1 (en) | 2015-02-05 |
CA2858210A1 (en) | 2013-06-27 |
WO2013092951A3 (de) | 2013-11-07 |
EP3470847A3 (de) | 2019-08-07 |
EP2795336A2 (de) | 2014-10-29 |
CN108593937A (zh) | 2018-09-28 |
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