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1. 发明授权

US5973121A Immunoassay for peanut allergen 失效
公开(公告)号：US5973121A
公开(公告)日：1999-10-26
申请号：US610424
申请日：1996-03-04
申请人： A. Wesley Burks, Jr. , Ricki M. Helm
发明人： A. Wesley Burks, Jr. , Ricki M. Helm
IPC分类号： A61K38/00 , A61K39/00 , C07K14/415 , C07K16/16
CPC分类号： C07K14/415 , C07K16/16 , A61K38/00 , A61K39/00 , Y10S424/81 , Y10S530/868
摘要： Peanuts are a common cause of food hypersensitivity reactions. The sera of 10 patients who had atopic dermatitis and a positive double-blind placebo-controlled food challenge to peanut were used to investigate the major allergens of peanut. Crude Florunner extracts were fractionated by anion-exchange chromatography using a step gradient (limit buffer, 0.05M BisTris/1.5M NaCl). One hundred microliters of each 2.0 ml fraction was dot-blotted onto nitrocellulose paper and IgE-binding activity assessed using the serum pool to select allergen-containing fractions. A protein peak (OD 280) which eluted at 10% NaCl and demonstrated intense IgE-binding was further analyzed by two-dimensional SDS-PAGE/immunoblot analysis. The majority of this fraction is a protein which has a molecular weight of 17 kD and a pI of 5.2. Sequencing data from the N-terminus revealed the following initial 9 amino acids: (*)-Q-Q-(*)-E-L-Q-D-L. Based on IgE-binding activity and no known amino acid sequence identity to other allergens, this allergen is designated Ara h II.

2. 发明申请

US20120283421A1 METHODS AND REAGENTS FOR DECREASING CLINICAL REACTION TO ALLERGY 审中-公开
标题翻译：减少临床反应过敏的方法和试剂
公开(公告)号：US20120283421A1
公开(公告)日：2012-11-08
申请号：US13183892
申请日：2011-07-15
申请人： Michael J. Caplan , Howard B. Sosin , Hugh A. Sampson , Gary A. Bannon , A. Wesley Burks, JR. , Gael Cockrell , Cesar M. Compadre , Cathie Connaughton , Ricki M. Helm , Nina E. King , Randall A. Kopper , Soheila J. Maleki , Patrick A. Rabjohn , David S. Shin , J. Steven Stanley
发明人： Michael J. Caplan , Howard B. Sosin , Hugh A. Sampson , Gary A. Bannon , A. Wesley Burks, JR. , Gael Cockrell , Cesar M. Compadre , Cathie Connaughton , Ricki M. Helm , Nina E. King , Randall A. Kopper , Soheila J. Maleki , Patrick A. Rabjohn , David S. Shin , J. Steven Stanley
IPC分类号： C07K14/00
CPC分类号： C07K14/415 , A01K2217/05 , A61K38/168 , A61K39/00 , A61K2039/57 , C07K16/16 , C07K2317/34
摘要： It has been determined that allergens, which are characterized by both humoral (IgE) and cellular (T-cell) binding sites, can be modified to be less allergenic by modifying the IgE binding sites. The IgE binding sites can be converted to non-IgE binding sites by altering as little as a single amino acid within the protein, preferably a hydrophobic residue towards the center of the IgE epitope, to eliminate IgE binding. Additionally or alternatively a modified allergen with reduced IgE binding may be prepared by disrupting one or more of the disulfide bonds that are present in the natural allergen. The disulfide bonds may be disrupted chemically, e.g., by reduction and alkylation or by mutating one or more cysteine residues present in the primary amino acid sequence of the natural allergen. In certain embodiments, modified allergens are prepared by both altering one or more linear IgE epitopes and disrupting one or more disulfide bonds of the natural allergen. In certain embodiments, the methods of the present invention allow allergens to be modified while retaining the ability of the protein to activate T-cells, and, in some embodiments by not significantly altering or decreasing IgG binding capacity. The Examples provided herein use peanut allergens to illustrate applications of the invention.
摘要翻译：已经确定，通过体液（IgE）和细胞（T细胞）结合位点的特征的过敏原可以通过修饰IgE结合位点而被修饰为更低的过敏原。 IgE结合位点可以通过将蛋白质内的单个氨基酸，优选向IgE表位中心的疏水性残基改变，以消除IgE结合而转化为非IgE结合位点。另外或替代地，具有降低的IgE结合的修饰的变应原可以通过破坏天然过敏原中存在的一种或多种二硫键来制备。二硫键可以化学破坏，例如通过还原和烷基化或通过突变存在于天然过敏原的一级氨基酸序列中的一个或多个半胱氨酸残基来破坏。在某些实施方案中，通过改变一种或多种线性IgE表位并破坏天然过敏原的一个或多个二硫键来制备修饰的变应原。在某些实施方案中，本发明的方法允许改变变应原，同时保持蛋白质激活T细胞的能力，并且在一些实施方案中通过不显着改变或降低IgG结合能力。本文提供的实施例使用花生过敏原来说明本发明的应用。

3. 发明授权

US07485708B2 Nucleic acids encoding ara h 3 polypeptides 失效
标题翻译：编码ara h 3多肽的核酸
公开(公告)号：US07485708B2
公开(公告)日：2009-02-03
申请号：US10228806
申请日：2002-08-26
申请人： A. Wesley Burks, Jr. , Gary A. Bannon , Hugh A. Sampson , Ricki M. Helm , J. Steven Stanley , Patrick A. Rabjohn
发明人： A. Wesley Burks, Jr. , Gary A. Bannon , Hugh A. Sampson , Ricki M. Helm , J. Steven Stanley , Patrick A. Rabjohn
IPC分类号： C07H21/04
CPC分类号： C07K14/415 , A01K2217/05 , A61K38/00 , Y10S530/806 , Y10S530/868
摘要： It has been determined that allergens, which are characterized by both humoral (IgE) and cellular (T cell) binding sites, can be modified to be less allergenic by modifying the IgE binding sites. The IgE binding sites can be converted to non-IgE binding sites by masking the site with a compound that prevents IgE binding or by altering as little as a single amino acid within the protein, most typically a hydrophobic residue towards the center of the IgE binding epitope, to eliminate IgE binding. The method allows the protein to be altered as minimally as possible, other than within the IgE-binding sites, while retaining the ability of the protein to activate T cells, and, in some embodiments by not significantly altering or decreasing IgG binding capacity. The examples use peanut allergens to demonstrate alteration of IgE binding sites. The critical amino acids within each of the IgE binding epitopes of the peanut protein that are important to immunoglobulin binding have been determined. Substitution of even a single amino acid within each of the epitopes led to loss of IgE binding. Although the epitopes shared no common amino acid sequence motif, the hydrophobic residues located in the center of the epitope appeared to be most critical to IgE binding.
摘要翻译：已经确定，通过改变IgE结合位点，可以将以体液（IgE）和细胞（T细胞）结合位点为特征的过敏原修饰为较不敏感。通过用防止IgE结合的化合物掩蔽位点或通过改变蛋白质内的单个氨基酸，最通常的是向IgE结合中心的疏水性残基，将IgE结合位点转化为非IgE结合位点表位，以消除IgE结合。该方法允许尽可能最小化蛋白质，除了在IgE结合位点之内，同时保持蛋白质激活T细胞的能力，并且在一些实施方案中，不显着改变或降低IgG结合能力。实施例使用花生过敏原来证明IgE结合位点的改变。确定了对免疫球蛋白结合重要的花生蛋白的每个IgE结合表位内的关键氨基酸。每个表位中甚至单个氨基酸的取代导致IgE结合的丧失。尽管表位不具有共同的氨基酸序列基序，但位于该表位中心的疏水性残基似乎对IgE结合最为关键。

4. 发明授权

US07879977B2 Methods and reagents for decreasing clinical reaction to allergy 失效
标题翻译：减少临床反应过敏的方法和试剂
公开(公告)号：US07879977B2
公开(公告)日：2011-02-01
申请号：US11329924
申请日：2006-01-10
申请人： A. Wesley Burks, Jr. , Gary A. Bannon , Hugh A. Sampson , Ricki M. Helm , Gael Cockrell , J. Steven Stanley , Nina E. King
发明人： A. Wesley Burks, Jr. , Gary A. Bannon , Hugh A. Sampson , Ricki M. Helm , Gael Cockrell , J. Steven Stanley , Nina E. King
IPC分类号： C07K14/415 , A61K39/35
CPC分类号： C07K14/415
摘要： It has been determined that allergens, which are characterized by both humoral (IgE) and cellular (T cell) binding sites, can be modified to be less allergenic by modifying the IgE binding sites. The IgE binding sites can be converted to non-IgE binding sites by masking the site with a compound that prevents IgE binding or by altering as little as a single amino acid within the protein, most typically a hydrophobic residue towards the center of the IgE-binding epitope, to eliminate IgE binding. The method allows the protein to be altered as minimally as possible, other than-within the IgE-binding sites, while retaining the ability of the protein to activate T cells, and, in some embodiments by not significantly altering or decreasing IgG binding capacity The examples use peanut allergens to demonstrate alteration of IgE binding sites. The critical amino acids within each of the IgE binding epitopes of the peanut protein that are important to immunoglobulin binding have been determined. Substitution of even a single amino acid within each of the epitopes led to loss of IgE binding. Although the epitopes shared no common amino acid sequence motif, the hydrophobic residues located in the center of the epitope appeared to be most critical to IgE binding.
摘要翻译：已经确定，通过改变IgE结合位点，可以将以体液（IgE）和细胞（T细胞）结合位点为特征的过敏原修饰为较不敏感。通过用防止IgE结合的化合物掩蔽位点或通过改变蛋白质内的单个氨基酸，最常见的是向IgE-中心的疏水残基，将IgE结合位点转化为非IgE结合位点，结合表位，以消除IgE结合。该方法允许尽可能最小化蛋白质，除了在IgE结合位点之内，同时保持蛋白质激活T细胞的能力，并且在一些实施方案中通过不显着改变或降低IgG结合能力。实例使用花生过敏原来证明IgE结合位点的改变。确定了对免疫球蛋白结合重要的花生蛋白的每个IgE结合表位内的关键氨基酸。每个表位中甚至单个氨基酸的取代导致IgE结合的丧失。尽管表位不具有共同的氨基酸序列基序，但位于该表位中心的疏水性残基似乎对IgE结合最为关键。

5. 发明授权

US06486311B1 Peanut allergens and methods 失效
标题翻译：花生过敏原及方法
公开(公告)号：US06486311B1
公开(公告)日：2002-11-26
申请号：US09106872
申请日：1998-06-29
申请人： A. Wesley Burks, Jr. , J. Steven Stanley , Gael Cockrell , Nina E. King , Hugh A. Sampson , Ricki M. Helm , Gary A. Bannon
发明人： A. Wesley Burks, Jr. , J. Steven Stanley , Gael Cockrell , Nina E. King , Hugh A. Sampson , Ricki M. Helm , Gary A. Bannon
IPC分类号： C07H2104
CPC分类号： C07K14/415 , A61K39/00 , C07K16/16 , C07K2317/34
摘要： Peanuts are a common cause of food hypersensitivity reactions. The sera of 10 patients who had atopic dermatitis and a positive double-blind placebo-controlled food challenge to peanut were used to investigate the major allergens of peanut. Crude Florunner extracts were fractionated by anion-exchange chromatography using a step gradient (limit buffer, 0.05M BisTris/1.5M NaCl). A protein peak (OD 280) which eluted at 10% NaCl and demonstrated intense IgE-binding was further analyzed by two-dimensional SDS-PAGE/immunoblot analysis. The majority of this fraction is a protein which has a molecular weight of 17 kD and a pI of 5.2. Sequencing data from the N-terminus revealed the following initial 9 amino acids: (*)-Q-Q-(*)-E-L-Q-D-L. Based on IgE-binding activity and no known amino acid sequence identity to other allergens, this allergen is designated Ara h II. Ara h II may be used to detect and quantify peanut allergens in foodstuffs. Serum IgE from patients with documented peanut hypersensitivity reactions and a peanut cDNA expression library were used to identify clones that encode peanut allergens.
摘要翻译：花生是食物超敏反应的常见原因。 10例患有特应性皮炎和对花生进行双盲安慰剂对照食物挑战的阳性患者的血清用于调查花生的主要过敏原。通过阴离子交换色谱法使用梯度梯度（极限缓冲液，0.05M BisTris / 1.5M NaCl）分批粗制Florunner提取物。通过二维SDS-PAGE /免疫印迹分析进一步分析在10％NaCl下洗脱并表现出强烈IgE结合的蛋白质峰（OD 280）。该部分的大部分是分子量为17kD且pI为5.2的蛋白质。来自N末端的测序数据显示出以下初始的9个氨基酸：（*）-Q-Q-（*）-E-L-Q-D-L。基于IgE结合活性，并且与其他过敏原没有已知的氨基酸序列同一性，该变应原被命名为Ara h II。 Ara h II可用于检测和量化食品中的花生过敏原。使用记录花生超敏反应的患者的血清IgE和花生cDNA表达文库用于鉴定编码花生过敏原的克隆。

6. 发明授权

US06835824B1 Peanut allergens and methods 失效
标题翻译：花生过敏原及方法
公开(公告)号：US06835824B1
公开(公告)日：2004-12-28
申请号：US09191593
申请日：1998-11-13
申请人： A. Wesley Burks, Jr. , J. Steven Stanley , Gary A. Bannon , Gael Cockrell , Ricki M. Helm
发明人： A. Wesley Burks, Jr. , J. Steven Stanley , Gary A. Bannon , Gael Cockrell , Ricki M. Helm
IPC分类号： C07H2104
CPC分类号： C07K16/16 , A61K39/00 , C07K14/415 , C07K2317/34
摘要： One of the major peanut allergens, Ara h I, was selected from cDNA expression library clones using Ara h I specific oligo-nucleotides and polymerase chain reaction technology. The Ara h I clone identified a 2.3 kb mRNA species on a Northern blot containing peanut poly A+RNA. DNA sequence analysis of the cloned inserts revealed that the Ara h I allergen has significant homology with the vicilin seed storage protein family found in most higher plants. The isolation of the Ara h I clones allowed the synthesis of this protein in E. coli cells and subsequent recognition of this. recombinant protein in immunoblot analysis using serum IgE from patients with peanut hypersensitivity.
摘要翻译：使用Ara h I特异性寡核苷酸和聚合酶链反应技术，从cDNA表达文库克隆中选出主要花生过敏原之一Ara h I。 Ara h I克隆在含有花生聚A + RNA的Northern印迹上鉴定出2.3kb的mRNA种类。克隆插入物的DNA序列分析显示，Ara h I变应原与大多数高等植物中发现的vicilin种子储存蛋白家族具有显着的同源性。 Ara h I克隆的分离允许在大肠杆菌细胞中合成这种蛋白质，并随后识别这一点。重组蛋白在免疫印迹分析中使用花生超敏反应患者血清IgE。

7. 发明授权

US06441142B1 Immunoassay for peanut allergen 失效
标题翻译：花生过敏原免疫测定
公开(公告)号：US06441142B1
公开(公告)日：2002-08-27
申请号：US09336463
申请日：1999-06-18
申请人： A. Wesley Burks, Jr. , Ricki M. Helm
发明人： A. Wesley Burks, Jr. , Ricki M. Helm
IPC分类号： C07K1600
CPC分类号： C07K14/415 , A61K38/00 , A61K39/00 , C07K16/16 , Y10S424/81 , Y10S530/868
摘要： Peanuts are a common cause of food hypersensitivity reactions. The sera of 10 patients who had atopic dermatitis and a positive double-blind placebo-controlled food challenge to peanut were used to investigate the major allergens of peanut. Crude Florunner extracts were fractionated by anion-exchange chromatography using a step gradient (limit buffer, 0.05M BisTris/1.5M NaCl). One hundred microliters of each 2.0 ml fraction was dot-blotted onto nitrocellulose paper and IgE-binding activity assessed using the serum pool to select allergen-containing fractions. A protein peak (OD 280) which eluted at 10% NaCl and demonstrated intense IgE-binding was further analyzed by two-dimensional SDS-PAGE/immunoblot analysis. The majority of this fraction is a protein which has a molecular weight of 17 kD and a pI of 5.2. Sequencing data from the N-terminus revealed the following initial 9 amino acids: (*)-Q-Q-(*)-E-L-Q-D-L. Based on IgE-binding activity and no known amino acid sequence identity to other allergens, this allergen is designated Ara h II.
摘要翻译：花生是食物超敏反应的常见原因。 10例患有特应性皮炎和对花生进行双盲安慰剂对照食物挑战的阳性患者的血清用于调查花生的主要过敏原。通过阴离子交换色谱法使用梯度梯度（极限缓冲液，0.05M BisTris / 1.5M NaCl）分批粗制Florunner提取物。将每个2.0ml级分的100微升点印在硝酸纤维素纸上，并使用血清池评估IgE结合活性以选择含过敏原的级分。通过二维SDS-PAGE /免疫印迹分析进一步分析在10％NaCl下洗脱并表现出强烈IgE结合的蛋白质峰（OD 280）。该部分的大部分是分子量为17kD且pI为5.2的蛋白质。来自N末端的测序数据显示出以下初始的9个氨基酸：（*）-Q-Q-（*）-E-L-Q-D-L。基于IgE结合活性，并且与其他过敏原没有已知的氨基酸序列同一性，该变应原被命名为Ara h II。

8. 发明授权

US5558869A Major peanut allergen ara h II 失效
标题翻译：主要花生过敏原
公开(公告)号：US5558869A
公开(公告)日：1996-09-24
申请号：US158704
申请日：1993-11-29
申请人： A. Wesley Burks, Jr. , Ricki M. Helm
发明人： A. Wesley Burks, Jr. , Ricki M. Helm
IPC分类号： A61K38/00 , A61K39/00 , C07K14/415 , C07K16/16
CPC分类号： C07K14/415 , C07K16/16 , A61K38/00 , A61K39/00 , Y10S424/81 , Y10S530/868
摘要： Peanut allergen Ara h II was identified using the sera of patients who had atopic dermatitis and a positive food challenge to peanut. The Ara h II allergen, having a molecular weight of 17 kD and a pI of 5.2, was isolated by anion exchange chromatography. Ara h II may be used to detect and quantify peanut allergens in foodstuffs.
摘要翻译：使用具有特应性皮炎和对花生的积极食物挑战的患者的血清来鉴定花生过敏原Ara h II。通过阴离子交换色谱分离分子量为17kD，pI为5.2的Ara h II变应原。 Ara h II可用于检测和量化食品中的花生过敏原。

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