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1. 发明申请

WO02074250A3 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：WO02074250A3
公开(公告)日：2003-10-09
申请号：PCT/US0209108
申请日：2002-03-18
申请人： PANACEA PHARMACEUTICALS , SINAI SCHOOL MEDICINE , UNIV ARKANSAS , CAPLAN MICHAEL , SOSIN HOWARD , SAMPSON HUGH , BANNON GARY A , BURKS WESLEY A , COCKRELL GAEL , COMPADRE CESAR M , CONNAUGHTON CATHIE , HELM RICKI M , KING NINA E , KOPPER RANDALL A , MALEKI SOHELIA J , RABJOHN PATRICK A , SHIN DAVID S , STANLEY J STEVEN
发明人： CAPLAN MICHAEL , SOSIN HOWARD , SAMPSON HUGH , BANNON GARY A , BURKS WESLEY A , COCKRELL GAEL , COMPADRE CESAR M , CONNAUGHTON CATHIE , HELM RICKI M , KING NINA E , KOPPER RANDALL A , MALEKI SOHELIA J , RABJOHN PATRICK A , SHIN DAVID S , STANLEY J STEVEN
IPC分类号： A61K38/16 , C12P21/08 , C07K14/415 , A61K39/35 , C07K14/555 , G01N33/536
CPC分类号： A61K38/168
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 eitopes 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，可以通过破坏存在于天然过敏原中的一种或多种二硫键来制备具有降低的IgE结合的修饰的变应原。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试剂并破坏天然过敏原的一个或多个二硫键来制备经修饰的变应原。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. 发明申请

WO0052154A3 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：WO0052154A3
公开(公告)日：2001-01-11
申请号：PCT/US0005487
申请日：2000-03-02
申请人： UNIV ARKANSAS , SINAI SCHOOL MEDICINE
发明人： BANNON GARY A , BURKS A WESLEY JR , SAMPSON HUGH A , SOSIN HOWARD B , KING NINA E , MALEKI SOHEILA J , CONNAUGHTON CATHIE , KOPPER RANDALL A , RABJOHN PATRICK A , SHIN DAVID S , COMPADRE CESAR M
IPC分类号： A61K38/11 , C07K14/415 , C12N15/11 , A01H5/00 , A01K67/027 , A61K39/35 , A61P37/08 , C12N15/12 , C12N15/29 , G01N33/50
CPC分类号： C07K14/415 , A01K2217/05 , A61K38/00 , A61K2039/57
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。该方法允许蛋白质除了在IgE结合位点之内尽可能地最小化，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. 发明专利

CA2319437C METHODS AND REAGENTS FOR DECREASING ALLERGIC REACTIONS 未知
公开(公告)号：CA2319437C
公开(公告)日：2009-06-16
申请号：CA2319437
申请日：1999-01-29
申请人： UNIV ARKANSAS , SINAI SCHOOL MEDICINE
发明人： COCKRELL GAEL , HELM RICKI M , KING NINA E , STANLEY J STEVEN , SHIN DAVID S , SAMPSON HUGH A , BURKS A WESLEY JR , BANNON GARY A
IPC分类号： A01H5/00 , C07K14/415 , A01K67/027 , A61K38/00 , A61K39/35 , C07K14/37 , C07K14/435 , C07K14/47 , C12N1/15 , C12N1/19 , C12N1/21 , C12N5/00 , C12N5/10 , C12N15/09 , C12N15/29
摘要： It has been determined that allergens, which are characterized by both humor al (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 singl e amino acid within each of the epitopes led to loss of IgE binding. Although the epitopes shared no common amino acid sequence motif, t he hydrophobic residues located in the center of the epitope appeared to be most critical to IgE binding.

5. 发明专利

CA2241918C PEANUT ALLERGENS AND METHODS 未知
公开(公告)号：CA2241918C
公开(公告)日：2008-12-02
申请号：CA2241918
申请日：1996-09-23
申请人： UNIV ARKANSAS , SINAI SCHOOL MEDICINE
发明人： STANLEY J STEVEN , HELM RICKI M , BURKS A WESLEY JR , COCKRELL GAEL , BANNON GARY A , KING NINA E , SAMPSON HUGH A , SHIN DAVID S
IPC分类号： C12N15/09 , C12N15/29 , A61K36/18 , A61K38/00 , A61K39/00 , A61K39/35 , A61K39/39 , A61P37/04 , A61P37/08 , C07H21/04 , C07K14/415 , C07K16/16
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 10t 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. One of the major peanut allergens, Ara h I, was selected from these clones using Ara h I specific oligo-nucleotides and polymerase chain reaction technology. The Ara h I clone identified a2.3 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.

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