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1. 发明申请

US20110124528A1 Generation and affinity maturation of antibody library in silico 审中-公开
标题翻译：抗体库的生成和亲和力成熟
公开(公告)号：US20110124528A1
公开(公告)日：2011-05-26
申请号：US12916077
申请日：2010-10-29
申请人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang , Yicheng Cao , Shengjiang Liu
发明人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang , Yicheng Cao , Shengjiang Liu
IPC分类号： C40B50/02
CPC分类号： C07K16/22 , B01J2219/00689 , B01J2219/00695 , B01J2219/007 , B01J2219/00725 , C07K16/00 , C07K2299/00 , C07K2317/21 , C07K2317/24 , C07K2317/565 , C07K2317/567 , C07K2317/622 , C07K2317/92 , C07K2319/00 , C40B40/10 , G16B35/00 , G16C20/60
摘要： The present invention provides a methodology for efficiently generating and screening protein libraries for optimized proteins with desirable biological functions, such as improved binding affinity towards biologically and/or therapeutically important target molecules. The process is carried out computationally in a high throughput manner by mining the ever-expanding databases of protein sequences of all organisms, especially human. In one embodiment, a method for constructing a library of designed proteins, comprising the steps of: providing an amino acid sequence derived from a lead protein, the amino acid sequence being designated as a lead sequence; comparing the lead sequence with a plurality of tester protein sequences; and selecting from the plurality of tester protein sequences at least two peptide segments that have at least 15% sequence identity with the lead sequence, the selected peptide segments forming a hit library; and forming a library of designed proteins by substituting the lead sequence with the hit library. The library of designed proteins can be expressed in vitro or in vivo to produce a library of recombinant proteins that can be screened for novel or improved function(s) over the lead protein, such as an antibody against therapeutically important target.
摘要翻译：本发明提供了一种用于有效地产生和筛选具有所需生物学功能的优化蛋白质的蛋白质文库的方法，例如改善对生物和/或治疗重要的靶分子的结合亲和力。该过程以高通量方式通过开发不断扩大的所有生物体，特别是人的蛋白质序列数据库进行。在一个实施方案中，构建设计蛋白质文库的方法，包括以下步骤：提供衍生自铅蛋白的氨基酸序列，所述氨基酸序列指定为引导序列; 将引导序列与多个测试蛋白序列进行比较; 以及从所述多个测试蛋白序列中选择与所述引物序列具有至少15％序列同一性的至少两个肽片段，所选择的肽片段形成命中文库; 并通过用命中库替换引导序列形成设计蛋白质的文库。设计的蛋白质文库可以在体外或体内表达，以产生重组蛋白文库，该文库可以筛选出超过铅蛋白质的新的或改进的功能，例如针对治疗重要靶标的抗体。

2. 发明申请

US20120129702A1 Structure-Based Selection and Affinity Maturation of Antibody Library 审中-公开
标题翻译：基于结构的选择和亲和力成熟的抗体库
公开(公告)号：US20120129702A1
公开(公告)日：2012-05-24
申请号：US12914105
申请日：2010-10-28
申请人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang
发明人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang
IPC分类号： C40B10/00
CPC分类号： C07K16/00 , B01J2219/00689 , B01J2219/00695 , B01J2219/007 , B01J2219/00725 , C07K16/005 , C07K16/22 , C07K2299/00 , C07K2317/21 , C07K2317/24 , C07K2317/565 , C07K2317/622 , C07K2319/00 , C12N15/1089 , C40B40/10 , G16B35/00 , G16C20/60
摘要： The present invention provides a structure-based methodology for efficiently generating and screening a library of recombinant antibodies for optimized antibodies with desirable functions, such as higher binding affinity or low immunogenicity. In one embodiment, a method is provided for constructing a library of antibody sequences based on a three dimensional structure of a lead antibody. The method comprises: providing a lead structural template comprising the amino acid sequence of the variable region of the heavy chain (VH) or light chain (VL) of a lead antibody, comparing the lead template sequence with a plurality of tester protein sequences; selecting a hit library from the tester protein sequences; determining if a member of the hit library is structurally compatible with the lead structural template using a scoring function; selecting members for the hit library that score equal to or better than the lead sequence and screening members for improved function(s).
摘要翻译：本发明提供了一种基于结构的方法，用于有效地产生和筛选重组抗体文库，以获得具有所需功能的优化抗体，例如较高的结合亲和力或低免疫原性。在一个实施方案中，提供了一种基于铅抗体的三维结构构建抗体序列文库的方法。该方法包括：提供包含铅抗体的重链（VH）或轻链（VL）的可变区的氨基酸序列的引导结构模板，将引导模板序列与多个测试蛋白序列进行比较; 从测试蛋白序列中选择一个命中库; 确定命中库的成员是否使用得分函数在结构上与引导结构模板兼容; 选择得分等于或优于前导序列的命中库的成员，并筛选成员以改进功能。

3. 发明授权

US07117096B2 Structure-based selection and affinity maturation of antibody library 失效
标题翻译：抗体库的结构选择和亲和力成熟
公开(公告)号：US07117096B2
公开(公告)日：2006-10-03
申请号：US10153159
申请日：2002-05-20
申请人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang
发明人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang
IPC分类号： G01N33/48 , G01N31/00 , A61K38/00
CPC分类号： C07K16/00 , B01J2219/00689 , B01J2219/00695 , B01J2219/007 , B01J2219/00725 , C07K16/005 , C07K16/22 , C07K2299/00 , C07K2317/21 , C07K2317/24 , C07K2317/565 , C07K2317/622 , C07K2319/00 , C12N15/1089 , C40B40/10 , C40B50/02
摘要： The present invention provides a structure-based methodology for efficiently generating and screening protein libraries for optimized proteins with desirable biological functions, such as antibodies with high binding affinity and low immunogenicity in humans. In one embodiment, a method is provided for constructing a library of antibody sequences based on a three dimensional structure of a lead antibody. The method comprises: providing an amino acid sequence of the variable region of the heavy chain (VH) or light chain (VL) of a lead antibody, the lead antibody having a known three dimensional structure which is defined as a lead structural template; identifying the amino acid sequences in the CDRs of the lead antibody; selecting one of the CDRs in the VH or VL region of the lead antibody; providing an amino acid sequence that comprises at least 3 consecutive amino acid residues in the selected CDR, the selected amino acid sequence being a lead sequence; comparing the lead sequence profile with a plurality of tester protein sequences; selecting from the plurality of tester protein sequences at least two peptide segments that have at least 10% sequence identity with lead sequence, the selected peptide segments forming a hit library; determining if a member of the hit library is structurally compatible with the lead structural template using a scoring function; and selecting the members of the hit library that score equal to or better than or equal to the lead sequence. The selected members of the hit library can be expressed in vitro or in vivo to produce a library of recombinant antibodies that can be screened for novel or improved function(s) over the lead antibody.
摘要翻译：本发明提供了一种基于结构的方法，用于有效地产生和筛选具有所需生物学功能的优化蛋白质的蛋白质文库，例如人类具有高结合亲和力和低免疫原性的抗体。在一个实施方案中，提供了一种基于铅抗体的三维结构构建抗体序列文库的方法。该方法包括：提供铅抗体的重链（V H H H H）或轻链（V L L L）的可变区的氨基酸序列，所述引物抗体具有已知的三维结构，其被定义为引导结构模板; 识别引导抗体的CDR中的氨基酸序列; 选择引导抗体的V H H或V L L区域中的一个CDR; 提供在所选择的CDR中包含至少3个连续氨基酸残基的氨基酸序列，所选择的氨基酸序列是引导序列; 将引导序列谱与多个测试蛋白序列进行比较; 从多个测试蛋白序列中选择与引导序列具有至少10％序列同一性的至少两个肽段，所选择的肽段形成命中文库; 确定命中库的成员是否使用得分函数在结构上与引导结构模板兼容; 并且选择得分等于或者好于或等于前导序列的命中库的成员。命中文库的所选成员可以在体外或体内表达以产生重组抗体文库，其可以筛选出超过该抗体的新的或改进的功能。

4. 发明申请

US20070037217A1 Structure-based selection and affinity maturation of antibody library 审中-公开
标题翻译：抗体库的结构选择和亲和力成熟
公开(公告)号：US20070037217A1
公开(公告)日：2007-02-15
申请号：US11505649
申请日：2006-08-17
申请人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang
发明人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang
IPC分类号： C40B30/06 , C40B40/10
CPC分类号： C07K16/00 , B01J2219/00689 , B01J2219/00695 , B01J2219/007 , B01J2219/00725 , C07K16/005 , C07K16/22 , C07K2299/00 , C07K2317/21 , C07K2317/24 , C07K2317/565 , C07K2317/622 , C07K2319/00 , C12N15/1089 , C40B40/10 , G16B35/00 , G16C20/60
摘要： The present invention provides a structure-based methodology for efficiently generating and screening protein libraries for optimized proteins with desirable biological functions, such as antibodies with high binding affinity and low immunogenicity in humans. In one embodiment, a method is provided for constructing a library of antibody sequences based on a three dimensional structure of a lead antibody. The method comprises: providing an amino acid sequence of the variable region of the heavy chain VH) or light chain (VL) of a lead antibody, the lead antibody having a known three dimensional structure which is defined as a lead structural template; identifying the amino acid sequences in the CDRs of the lead antibody; selecting one of the CDRs in the VH or VL region of the lead antibody; providing an amino acid sequence that comprises at least 3 consecutive amino acid residues in the selected CDR, the selected amino acid sequence being a lead sequence; comparing the lead sequence profile with a plurality of tester protein sequences; selecting from the plurality of tester protein sequences at least two peptide segments that have at least 10% sequence identity with lead sequence, the selected peptide segments forming a hit library; determining if a member of the hit library is structurally compatible with the lead structural template using a scoring function; and selecting the members of the hit library that score equal to or better than or equal to the lead sequence. The selected members of the hit library can be expressed in vitro or in vivo to produce a library of recombinant antibodies that can be screened for novel or improved function(s) over the lead antibody.
摘要翻译：本发明提供了一种基于结构的方法，用于有效地产生和筛选具有所需生物学功能的优化蛋白质的蛋白质文库，例如人类具有高结合亲和力和低免疫原性的抗体。在一个实施方案中，提供了一种基于铅抗体的三维结构构建抗体序列文库的方法。所述方法包括：提供引物抗体的重链V H H或H链的可变区的氨基酸序列（V L L L L），所述引物抗体具有被定义为引导结构模板的已知三维结构; 识别引导抗体的CDR中的氨基酸序列; 选择引导抗体的V H H或V L L区域中的一个CDR; 提供在所选择的CDR中包含至少3个连续氨基酸残基的氨基酸序列，所选择的氨基酸序列是引导序列; 将引导序列谱与多个测试蛋白序列进行比较; 从多个测试蛋白序列中选择与引导序列具有至少10％序列同一性的至少两个肽段，所选择的肽段形成命中文库; 确定命中库的成员是否使用得分函数在结构上与引导结构模板兼容; 并且选择得分等于或者好于或等于前导序列的命中库的成员。命中文库的所选成员可以在体外或体内表达以产生重组抗体文库，其可以筛选出超过该抗体的新的或改进的功能。

5. 发明申请

US20070037214A1 Generation and selection of protein library in silico 审中-公开
标题翻译：蛋白质库的生成和选择
公开(公告)号：US20070037214A1
公开(公告)日：2007-02-15
申请号：US11502838
申请日：2006-08-10
申请人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang , Yicheng Cao , Shengjiang Liu
发明人： Peizhi Luo , Mark Hsieh , Pingyu Zhong , Caili Wang , Yicheng Cao , Shengjiang Liu
IPC分类号： C40B30/06 , C40B40/10
CPC分类号： C07K16/22 , B01J2219/00689 , B01J2219/00695 , B01J2219/007 , B01J2219/00725 , C07K16/00 , C07K2299/00 , C07K2317/21 , C07K2317/24 , C07K2317/565 , C07K2317/567 , C07K2317/622 , C07K2317/92 , C07K2319/00 , C40B40/10 , G16B35/00 , G16C20/60
摘要： The present invention provides a methodology for efficiently generating and screening protein libraries for optimized proteins with desirable biological functions, such as improved binding affinity towards biologically and/or therapeutically important target molecules. The process is carried out computationally in a high throughput manner by mining the ever-expanding databases of protein sequences of all organisms, especially human. In one embodiment, a method for constructing a library of designed proteins, comprising the steps of: providing an amino acid sequence derived from a lead protein, the amino acid sequence being designated as a lead sequence; comparing the lead sequence with a plurality of tester protein sequences; and selecting from the plurality of tester protein sequences at least two peptide segments that have at least 15% sequence identity with the lead sequence, the selected peptide segments forming a hit library; and forming a library of designed proteins by substituting the lead sequence with the hit library. The library of designed proteins can be expressed in vitro or in vivo to produce a library of recombinant proteins that can be screened for novel or improved function(s) over the lead protein, such as an antibody against therapeutically important target.
摘要翻译：本发明提供了一种用于有效地产生和筛选具有所需生物学功能的优化蛋白质的蛋白质文库的方法，例如改善对生物和/或治疗重要的靶分子的结合亲和力。该过程以高通量方式通过开发不断扩大的所有生物体，特别是人的蛋白质序列数据库进行。在一个实施方案中，构建设计蛋白质文库的方法，包括以下步骤：提供衍生自铅蛋白的氨基酸序列，所述氨基酸序列指定为引导序列; 将引导序列与多个测试蛋白序列进行比较; 以及从所述多个测试蛋白序列中选择与所述引物序列具有至少15％序列同一性的至少两个肽片段，所选择的肽片段形成命中文库; 并通过用命中库替换引导序列形成设计蛋白质的文库。设计的蛋白质文库可以在体外或体内表达，以产生重组蛋白文库，该文库可以筛选出超过铅蛋白质的新的或改进的功能，例如针对治疗重要靶标的抗体。

6. 发明授权

US06833441B2 Compositions and methods for generating chimeric heteromultimers 有权
标题翻译：用于产生嵌合异源多聚体的组合物和方法
公开(公告)号：US06833441B2
公开(公告)日：2004-12-21
申请号：US09921144
申请日：2001-08-01
申请人： Caili Wang , Pingyu Zhong , Shengjiang Liu , Peizhi Luo , Shengfeng Li , Xinwei Wang
发明人： Caili Wang , Pingyu Zhong , Shengjiang Liu , Peizhi Luo , Shengfeng Li , Xinwei Wang
IPC分类号： C07K1600
CPC分类号： C07K16/00 , C07K2317/56 , C07K2319/00
摘要： The present invention provides a technique for specific assembly of monomeric polypeptides to form a heteromultimer. This technique is particularly useful for generating a genetically diverse repertoire of heteromultimers such as antigen-binding units. The invention also provides both non-single-chain and single-chain antigen-binding units that are assembled by the technique described herein. The present invention also provides recombinant polynucleotides, vectors, host cells, and kits for producing the subject antigen-binding units. Further provided by the invention are methods of using the subject antigen-binding units.
摘要翻译：本发明提供了用于特异性组装单体多肽以形成异源多聚体的技术。该技术对于产生诸如抗原结合单位的异源多聚体的遗传多样性谱特别有用。本发明还提供通过本文所述技术组装的非单链和单链抗原结合单元。本发明还提供重组多核苷酸，载体，宿主细胞和用于产生受试者抗原结合单位的试剂盒。本发明进一步提供的是使用受试者抗原结合单元的方法。

7. 发明授权

US07429652B2 Compositions and methods for generating chimeric heteromultimers 有权
标题翻译：用于产生嵌合异源多聚体的组合物和方法
公开(公告)号：US07429652B2
公开(公告)日：2008-09-30
申请号：US10911127
申请日：2004-08-03
申请人： Caili Wang , Pingyu Zhong , Shengjiang Liu , Peizhi Luo , Shengfeng Li , Xinwei Wang
发明人： Caili Wang , Pingyu Zhong , Shengjiang Liu , Peizhi Luo , Shengfeng Li , Xinwei Wang
IPC分类号： C07H21/04 , C12Q1/70 , C12P21/04 , C12N7/00 , C12N15/00 , C12N5/06 , A61K39/395 , C12P21/08
CPC分类号： C07K16/00 , C07K2317/56 , C07K2319/00
摘要： The present invention provides a technique for specific assembly of monomeric polypeptides to form a heteromultimer. This technique is particularly useful for generating a genetically diverse repertoire of heteromultimers such as antigen-binding units. The invention also provides both non-single-chain and single-chain antigen-binding units that are assembled by the technique described herein. The present invention also provides recombinant polynucleotides, vectors, host cells, and kits for producing the subject antigen-binding units. Further provided by the invention are methods of using the subject antigen-binding units.
摘要翻译：本发明提供了用于特异性组装单体多肽以形成异源多聚体的技术。该技术对于产生诸如抗原结合单位的异源多聚体的遗传多样性谱特别有用。本发明还提供通过本文所述技术组装的非单链和单链抗原结合单元。本发明还提供重组多核苷酸，载体，宿主细胞和用于产生受试者抗原结合单位的试剂盒。本发明进一步提供的是使用受试者抗原结合单元的方法。

8. 发明申请

US20050009139A1 Compositions and methods for generating chimeric heteromultimers 有权
标题翻译：用于产生嵌合异源多聚体的组合物和方法
公开(公告)号：US20050009139A1
公开(公告)日：2005-01-13
申请号：US10911127
申请日：2004-08-03
申请人： Caili Wang , Pingyu Zhong , Shengjiang Liu , Peizhi Luo , Shengfeng Li , Xinwei Wang
发明人： Caili Wang , Pingyu Zhong , Shengjiang Liu , Peizhi Luo , Shengfeng Li , Xinwei Wang
IPC分类号： G01N33/53 , C07K14/705 , C07K16/00 , C07K16/46 , C07K19/00 , C12N1/15 , C12N1/19 , C12N1/21 , C12N5/10 , C12N15/09 , C12P21/08 , G01N33/566 , C12P21/02 , C07H21/04 , C07K16/44 , C12N5/06
CPC分类号： C07K16/00 , C07K2317/56 , C07K2319/00
摘要： The present invention provides a technique for specific assembly of monomeric polypeptides to form a heteromultimer. This technique is particularly useful for generating a genetically diverse repertoire of heteromultimers such as antigen-binding units. The invention also provides both non-single-chain and single-chain antigen-binding units that are assembled by the technique described herein. The present invention also provides recombinant polynucleotides, vectors, host cells, and kits for producing the subject antigen-binding units. Further provided by the invention are methods of using the subject antigen-binding units.
摘要翻译：本发明提供了用于特异性组装单体多肽以形成异源多聚体的技术。该技术对于产生诸如抗原结合单位的异源多聚体的遗传多样性谱特别有用。本发明还提供通过本文所述技术组装的非单链和单链抗原结合单元。本发明还提供重组多核苷酸，载体，宿主细胞和用于产生受试者抗原结合单位的试剂盒。本发明进一步提供的是使用受试者抗原结合单元的方法。

9. 发明授权

US07175983B2 Adapter-directed display systems 有权
标题翻译：适配器导向显示系统
公开(公告)号：US07175983B2
公开(公告)日：2007-02-13
申请号：US10033399
申请日：2001-11-02
申请人： Caili Wang , Pingyu Zhong , Xinwei Wang
发明人： Caili Wang , Pingyu Zhong , Xinwei Wang
IPC分类号： C12Q1/68
CPC分类号： C40B40/02 , C12N15/1037
摘要： The present invention provides adapter-directed display systems for expressing exogenous polypeptide within a host cell and/or displaying the exogenous polypeptide on the outer surface of a genetic package. This subject systems are particularly useful for displaying a genetically diverse repertoire of monomeric and multimeric polypeptides. The invention also provides both expression and helper vectors and kits containing components of the subject display systems. Also provided are genetic packages displaying the exogenous polypeptides of particular interest. Further provided by the invention are methods of using the subject display systems.
摘要翻译：本发明提供了用于在宿主细胞内表达外源多肽的和/或在遗传包装的外表面上显示外源多肽的适配器指导显示系统。该主题系统对于显示基因多样的单体和多聚体多肽的组成特别有用。本发明还提供表达和辅助载体和包含受试显示系统的组分的试剂盒。还提供显示特别感兴趣的外源多肽的遗传包。本发明进一步提供的是使用对象显示系统的方法。

10. 发明授权

US07910350B2 Adaptor-directed helper systems 有权
标题翻译：适配器导向的辅助系统
公开(公告)号：US07910350B2
公开(公告)日：2011-03-22
申请号：US11313270
申请日：2005-12-19
申请人： Caili Wang , Pingyu Zhong , Xinwei Wang
发明人： Caili Wang , Pingyu Zhong , Xinwei Wang
IPC分类号： C12N7/01
CPC分类号： C40B40/02 , C12N15/1037
摘要： The present invention provides adapter-directed display systems for expressing exogenous polypeptide within a host cell and/or displaying the exogenous polypeptide on the outer surface of a genetic package. This subject systems are particularly useful for displaying a genetically diverse repertoire of monomeric and multimeric polypeptides. The invention also provides both expression and helper vectors and kits containing components of the subject display systems. Also provided are genetic packages displaying the exogenous polypeptides of particular interest. Further provided by the invention are methods of using the subject display systems.
摘要翻译：本发明提供了用于在宿主细胞内表达外源多肽的和/或在遗传包装的外表面上显示外源多肽的适配器指导显示系统。该主题系统对于显示基因多样的单体和多聚体多肽的组成特别有用。本发明还提供表达和辅助载体和包含受试显示系统的组分的试剂盒。还提供显示特别感兴趣的外源多肽的遗传包。本发明进一步提供的是使用对象显示系统的方法。

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