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    Structure-based selection and affinity maturation of antibody library
    3.
    发明申请
    Structure-based selection and affinity maturation of antibody library 审中-公开
    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

    Applicant: Peizhi Luo ,  Mark Hsieh ,  Pingyu Zhong ,  Caili Wang

    Inventor： Peizhi Luo ,  Mark Hsieh ,  Pingyu Zhong ,  Caili Wang

    IPC: C40B30/06 ,  C40B40/10

    CPC classification number: 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

    Abstract: 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.

    Abstract translation: 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。

    Generation and selection of protein library in silico
    4.
    发明申请
    Generation and selection of protein library in silico 审中-公开
    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

    Applicant: Peizhi Luo ,  Mark Hsieh ,  Pingyu Zhong ,  Caili Wang ,  Yicheng Cao ,  Shengjiang Liu

    Inventor： Peizhi Luo ,  Mark Hsieh ,  Pingyu Zhong ,  Caili Wang ,  Yicheng Cao ,  Shengjiang Liu

    IPC: C40B30/06 ,  C40B40/10

    CPC classification number: 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

    Abstract: 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.

    Abstract translation: 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。

    Generation and affinity maturation of antibody library in silico
    6.
    发明申请
    Generation and affinity maturation of antibody library in silico 审中-公开
    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

    Applicant: Peizhi Luo ,  Mark Hsieh ,  Pingyu Zhong ,  Caili Wang ,  Yicheng Cao ,  Shengjiang Liu

    Inventor： Peizhi Luo ,  Mark Hsieh ,  Pingyu Zhong ,  Caili Wang ,  Yicheng Cao ,  Shengjiang Liu

    IPC: C40B50/02

    CPC classification number: 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

    Abstract: 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.

    Abstract translation: 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。

    Humanized antibodies against vascular endothelial growth factor
    9.
    发明授权
    Humanized antibodies against vascular endothelial growth factor 失效
    针对血管内皮生长因子的人源化抗体

    公开(公告)号：US07667004B2

    公开(公告)日：2010-02-23

    申请号：US10723434

    申请日：2003-11-26

    Applicant: Pingyu Zhong ,  Peizhi Luo ,  Kevin C. Wang ,  Mark Hsieh ,  Yan Li

    Inventor： Pingyu Zhong ,  Peizhi Luo ,  Kevin C. Wang ,  Mark Hsieh ,  Yan Li

    IPC: C12P21/08

    CPC classification number: C07K16/00 ,  B01J2219/00689 ,  B01J2219/00695 ,  B01J2219/007 ,  B01J2219/00725 ,  C07K16/22 ,  C07K2299/00 ,  C07K2317/21 ,  C07K2317/24 ,  C07K2317/56 ,  C07K2317/565 ,  C07K2317/622 ,  C07K2317/73 ,  C07K2317/92 ,  C07K2319/00 ,  C40B40/10 ,  Y02A90/26

    Abstract: Methods are provided for designing and selecting antibodies against human antigens with high affinity and specificity in silico and in vitro. In some particular embodiments, methods are provided for designing and selecting humanized or fully human antibodies against vascular endothelial growth factor (VEGF) with high affinity and specificity. In another aspect of the invention, monoclonal antibodies against VEGF are provided. In particular, humanized or human anti-VEGF monoclonal antibodies are provided with ability to bind to human VEGF with high affinity, inhibit VEGF-induced proliferation of endothelial cells in vitro and inhibit VEGF-induced angiogenesis in vivo. These antibodies and their derivative can be used in a wide variety of applications such as diagnosis, prevention, and treatment of diseases such as cancer, AMD, diabetic retinopathy, and other diseases derived from pathological angiogenesis.

    Abstract translation: 提供了用于在计算机和体外以高亲和力和特异性设计和选择针对人抗原的抗体的方法。 在一些具体实施方案中，提供了用于以高亲和力和特异性设计和选择针对血管内皮生长因子（VEGF）的人源化或完全人抗体的方法。 在本发明的另一方面，提供了针对VEGF的单克隆抗体。 特别地，人源化或人抗VEGF单克隆抗体具有以高亲和力结合人VEGF的能力，在体外抑制VEGF诱导的内皮细胞增殖并抑制体内VEGF诱导的血管生成。 这些抗体及其衍生物可用于广泛的应用，例如诊断，预防和治疗诸如癌症，AMD，糖尿病性视网膜病和其它源于病理血管发生的疾病。

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