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    Generation and affinity maturation of antibody library in silico
    2.
    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。

    Structure-Based Selection and Affinity Maturation of Antibody Library
    6.
    发明申请
    Structure-Based Selection and Affinity Maturation of Antibody Library 审中-公开
    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

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

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

    IPC: C40B10/00

    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 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).

    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。

    Structure-based selection and affinity maturation of antibody library
    9.
    发明授权
    Structure-based selection and affinity maturation of antibody library 失效
    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

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

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

    IPC: G01N33/48 ,  G01N31/00 ,  A61K38/00

    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 ,  C40B50/02

    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。 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。

    DYNAMIC HUMAN HEAVY CHAIN ANTIBODY LIBRARIES
    10.
    发明申请
    DYNAMIC HUMAN HEAVY CHAIN ANTIBODY LIBRARIES 审中-公开

    公开(公告)号：US20200248336A1

    公开(公告)日：2020-08-06

    申请号：US16640679

    申请日：2017-08-21

    Applicant: Peter Peizhi LUO ,  Adagene Inc.

    Inventor： Peter Peizhi LUO ,  Yan LI ,  Fangyong DU

    IPC: C40B40/08 ,  C40B50/04 ,  C07K16/00

    Abstract: Provided herein are libraries containing polynucleotides, where one of the polynucleotides encodes an antibody heavy chain with specific hypervariable regions HVR-H1 and HVR-H2. Further provided herein are libraries containing polynucleotides encoding a plurality of unique antibodies, wherein each antibody comprises a heavy chain variable region and a light chain variable region. Also provided are antibodies, polypeptide libraries, vector libraries, cells, non-human animals, antibody heavy chains, methods of making an antibody library, kits, and methods of generating a bispecific antibody related thereto.

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