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    Single-domain antigen-binding antibody fragments derived from llama antibodies
    3.
    发明授权
    Single-domain antigen-binding antibody fragments derived from llama antibodies 有权
    衍生自美洲驼抗体的单结构域抗原结合抗体片段

    公开(公告)号：US08257705B2

    公开(公告)日：2012-09-04

    申请号：US11477830

    申请日：2006-06-29

    申请人： Jamshid Tanha ,  Ginette Dubuc ,  Saran Narang

    发明人： Jamshid Tanha ,  Ginette Dubuc ,  Saran Narang

    IPC分类号： A61K39/395 ,  C07K16/44 ,  C40B40/08 ,  C40B40/10

    CPC分类号： C40B40/02 ,  C07K16/00 ,  C07K2317/22 ,  C07K2317/569 ,  C12N15/1037

    摘要： A phage display library of variable heavy domain (VHH or VH) fragments (sdAb fragments) derived from the antibody repertoire of a non-immunized llama is disclosed. The sdAb fragments of the library are characterized by the absence of cysteine residues in complementarity determining regions (CDRs) and a very low presence of residues of glutamic acid, arginine and glycine at positions 44, 45 and 47, respectively, of the VL interface of the variable heavy domain VHH. The large size of the library (in the order of 109) makes it a source of antigen-binding fragments having high affinity to almost any antigen of interest. The library is preferably generated using a modified fd-tet phage growing in plaques in the absence of a tetracycline.

    摘要翻译： 公开了衍生自未免疫的美洲驼抗体谱的可变重结构域（VHH或VH）片段（sdAb片段）的噬菌体展示文库。 文库的sdAb片段的特征在于在互补决定区（CDR）中不存在半胱氨酸残基，并且分别存在于VL界面的第44,45和47位的谷氨酸，精氨酸和甘氨酸残基的非常低的存在 可变重域VHH。 图书馆的大尺寸（大约为109个）使得它成为与几乎所有感兴趣的抗原具有高亲和力的抗原结合片段的来源。 优选使用在不存在四环素时在斑块中生长的修饰的fd-tet噬菌体产生文库。

    Single-domain brain-targeting antibody fragments derived from LLAMA antibodies
    4.
    发明申请
    Single-domain brain-targeting antibody fragments derived from LLAMA antibodies 审中-公开
    衍生自LLAMA抗体的单域脑靶向抗体片段

    公开(公告)号：US20090162422A1

    公开(公告)日：2009-06-25

    申请号：US11880817

    申请日：2007-07-23

    申请人： Arumugam Muruganandam ,  Jamshid Tanha ,  Saran Narang ,  Danica Stanimirovic

    发明人： Arumugam Muruganandam ,  Jamshid Tanha ,  Saran Narang ,  Danica Stanimirovic

    IPC分类号： A61K9/127 ,  C07K16/18 ,  A61K39/395

    CPC分类号： C07K16/28 ,  A61K2039/505 ,  C07K16/00 ,  C07K2317/22 ,  C07K2317/569 ,  C12N15/1037 ,  C40B40/02

    摘要： A phage-displayed library of llama single heavy domain antibodies (sdAbs) was enriched for species that selectively bind to and are internalized by human cerebromicrovascular endothelial cells (HCEC). From the enriched library, two sdAbs were selected, sequenced, subcloned, and expressed as fusion proteins with c-myc-His5 tags. Similarly as phage-displayed sdAbs, these soluble tagged sdAbs were shown to selectively bind to HCEC and to transmigrate across in vitro human blood-brain barrier (BBB) model. In contrast to an unrelated llama sdAb, these sdAbs were also detected in the brain after i.v. injection into mice. These small (˜13 kDa) antibody fragments have essential characteristics of brain-specific delivery vectors and can be used to facilitate drug transport across the BBB.

    摘要翻译： 美洲驼单重重抗体抗体（sdAb）的噬菌体展示库富集了选择性结合并被人脑微血管内皮细胞（HCEC）内化的物种。 从富集的文库中选出两个sdAb，测序，亚克隆，并用c-myc-His5标签表达为融合蛋白。 类似地，作为噬菌体展示的sdAb，这些可溶性标记的sdAb被证明选择性地结合HCEC并跨越体外人血脑屏障（BBB）模型。 与无关的美洲驼sdAb相反，这些sdAb也是在i.v.之后的大脑中检测到的。 注射入小鼠 这些小（〜13 kDa）抗体片段具有脑特异性转运载体的基本特征，可用于促进穿过BBB的药物转运。

    Single domain brain-targeting antibody fragments derived from llama antibodies
    5.
    发明授权
    Single domain brain-targeting antibody fragments derived from llama antibodies 有权
    衍生自美洲驼抗体的单结构域脑靶向抗体片段

    公开(公告)号：US08383107B2

    公开(公告)日：2013-02-26

    申请号：US13052441

    申请日：2011-03-21

    申请人： Arumugam Muruganandam ,  Jamshid Tanha ,  Saran Narang ,  Danica Stanimirovic

    发明人： Arumugam Muruganandam ,  Jamshid Tanha ,  Saran Narang ,  Danica Stanimirovic

    IPC分类号： A61K39/395 ,  A61K39/00 ,  A61K39/38 ,  C07K14/00 ,  C07K17/00

    CPC分类号： C07K16/28 ,  A61K2039/505 ,  C07K16/00 ,  C07K2317/22 ,  C07K2317/569 ,  C12N15/1037 ,  C40B40/02

    摘要： A phage-displayed library of llama single heavy domain antibodies (sdAbs) was enriched for species that selectively bind to and are internalized by human cerebromicrovascular endothelial cells (HCEC). From the enriched library, two sdAbs were selected, sequenced, subcloned, and expressed as fusion proteins with c-myc-His5 tags (His5 is SEQ ID NO:101). Similarly as phage-displayed sdAbs, these soluble tagged sdAbs were shown to selectively bind to HCEC and to transmigrate across in vitro human blood-brain barrier (BBB) model. In contrast to an unrelated llama sdAb, these sdAbs were also detected in the brain after i.v. injection into mice. These small (˜13 kDa) antibody fragments have essential characteristics of brain-specific delivery vectors and can be used to facilitate drug transport across the BBB.

    摘要翻译： 美洲驼单重重抗体抗体（sdAb）的噬菌体展示库富集了选择性结合并被人脑微血管内皮细胞（HCEC）内化的物种。 从富集的文库中选出两个sdAb，测序，亚克隆，并用c-myc-His5标签（His5为SEQ ID NO：101）表达为融合蛋白。 类似地，作为噬菌体展示的sdAb，这些可溶性标记的sdAb被证明选择性地结合HCEC并跨越体外人血脑屏障（BBB）模型。 与无关的美洲驼sdAb相反，这些sdAb也是在i.v.之后的大脑中检测到的。 注射入小鼠 这些小（〜13 kDa）抗体片段具有脑特异性转运载体的基本特征，可用于促进穿过BBB的药物转运。

    Method for isolation of soluble polypeptides
    8.
    发明授权
    Method for isolation of soluble polypeptides 有权
    分离可溶性多肽的方法

    公开(公告)号：US08293233B2

    公开(公告)日：2012-10-23

    申请号：US11887113

    申请日：2006-03-24

    申请人： Jamshid Tanha

    发明人： Jamshid Tanha

    IPC分类号： A61K39/395 ,  C07K14/00 ,  C07K16/00 ,  C12P21/08 ,  C40B40/10

    CPC分类号： C07K16/005 ,  C07K16/1271 ,  C07K16/1282 ,  C07K2317/21 ,  C07K2317/56 ,  C07K2317/92 ,  C07K2317/94 ,  C12N15/1037 ,  G01N33/6845

    摘要： Polypeptides with desirable biophysical properties such as solubility, stability, high expression, monomericity, binding specificity or non-aggregation, including monomeric human VHs and VLs, are identified using a high throughput method for screening polypeptides, comprising the steps of obtaining a phage display library, allowing infection of a bacterial lawn by the library phage, and identifying phage which form larger than average plaques on the bacterial lawn. Sequences of monomeric human VHs and VLs are identified, which may be useful for immunotherapy or as diagnostic agents. Multimer complexes of human VHs and VLs are also identified. The VHs and VLs identified may be used to create further libraries for identifying additional polypeptides. Further, the VHs and VLs may be subjected to DNA shuffling to select for improved biophysical properties.

    摘要翻译： 使用高通量方法鉴定多肽，其具有所需的生物物理性质如溶解度，稳定性，高表达，单体性，结合特异性或非聚集，包括单体人VH和VL，其包括以下步骤：获得噬菌体展示文库 ，允许文库噬菌体感染细菌草坪，并鉴定形成比细菌草坪上的平均斑块大的噬菌体。 确定单体人VH和VL的序列，其可用于免疫治疗或用作诊断剂。 还鉴定了人VH和VL的多聚体复合物。 鉴定的VH和VL可用于产生用于鉴定另外的多肽的进一步的文库。 此外，可以对VH和VL进行DNA改组以选择改善的生物物理性质。

    ENGINEERING OF IMMUNOGLOBULIN DOMAINS
    9.
    发明申请
    ENGINEERING OF IMMUNOGLOBULIN DOMAINS 有权
    免疫球蛋白域的工程

    公开(公告)号：US20130303406A1

    公开(公告)日：2013-11-14

    申请号：US13981967

    申请日：2012-01-27

    申请人： Dae Young Kim ,  Jamshid Tanha

    发明人： Dae Young Kim ,  Jamshid Tanha

    IPC分类号： C07K16/00

    CPC分类号： C07K16/005 ,  C07K16/18 ,  C07K16/40 ,  C07K2317/56 ,  C07K2317/565 ,  C07K2317/567 ,  C07K2317/569 ,  C07K2317/624 ,  C07K2317/92 ,  C07K2317/94 ,  C07K2318/00 ,  C40B40/10

    摘要： The present invention provides a single domain antibody (sdAb) scaffold comprising one or more than one non-canonical disulfide bond in the framework region (FR). The one or more than one non-canonical disulfide bond may be formed between cysteines introduced by mutations in FR2 and FR3. In the case where the sdAb scaffold is a VH, the Cys may be introduced at any one of positions (47-49) and any one of positions (67-71), based on Kabat numbering; in one example, the Cys may be introduced at positions (49) and (69), based on Kabat numbering. In the case where the sdAb scaffold is a VL, the Cys residues may be introduced at any one of positions 46-49 and any one of positions (62-66), based on Kabat numbering; in one example, the Cys residues may be introduced at positions (48 and 64), based on Kabat numbering.

    摘要翻译： 本发明提供在框架区（FR）中包含一个或多于一个非规范二硫键的单结构域抗体（sdAb）支架。 在由FR2和FR3中的突变引入的半胱氨酸之间可以形成一个或多于一个非规范的二硫键。 在sdAb脚手架为VH的情况下，Cys可以基于Kabat编号引入位置（47-49）和位置（67-71）中的任何一个位置。 在一个示例中，基于Kabat编号可以在位置（49）和（69）处引入Cys。 在sdAb支架是VL的情况下，Cys残基可以基于Kabat编号引入位置46-49和位置（62-66）中的任何一个位置; 在一个实例中，Cys残基可以基于Kabat编号引入位置（48和64）。