Recombinant human EPO-Fc fusion proteins with prolonged half-life and enhanced erythropoietic activity in vivo

    公开(公告)号:US10117949B2

    公开(公告)日:2018-11-06

    申请号:US12162320

    申请日:2007-01-25

    Abstract: A recombinant fusion protein comprising a human erythropoietin peptide portion linked to an immunoglobulin peptide portion is described. The fusion protein has a prolonged half-life in vivo in comparison to naturally occurring or recombinant native human erythropoietin. In one embodiment of the invention the protein has a half-life in vivo at least three fold higher than native human erythropoietin. The fusion protein also exhibits enhanced erythropoietic bioactivity in comparison to native human erythropoietin. In one embodiment, the fusion protein comprises the complete peptide sequence of a human erythropoietin (EPO) molecule and the peptide sequence of an Fc fragment of human immunoglobulin IgG1. The Fc fragment in the fusion protein includes the hinge region, CH2 and CH3 domains of human immunoglobulin IgG1. The EPO molecule may be linked directly to the Fc fragment to avoid extraneous peptide linkers and lessen the risk of an immunogenic response when administered in vivo. In one embodiment the hinge region is a human Fc fragment variant having a non-cysteine residue at amino acid 6. The invention also relates to nucleic acid and amino acid sequences encoding the fusion protein and transfected cell lines and methods for producing the fusion protein. The invention further includes pharmaceutical compositions comprising the fusion protein and methods of using the fusion protein and/or the pharmaceutical compositions, for example to stimulate erythropoiesis in subjects in need of therapy.

    FUSION PROTEINS HAVING MUTATED IMMUNOGLOBULIN HINGE REGION
    2.
    发明申请
    FUSION PROTEINS HAVING MUTATED IMMUNOGLOBULIN HINGE REGION 审中-公开
    具有突变型免疫球蛋白HINGE区域的融合蛋白

    公开(公告)号:US20120100099A1

    公开(公告)日:2012-04-26

    申请号:US13275205

    申请日:2011-10-17

    Abstract: A fusion protein having a non-immunoglobulin polypeptide having a cysteine residue proximal to the C terminal thereof, and an immunoglobulin component with a mutated hinge region is provided. The mutation comprises a point mutated site corresponding in position to the position in a native hinge region of the cysteine residue located nearest the cysteine residue of the non-Ig component. The distance from the cysteine residue of the non-immunoglobulin polypeptide and any remaining cysteine residues of the mutated hinge region is sufficient to prevent the formation of a disulphide bond therebetween.

    Abstract translation: 提供了具有非免疫球蛋白多肽的融合蛋白,其具有接近其C末端的半胱氨酸残基和具有突变的铰链区的免疫球蛋白组分。 该突变包括位于位于最接近非Ig组分的半胱氨酸残基的半胱氨酸残基的天然铰链区的位置的点突变位点。 与非免疫球蛋白多肽的半胱氨酸残基和突变的铰链区的任何剩余半胱氨酸残基的距离足以防止其间形成二硫键。

    Fusion proteins having mutated immunoglobulin hinge region
    3.
    发明授权
    Fusion proteins having mutated immunoglobulin hinge region 有权
    具有突变的免疫球蛋白铰链区的融合蛋白

    公开(公告)号:US08067548B2

    公开(公告)日:2011-11-29

    申请号:US12180455

    申请日:2008-07-25

    Abstract: A fusion protein having a non-immunoglobulin polypeptide having a cysteine residue proximal to the C terminal thereof, and an immunoglobulin component with a mutated hinge region is provided. The mutation comprises a point mutated site corresponding in position to the position in a native hinge region of the cysteine residue located nearest the cysteine residue of the non-Ig component. The distance from the cysteine residue of the non-immunoglobulin polypeptide and any remaining cysteine residues of the mutated hinge region is sufficient to prevent the formation of a disulphide bond therebetween.

    Abstract translation: 提供了具有非免疫球蛋白多肽的融合蛋白,其具有接近其C末端的半胱氨酸残基和具有突变的铰链区的免疫球蛋白组分。 该突变包括位于位于最接近非Ig组分的半胱氨酸残基的半胱氨酸残基的天然铰链区的位置的点突变位点。 与非免疫球蛋白多肽的半胱氨酸残基和突变的铰链区的任何剩余半胱氨酸残基的距离足以防止其间形成二硫键。

    HEAT DISSIPATION APPARATUS
    5.
    发明申请
    HEAT DISSIPATION APPARATUS 审中-公开
    散热装置

    公开(公告)号:US20100147495A1

    公开(公告)日:2010-06-17

    申请号:US12485326

    申请日:2009-06-16

    CPC classification number: H01L23/467 H01L2924/0002 H01L2924/00

    Abstract: A heat dissipation apparatus includes a heat sink configured to contact a heat source, and a fan mounted to the heat sink. The heat sink includes a base with a bottom surface for contacting the heat source, and a plurality of radial fins angling upwardly from a top surface of the base to form a truncated conical space in the middle of the heat sink. A cross section area of the truncated conical space gradually increases from the top surface of the base to top of the fins.

    Abstract translation: 散热装置包括被配置为接触热源的散热器和安装到散热器的风扇。 散热器包括具有用于接触热源的底表面的基座和从基座的顶表面向上倾斜的多个径向翅片,以在散热器的中间形成截锥形空间。 截头圆锥形空间的横截面积从底部的顶表面逐渐增加到鳍的顶部。

    RECOMBINANT HUMAN EPO-FC FUSION PROTEINS WITH PROLONGED HALF-LIFE AND ENHANCED ERYTHROPOIETIC ACTIVITY IN VIVO
    6.
    发明申请
    RECOMBINANT HUMAN EPO-FC FUSION PROTEINS WITH PROLONGED HALF-LIFE AND ENHANCED ERYTHROPOIETIC ACTIVITY IN VIVO 有权
    重组人EPO-FC融合蛋白,具有延长的半衰期和增强的生殖活性

    公开(公告)号:US20090297522A1

    公开(公告)日:2009-12-03

    申请号:US12162320

    申请日:2007-01-27

    Abstract: A recombinant fusion protein comprising a human erythropoietin peptide portion linked to an immunoglobulin peptide portion is described. The fusion protein has a prolonged half-life in vivo in comparison to naturally occurring or recombinant native human erythropoietin. In one embodiment of the invention the protein has a half-life in vivo at least three fold higher than native human erythropoietin. The fusion protein also exhibits enhanced erythropoietic bioactivity in comparison to native human erythropoietin. In one embodiment, the fusion protein comprises the complete peptide sequence of a human erythropoietin (EPO) molecule and the peptide sequence of an Fc fragment of human immunoglobulin IgG1. The Fc fragment in the fusion protein includes the hinge region, CH2 and CH3 domains of human immunoglobulin IgG1. The EPO molecule may be linked directly to the Fc fragment to avoid extraneous peptide linkers and lessen the risk of an immunogenic response when administered in vivo. In one embodiment the hinge region is a human Fc fragment variant having a non-cysteine residue at amino acid 6. The invention also relates to nucleic acid and amino acid sequences encoding the fusion protein and transfected cell lines and methods for producing the fusion protein. The invention further includes pharmaceutical compositions comprising the fusion protein and methods of using the fusion protein and/or the pharmaceutical compositions, for example to stimulate erythropoiesis in subjects in need of therapy.

    Abstract translation: 描述了包含与免疫球蛋白肽部分连接的人促红细胞生成素肽部分的重组融合蛋白。 与天然存在的或重组的天然人促红细胞生成素相比,融合蛋白在体内具有延长的半衰期。 在本发明的一个实施方案中,蛋白质的体内半衰期比天然人促红细胞生成素高至少三倍。 与天然人促红细胞生成素相比,融合蛋白也表现出增强的红细胞生物活性。 在一个实施方案中,融合蛋白包含人促红细胞生成素(EPO)分子的完整肽序列和人免疫球蛋白IgG1的Fc片段的肽序列。 融合蛋白中的Fc片段包括人免疫球蛋白IgG1的铰链区,CH2和CH3结构域。 EPO分子可以直接连接到Fc片段,以避免外来的肽接头并且当在体内施用时减轻免疫原性应答的风险。 在一个实施方案中,铰链区是在氨基酸6具有非半胱氨酸残基的人Fc片段变体。本发明还涉及编码融合蛋白和转染细胞系的核酸和氨基酸序列以及用于产生融合蛋白的方法。 本发明还包括包含融合蛋白的药物组合物和使用融合蛋白和/或药物组合物的方法,例如刺激需要治疗的受试者的红细胞生成。

    METHOD AND APPARATUS FOR MULTI-CHIP PACKAGING
    8.
    发明申请
    METHOD AND APPARATUS FOR MULTI-CHIP PACKAGING 有权
    多芯片包装的方法和装置

    公开(公告)号:US20080142942A1

    公开(公告)日:2008-06-19

    申请号:US11612992

    申请日:2006-12-19

    Applicant: Yong Du John Yan

    Inventor: Yong Du John Yan

    Abstract: A method and apparatus are provided for multi-chip packaging. A multi-chip package (100) includes a substrate (105) and a plurality of semiconductor dice (110, 120, 130). A first semiconductor die (110) is physically coupled to an upper face of the substrate (105), the first semiconductor die (110) being a smallest one of the plurality of semiconductor dice (110, 120, 130).

    Abstract translation: 提供了用于多芯片封装的方法和装置。 多芯片封装(100)包括基板(105)和多个半导体晶片(110,120,130)。 第一半导体管芯(110)物理耦合到衬底(105)的上表面,第一半导体管芯(110)是多个半导体管芯(110,120,130)中的最小的一个。

    Optical fiber connector having stopping means
    9.
    发明授权
    Optical fiber connector having stopping means 失效
    具有停止装置的光纤连接器

    公开(公告)号:US07186034B2

    公开(公告)日:2007-03-06

    申请号:US10979900

    申请日:2004-11-01

    Inventor: Lun Song Hu Yong Du

    CPC classification number: G02B6/4292 G02B6/4201 G02B6/4256

    Abstract: An optical fiber connector (1) includes a housing (10), an insulated body (20), an optical element (30) received in the housing, and a spacer (40) for securing the optical element in the housing. The housing defines a front and a rear receiving spaces (11, 12). The front receiving space is for receiving the insulated body and an optical plug (60), and the rear receiving space is for receiving the optical element. A partition wall (13) is formed between the front and the rear receiving spaces and defines an aperture (14) thereon. The aperture forms a tapered face (15) at a rear portion thereof for preventing the optical fiber plug from inserting into the optical fiber connector.

    Abstract translation: 光纤连接器(1)包括壳体(10),绝缘体(20),容纳在壳体中的光学元件(30)和用于将光学元件固定在壳体中的间隔物(40)。 壳体限定前部和后部接收空间(11,12)。 前接收空间用于接收绝缘体和光学插头(60),后接收空间用于接收光学元件。 分隔壁(13)形成在前和后接收空间之间并且在其上限定孔(14)。 孔在其后部形成锥形面(15),用于防止光纤插头插入光纤连接器。

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