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    Ligand antagonists for treatment of breast cancer
    3.
    发明授权
    Ligand antagonists for treatment of breast cancer 失效
    用于治疗乳腺癌的配体拮抗剂

    公开(公告)号：US06429186B1

    公开(公告)日：2002-08-06

    申请号：US08308879

    申请日：1994-09-19

    Applicant: Germaine Fuh ,  James A. Wells

    Inventor： Germaine Fuh ,  James A. Wells

    IPC: A01N3718

    CPC classification number: G01N33/74 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2267/0331 ,  A61K38/00 ,  C07K14/505 ,  C07K14/535 ,  C07K14/5412 ,  C07K14/57554 ,  C07K14/61 ,  C07K14/72 ,  C07K16/2869 ,  C07K2317/73 ,  C12N15/8509 ,  G01N2333/61

    Abstract: We have discovered that growth hormones form ternary complexes with their receptors in which site 1 on the hormone first binds to one molecule of receptor and then hormone site 2 then binds to another molecule of receptor, thereby producing a 1:2 complex. We believe this phenomenon is shared by other ligands having similar conformational structure. Assays based on this phenomenon are useful for identifying ligand agonists and antagonists. Sites 1 and 2 are structurally identified to facilitate generation of amino acid sequence variants of ternary complex-forming ligands. Novel variants of growth hormone, prolactin placental lactogen and other related ligands are provided. As a result of our studies with the ternary complex we have determined that selected antibodies to the receptor for these ligands are capable of acting as ligand agonists or antagonists. Novel growth hormones and novel uses for anti-growth hormone receptor antibodies are described. Methods for inhibiting the growth of breast cancer cells are also described.

    Abstract translation: 我们发现生长激素与其受体形成三元复合物，其中激素上的位点1首先与一个受体分子结合，然后激素位点2然后结合另一个受体分子，从而产生1：2复合物。 我们认为这种现象由具有相似构象结构的其他配体共享。 基于此现象的分析可用于鉴定配体激动剂和拮抗剂。 在结构上鉴定了位点1和2，以便于产生三元复合物形成配体的氨基酸序列变体。 提供了生长激素，催乳素胎盘乳酸和其他相关配体的新型变体。 作为我们用三元复合物研究的结果，我们确定了这些配体的受体的选定抗体能够作为配体激动剂或拮抗剂。 描述了抗生长激素受体抗体的新型生长激素和新用途。 还描述了抑制乳腺癌细胞生长的方法。

    Method for identifying active domains and amino acid residues in polypeptides and hormone variants
    4.
    发明授权
    Method for identifying active domains and amino acid residues in polypeptides and hormone variants 失效
    用于鉴定多肽和激素变体中活性结构域和氨基酸残基的方法

    公开(公告)号：US06428954B1

    公开(公告)日：2002-08-06

    申请号：US08483039

    申请日：1995-06-06

    Applicant: James A. Wells ,  Brian C. Cunningham

    Inventor： James A. Wells ,  Brian C. Cunningham

    IPC: C12Q168

    CPC classification number: C40B40/02 ,  C07K14/575 ,  C07K14/61 ,  C07K2319/00 ,  C07K2319/75 ,  C12N15/1037 ,  C12N15/1058 ,  C12N15/62 ,  G01N33/6878 ,  G01N33/74 ,  G01N2333/61 ,  Y10S530/806 ,  Y10S530/808

    Abstract: The invention provides methods for the systematic analysis of the structure and function of polypeptides by identifying active domains which influence the activity of the polypeptide with a target substance. Such active domains are determined by substituting selected amino acid segments of the polypeptide with an analogous polypeptide segment from an analog to the polypeptide. The analog has a different activity with the target substance as compared to the parent polypeptide. The activities of the segment-substituted polypeptides are compared to the same activity for the parent polypeptide for the target. A comparison of such activities provides an indication of the location of the active domain in the parent polypeptide. The invention also provides methods for identifying the active amino acid residues within the active domain of the parent polypeptide. The method comprises substituting a scanning amino acid for one of the amino acid residues within the active domain of the parent polypeptide and assaying the residue-substituted polypeptide so formed with a target substance. The invention further provides polypeptide variants comprising segment-substituted and residue-substituted growth hormones, prolactens and placental lactogens.

    Abstract translation: 本发明提供了通过鉴定影响多肽与靶物质的活性的活性结构域来系统分析多肽的结构和功能的方法。 通过用类似物与多肽的类似多肽片段取代多肽的选定氨基酸片段来确定此类活性结构域。 与亲本多肽相比，类似物与目标物质具有不同的活性。 将段取代的多肽的活性与目标的亲本多肽的相同活性进行比较。 这些活性的比较提供了活性结构域在亲本多肽中的位置的指示。 本发明还提供鉴定亲本多肽活性结构域内活性氨基酸残基的方法。 该方法包括用扫描氨基酸取代母体多肽的活性结构域内的氨基酸残基之一，并测定与靶物质形成的残基取代的多肽。 本发明进一步提供了包含片段取代和残基取代的生长激素，催乳激素和胎盘乳糖的多肽变体。

    Identification of novel substrates
    9.
    发明授权
    Identification of novel substrates 失效
    鉴定新基质

    公开(公告)号：US5846765A

    公开(公告)日：1998-12-08

    申请号：US441871

    申请日：1995-05-16

    Applicant: David J. Matthews ,  James A. Wells ,  Mark J. Zoller

    Inventor： David J. Matthews ,  James A. Wells ,  Mark J. Zoller

    IPC: C12N15/10 ,  C40B40/02 ,  C12P21/06 ,  C12N15/00 ,  C12Q1/00

    CPC classification number: C40B40/02 ,  C12N15/1037 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/735 ,  C07K2319/75

    Abstract: A method for identifying and selecting novel substrates for enzymes is provided. The method comprises constructing a gene fusion comprising DNA encoding a polypeptide fused to DNA encoding a substrate peptide, which in turn is fused to DNA encoding at least a portion of a phage coat protein. The DNA encoding the substrate peptide is mutated at one or more codons thereby generating a family of mutants. The fusion protein is expressed on the surface of a phagemid particle and subjected to chemical or enzymatic modification of the substrate peptide. Those phagemid particles which have been modified are then separated from those that have not.

    Abstract translation: 提供了用于鉴定和选择酶的新基质的方法。 该方法包括构建包含编码与编码底物肽的DNA融合的多肽的DNA的基因融合物，其又与编码至少一部分噬菌体外壳蛋白质的DNA融合。 编码底物肽的DNA以一个或多个密码子突变，从而产生突变体家族。 融合蛋白在噬菌粒的表面上表达并进行底物肽的化学或酶修饰。 然后将已经被修饰的那些噬菌粒颗粒与那些未被修饰的噬菌粒分离出来。

    Subtilisin variants capable of cleaving substrates containing basic residues
    10.
    发明授权
    Subtilisin variants capable of cleaving substrates containing basic residues 失效
    能够裂解含有碱性残基的底物的枯草杆菌蛋白酶变体

    公开(公告)号：US5837516A

    公开(公告)日：1998-11-17

    申请号：US504265

    申请日：1995-07-19

    Applicant: Marcus D. Ballinger ,  James A. Wells

    Inventor： Marcus D. Ballinger ,  James A. Wells

    IPC: C12N9/54 ,  C12N9/64 ,  C12N15/57 ,  C12N15/62 ,  C12P21/06 ,  C12N15/75

    CPC classification number: C12N9/6454 ,  C12N15/62 ,  C12N9/54 ,  C12P21/06 ,  C07K2319/00 ,  C07K2319/50 ,  C07K2319/75

    Abstract: The bacterial serine protease, subtilisin BPN', has been mutated so that it will efficiently and selectively cleave substrates containing basic residues. Combination mutants, where Asn 62 was changed to Asp, Gly 166 was changed to Asp (N62D/G166D), and optionally Tyr 104 was changed to Asp had a larger than additive shift in specificity toward substrates containing basic residues. Suitable substrates of the variant subtilisin were revealed by sorting a library of phage particles (substrate phage) containing five contiguous randomized residues. This method identified a particularly good substrate, Asn-Leu-Met-Arg-Lys- (SEQ ID NO: 35), that was selectively cleaved in the context of a fusion protein by the N62D/G166D subtilisin variant. A particularly good substrate for N62D/G166D/Y104D would be Asn-Arg-Met-Arg-Lys- (SEQ ID NO: 76). Accordingly, these variant subtilisin are useful for cleaving fusion proteins with basic substrate linkers and processing hormones or other proteins (in vitro or in vivo) that contain basic cleavage sites.

    Abstract translation: 细菌丝氨酸蛋白酶枯草杆菌蛋白酶BPN'已被突变，从而能有效地选择性地切割含有碱性残基的底物。 将Asn 62改变为Asp的组合突变体，将Gly 166改变为Asp（N62D / G166D），并且任选地将Tyr 104改变为Asp，对于含有碱性残基的底物的特异性大于添加位移。 通过分选含有五个连续随机残留物的噬菌体颗粒（底物噬菌体）文库来揭示变体枯草杆菌蛋白酶的合适底物。 该方法鉴定了通过N62D / G166D枯草杆菌蛋白酶变体在融合蛋白的上下文中选择性切割的特别良好的底物Asn-Leu-Met-Arg-Lys-（SEQ ID NO：35）。 N62D / G166D / Y104D特别好的底物是Asn-Arg-Met-Arg-Lys-（SEQ ID NO：76）。 因此，这些变体枯草杆菌蛋白酶可用于用碱性底物接头和加工激素或其它含有碱基切割位点的蛋白质（体外或体内）切割融合蛋白。

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