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1.发明授权Pituitary adenylate cyclase activating peptide (PACAP)receptor 3 (R3) agonists and their pharmacological methods of use 失效垂体腺苷酸环化酶活化肽（PACAP）受体3（R3）激动剂及其药理学用途公开(公告)号：US06972319B1
公开(公告)日：2005-12-06
申请号：US09671773
申请日：2000-09-27
申请人： Clark Pan , Manami Tsutsumi , Armen B. Shanafelt
发明人： Clark Pan , Manami Tsutsumi , Armen B. Shanafelt
CPC分类号： C07K14/72 , A61K38/00 , C07K14/4705
摘要： This invention provides novel peptides that function in vivo to stimulate insulin release from pancreatic beta cells in a glucose-dependent fashion. These insulin secretagogue peptides are shown to stimulate insulin release in rat islet cells in vitro, and in vivo. The peptides of the present invention provide a new therapy for patients with decreased endogenous insulin secretion, in particular type 2 diabetics. In particular, the invention is a polypeptide selected from a specific group of VIP/PACAP-related polypeptides, or functional equivalents thereof. The invention is also directed to a method of treating a metabolic disease in a mammal comprising administering a therapeutically effective amount of the insulin secretagogue peptides to said mammal. Also disclosed are methods of making the peptides, both recombinant and synthetic.
摘要翻译： 本发明提供了新的肽，其在体内起作用以以葡萄糖依赖的方式刺激胰腺β细胞的胰岛素释放。 这些胰岛素促分泌肽显示能够在体外和体内刺激大鼠胰岛细胞中的胰岛素释放。 本发明的肽为具有降低的内源性胰岛素分泌的患者特别是2型糖尿病患者提供了新的疗法。 特别地，本发明是选自VIP / PACAP相关多肽的特定组的多肽或其功能等同物。 本发明还涉及一种治疗哺乳动物代谢疾病的方法，包括向所述哺乳动物施用治疗有效量的胰岛素促分泌肽。 还公开了制备重组体和合成肽的方法。
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2.发明授权Pituitary adenylate cyclase activating peptide (PACAP) receptor 3 (R3) agonists and their pharmacological methods of use 有权垂体腺苷酸环化酶活化肽（PACAP）受体3（R3）激动剂及其药理学用途公开(公告)号：US07507714B2
公开(公告)日：2009-03-24
申请号：US10892981
申请日：2004-07-15
申请人： Clark Pan , Manami Tsutsumi , Armen B. Shanafelt
发明人： Clark Pan , Manami Tsutsumi , Armen B. Shanafelt
CPC分类号： C07K14/575 , A61K38/00 , A61K48/00
摘要： This invention provides novel peptides that function in vivo to stimulate insulin release from pancreatic beta cells in a glucose-dependent fashion. These insulin secretagogue peptides are shown to stimulate insulin release in rat islet cells in vitro, and in vivo. The peptides of the present invention provide a new therapy for patients with decreased endogenous insulin secretion, in particular type 2 diabetics. In particular, the invention is a polypeptide selected from a specific group of VIP/PACAP-related polypeptides, or functional equivalents thereof. The invention is also directed to a method of treating a metabolic disease in a mammal comprising administering a therapeutically effective amount of the insulin secretagogue peptides to said mammal. Also disclosed are methods of making the peptides, both recombinant and synthetic.
摘要翻译： 本发明提供了新的肽，其在体内起作用以以葡萄糖依赖的方式刺激胰腺β细胞的胰岛素释放。 这些胰岛素促分泌肽显示能够在体外和体内刺激大鼠胰岛细胞中的胰岛素释放。 本发明的肽为具有降低的内源性胰岛素分泌的患者特别是2型糖尿病患者提供了新的疗法。 特别地，本发明是选自VIP / PACAP相关多肽的特定组的多肽或其功能等同物。 本发明还涉及一种治疗哺乳动物代谢疾病的方法，包括向所述哺乳动物施用治疗有效量的胰岛素促分泌肽。 还公开了制备重组体和合成肽的方法。
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公开(公告)号：US06313272B1
公开(公告)日：2001-11-06
申请号：US09350823
申请日：1999-07-09
IPC分类号： C07K100
CPC分类号： C07K14/5406 , A61K38/00 , Y10S930/141
摘要： A recombinant human IL-4 mutein numbered in accordance with wild-type IL-4 wherein the mutein comprises at least one amino acid substitution in the binding surface of either the A- or C-alpha helices of the wild-type IL-4 whereby the mutein binds to the IL-4R&agr; receptor with at least greater affinity than native IL-4. The substitution is more preferably selected from the group of positions consisting of, in the A-helix, positions 13 and 16, and in the C-helix, positions 81 and 89. A most preferred embodiment is the recombinant human IL-4 mutein wherein the substitution at position 13 is Thr to Asp. Pharmaceutical compositions, amino acid and polynucleotide sequences encoding the muteins, transformed host cells, antibodies to the muteins, and methods of treatment are also described.
摘要翻译： 根据野生型IL-4编号的重组人IL-4突变蛋白，其中所述突变蛋白包含在野生型IL-4的A或C-α螺旋的结合表面中的至少一个氨基酸取代，由此 突变蛋白以比天然IL-4至少更高的亲和力与IL-4Rα受体结合。 该取代更优选选自由A-螺旋中的第13位和第16位以及C-螺旋81和89组成的位置。最优选的实施方案是重组人IL-4突变蛋白，其中 位置13的取代是Thr至Asp。 还描述了编码突变蛋白，转化的宿主细胞，突变蛋白的抗体和治疗方法的药物组合物，氨基酸和多核苷酸序列。
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公开(公告)号：US5986059A
公开(公告)日：1999-11-16
申请号：US874697
申请日：1997-06-13
申请人： Armen B. Shanafelt , Jeffrey Greve , Robert Gundel
发明人： Armen B. Shanafelt , Jeffrey Greve , Robert Gundel
CPC分类号： C07K14/5406 , A61K38/00 , Y10S930/141
摘要： The invention is directed to human IL-4 muteins numbered in accordance with wild-type IL-4 having T cell activating activity, but having reduced endothelial cell activating activity. In particular, the invention is related to human IL-4 muteins wherein the surface-exposed residues of the D helix of the wild-type IL-4 are mutated whereby the resulting mutein causes T cell proliferation, and causes reduced IL-6 secretion from HUVECs, relative to wild-type IL-4. This invention realizes a less toxic IL-4 mutant that allows greater therapeutic use of this interleukin. Further, the invention is directed to IL-4 muteins having single, double and triple mutations represented by the designators R121A, R121D, R121E, R121F, R121H, R1211, R121K, R121N, R121P, R121T, R121W; Y124A, Y124Q, Y124R, Y124S, Y124T; Y124A/S125A, T13D/R121E; and R121T/E122F/Y124Q, when numbered in accordance with wild type IL-4 (His=1). The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.
摘要翻译： 本发明涉及根据具有T细胞活化活性但具有降低的内皮细胞活化活性的野生型IL-4编号的人IL-4突变蛋白。 特别地，本发明涉及人IL-4突变蛋白，其中暴露于野生型IL-4的D螺旋的表面暴露残基被突变，由此产生的突变蛋白导致T细胞增殖，并导致IL-6分泌降低 HUVECs相对于野生型IL-4。 本发明实现了一种毒性较小的IL-4突变体，可以更好地治疗这种白介素。 此外，本发明涉及具有由指示符R121A，R121D，R121E，R121F，R121H，R1211，R121K，R121N，R121P，R121T，R121W表示的单，双和三重突变的IL-4突变蛋白; Y124A，Y124Q，Y124R，Y124S，Y124T; Y124A / S125A，T13D / R121E; 和R121T / E122F / Y124Q，根据野生型IL-4（His = 1）编号。 本发明还包括编码本发明的突变蛋白的多核苷酸，含有多核苷酸的载体，转化的宿主细胞，包含突变蛋白的药物组合物和治疗方法。
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5.发明申请Interleukin-9 Antagonist Muteins and Their Pharmacological Methods of Use 审中-公开白细胞介素-9拮抗剂突变体及其药理学方法公开(公告)号：US20090148403A1
公开(公告)日：2009-06-11
申请号：US12197139
申请日：2008-08-22
IPC分类号： A61K38/20 , C07K14/54 , C12N15/24 , C12P21/02 , A61P35/02 , A61P35/00 , A61P11/00 , C12N15/86 , C12N5/10
CPC分类号： C07K14/5425
摘要： This invention relates to IL-9 muteins that inhibit the activity of wild-type IL-9, multimers and Fc-fusion constructs of IL-9 proteins, and an efficient method to purify IL-9 proteins produced by eukaryotic cells. Related formulations, dosages and methods of administration thereof for therapeutic purposes are also provided. More particularly, these IL-9 muteins, compositions, and methods provide a treatment option for individuals afflicted with conditions where inhibiting IL-9 mediated immune responses would be beneficial, such as allergy, asthma, chronic obstructive pulmonary disease (emphysema and chronic bronchitis), pulmonary and gastro-intestinal mucus hyperplasia, inflammation, immunological disorders, leukemia, and lymphoma.
摘要翻译： 本发明涉及抑制野生型IL-9，IL-9蛋白的多聚体和Fc融合构建体的活性的IL-9突变蛋白，以及用于纯化真核细胞产生的IL-9蛋白的有效方法。 还提供了用于治疗目的的相关制剂，剂量和施用方法。 更具体地说，这些IL-9突变蛋白，组合物和方法为患有抑制IL-9介导的免疫应答是有益的病症（例如过敏，哮喘，慢性阻塞性肺病（肺气肿和慢性支气管炎））的患者提供治疗选择， ，肺和胃肠粘液增生，炎症，免疫学障碍，白血病和淋巴瘤。
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公开(公告)号：US07105653B2
公开(公告)日：2006-09-12
申请号：US10826809
申请日：2004-04-17
摘要： The invention is directed to a polypeptide comprising a human IL-2 mutein numbered in accordance with wild-type IL-2 wherein said human IL-2 is substituted at at least one of positions 20, 88 or 126, whereby said mutein preferentially activates T cells over NK cells. D20H and I, N88G, I, and R, in particular have a relative T cell-differential activity much greater than native IL-2, with predicted associated reduced in vivo toxicity. The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.
摘要翻译： 本发明涉及包含根据野生型IL-2编号的人IL-2突变蛋白的多肽，其中所述人IL-2在20,88或126位中的至少一个被取代，其中所述突变蛋白优先激活T 细胞在NK细胞上。 D20H和I，N88G，I和R特别具有比天然IL-2大得多的相对T细胞差异活性，预测相关的体内毒性降低。 本发明还包括编码本发明的突变蛋白的多核苷酸，含有多核苷酸的载体，转化的宿主细胞，包含突变蛋白的药物组合物和治疗方法。
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公开(公告)号：US5624809A
公开(公告)日：1997-04-29
申请号：US436053
申请日：1995-05-05
IPC分类号： G01N33/543 , G01N33/558 , G01N33/548
CPC分类号： G01N33/54366 , G01N33/54386 , G01N33/558 , Y10S435/805 , Y10S435/97 , Y10S435/975 , Y10T436/19
摘要： Methods are disclosed for conducting assays. One such method comprises providing in combination a first bibulous member zone ("first zone") and a liquid medium containing a component. The first zone has non-diffusively bound thereto a reagent interreactive with the component. Conditions are selected wherein the liquid medium and at least a portion of the component contained therein traverse all of the first zone and migrate by capillary migration into a second bibulous member zone ("second zone"). The second zone is of a different composition than the first zone and is incapable of specifically binding the component except when an analyte is to be detected and the method further includes causing a reagent to become bound to the first bibulous member zone in relation to the amount of analyte present. The distance the component has migrated into the second zone or the difference in the distances the medium and the component have migrated into the second zone is determined, the distance or the difference being related to the amount of the component in the liquid medium or the amount of the reagent.
摘要翻译： 公开了用于进行测定的方法。 一种这样的方法包括组合提供第一吸引构件区域（“第一区域”）和含有组分的液体介质。 第一区域非扩散地结合与组分反应的试剂。 选择条件，其中液体介质和其中包含的成分的至少一部分穿过所有第一区域并通过毛细管迁移迁移到第二吸水构件区域（“第二区域”）中。 第二区域具有与第一区域不同的组成，并且不能特异性地结合该组分，除了当要分析物被检测时，该方法还包括使试剂与第一吸水构件区域相关的量结合 的分析物存在。 确定组件已经迁移到第二区域的距离或介质和组件迁移到第二区域的距离差，距离或差异与液体介质中组分的量或量 的试剂。
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公开(公告)号：US06433157B1
公开(公告)日：2002-08-13
申请号：US09408629
申请日：1999-09-30
申请人： Armen B. Shanafelt , Jeffrey Greve , Robert Gundel
发明人： Armen B. Shanafelt , Jeffrey Greve , Robert Gundel
IPC分类号： C07H2104
CPC分类号： C07K14/5406 , A61K38/00 , Y02A50/401 , Y02A50/411 , Y10S930/141
摘要： The invention is directed to human IL-4 muteins numbered in accordance with wild-type IL-4 having T cell activating activity, but having reduced endothelial cell activating activity. In particular, the invention is related to human IL-4 muteins wherein the surface-exposed residues of the D helix of the wild-type IL-4 are mutated whereby the resulting mutein causes T cell proliferation, and causes reduced IL-6 secretion from HUVECs, relative to wild-type IL-4. This invention realizes a less toxic IL-4 mutant that allows greater therapeutic use of this interleukin. Further, the invention is directed to IL-4 muteins having single, double and triple mutations represented by the designators R121A, R121D, R121E, R121F, R121H, R121I, R121K, R121N, R121P, R121T, R121W; Y124A, Y124Q, Y124R, Y124S, Y124T; Y124A/S125A, T13D/R121E; and R121T/E122F/Y124Q, when numbered in accordance with wild type IL-4 (His=1). The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.
摘要翻译： 本发明涉及根据具有T细胞活化活性但具有降低的内皮细胞活化活性的野生型IL-4编号的人IL-4突变蛋白。 特别地，本发明涉及人IL-4突变蛋白，其中暴露于野生型IL-4的D螺旋的表面暴露残基被突变，由此产生的突变蛋白导致T细胞增殖，并导致IL-6分泌降低 HUVECs相对于野生型IL-4。 本发明实现了一种毒性较小的IL-4突变体，可以更好地治疗这种白介素。 此外，本发明涉及具有由指示符R121A，R121D，R121E，R121F，R121H，R121I，R121K，R121N，R121P，R121T，R121W表示的单，双和三重突变的IL-4突变蛋白; Y124A，Y124Q，Y124R，Y124S，Y124T; Y124A / S125A，T13D / R121E; 和R121T / E122F / Y124Q，根据野生型IL-4（His = 1）编号。 本发明还包括编码本发明的突变蛋白的多核苷酸，含有多核苷酸的载体，转化的宿主细胞，包含突变蛋白的药物组合物和治疗方法。
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公开(公告)号：US06335426B1
公开(公告)日：2002-01-01
申请号：US09298374
申请日：1999-04-23
IPC分类号： C07K100
CPC分类号： C07K14/5406 , A61K38/00 , Y02A50/401 , Y02A50/411
摘要： This invention realizes a less toxic IL-4 mutant that allows greater therapeutic use of interleukin 4. Further, the invention is directed to IL-4 muteins having single and double mutations represented by the designators R121E and T13D/R121E, numbered in accordance with wild type IL-4 (His=1). The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.
摘要翻译： 本发明实现了一种毒性较小的IL-4突变体，其允许白细胞介素4的更大治疗用途。此外，本发明涉及具有按照野生型编号的指示符R121E和T13D / R121E表示的单突变和双突变的IL-4突变蛋白 类型IL-4（His = 1）。 本发明还包括编码本发明的突变蛋白的多核苷酸，含有多核苷酸的载体，转化的宿主细胞，包含突变蛋白的药物组合物和治疗方法。
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公开(公告)号：US6028176A
公开(公告)日：2000-02-22
申请号：US897020
申请日：1997-07-18
CPC分类号： C07K14/5406 , A61K38/00 , Y10S930/141
摘要： This invention is directed to recombinant human IL-4 muteins numbered in accordance with wild-type IL-4 wherein the muteins comprise at least one amino acid substitution selected from the group consisting of substitutions at positions 13, 16, 81 and 89 of the wild-type IL-4, whereby the mutein binds to the IL-4R.alpha. receptor with at least greater affinity than native IL-4. The invention is further directed to recombinant human IL-4 antagonist muteins numbered in accordance with wild-type IL-4 wherein the muteins comprise substitutions R121D and Y124D in the D-helix of said wild-type IL-4; and at least one amino acid substitution selected from the group consisting of substitutions at positions 13, 16, 81 and 89 of said wild-type IL-4, whereby the mutein binds to the IL-4R.alpha. receptor with at least greater affinity than native IL-4. The invention is also directed to pharmaceutical compositions comprising individual muteins in combination with pharmaceutically acceptable carriers.
摘要翻译： 本发明涉及根据野生型IL-4编号的重组人IL-4突变蛋白，其中突变蛋白包含至少一种选自野生型第13,16,81和89位的取代的氨基酸取代 型IL-4，其中突变蛋白以比天然IL-4至少更高的亲和力与IL-4Rα受体结合。 本发明还涉及根据野生型IL-4编号的重组人IL-4拮抗剂突变蛋白，其中突变蛋白包含所述野生型IL-4的D-螺旋中的取代R121D和Y124D; 和至少一个选自所述野生型IL-4的第13,16,81和89位的取代的氨基酸取代基，其中所述突变蛋白以比天然的更高的亲和力与IL-4Rα受体结合 IL-4。 本发明还涉及包含单独的突变蛋白与药学上可接受的载体组合的药物组合物。
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