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1.发明授权公开(公告)号：US09707276B2
公开(公告)日：2017-07-18
申请号：US14648752
申请日：2013-11-22
发明人： Michael Meehl , Richard D. DiMarchi , Pengyun Li
摘要： Compositions and formulations comprising insulin or insulin analogs comprising a carboxy terminal portion (CTP) peptide comprising amino acids 112-118 to 145 of the beta subunit of human chorionic gonadotropin (hCGβ) or a partial variant thereof that includes at least one O-glycosylation site of the CTP peptide, wherein the CTP peptide of the CTP peptide-based insulin or insulin analog is O-glycosylated are described. In particular embodiments, the O-glycosylated insulin analogs are produced in vivo and in further embodiments, the O-glycosylated CTP-based insulin analogs comprise predominantly mannotriose and mannotetrose O-glycans or predominantly mannose O-glycans.
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公开(公告)号：US09458220B2
公开(公告)日：2016-10-04
申请号：US14563362
申请日：2014-12-08
发明人： Richard D. DiMarchi , Yulia Azriel , Zachary Kaur , Jonathan Meyers , Todd Parody , Yan Zhao
摘要： Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.
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3.发明授权公开(公告)号：US08859491B2
公开(公告)日：2014-10-14
申请号：US13679121
申请日：2012-11-16
发明人： Richard D. DiMarchi , Bin Yang
IPC分类号： A61K38/00 , C07K14/605 , A61K38/26 , A61K31/56
CPC分类号： C07K14/605 , A61K38/00 , A61K47/554 , C07K2319/715
摘要： Provided herein are glucagon superfamily peptides conjugated with GR ligands that are capable of acting at a glucocorticoid receptor. Also provided herein are pharmaceutical compositions and kits of the conjugates of the invention. Further provided herein are methods of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the conjugates of the invention.
摘要翻译： 本文提供了与能够作用于糖皮质激素受体的GR配体缀合的胰高血糖素超家族肽。 本文还提供了本发明的缀合物的药物组合物和试剂盒。 本文还提供了治疗疾病，例如代谢紊乱（例如糖尿病和肥胖症）的方法，其包括施用本发明的缀合物。
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公开(公告)号：US10730923B2
公开(公告)日：2020-08-04
申请号：US16241932
申请日：2019-01-07
IPC分类号： A61K38/26 , C07K14/605 , A61K47/60 , G01N33/74 , A61K39/395 , C07K16/28 , A61K49/00 , A61K38/00
摘要： Provided herein are peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor, as compared to native glucagon.
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5.发明授权Glucagon antagonist-GIP agonist conjugates and compositions for the treatment of metabolic disorders and obesity 有权胰岛素拮抗剂-GIP激动剂缀合物和用于治疗代谢紊乱和肥胖症的组合物公开(公告)号：US09487571B2
公开(公告)日：2016-11-08
申请号：US14026671
申请日：2013-09-13
发明人： Richard D. DiMarchi , Tao Ma
IPC分类号： A61K38/26 , A61K38/00 , C07K14/605
CPC分类号： C07K14/605 , A61K38/26 , A61K2300/00
摘要： Provided herein are peptide combinations comprising a GIP agonist peptide and a glucagon antagonist peptide. In some embodiments, the peptide combination is provided as a composition, e.g., a pharmaceutical composition, while in other embodiments, the peptide combination is provided as a kit. In yet other embodiments, the peptide combination is provided as a conjugate, e.g., a fusion peptide, a heterodimer. In specific aspects, the GIP agonist peptide is an analog of native human glucagon. In specific aspects, the glucagon antagonist peptide is an analog of native human glucagon. In some embodiments, the GIP agonist peptide is covalently attached to the glucagon antagonist peptide via a linker. Method of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the peptide compositions described herein are further provided.
摘要翻译： 本文提供了包含GIP激动剂肽和胰高血糖素拮抗肽的肽组合。 在一些实施方案中，肽组合作为组合物例如药物组合物提供，而在其它实施方案中，肽组合作为试剂盒提供。 在其它实施方案中，肽组合作为缀合物提供，例如融合肽，异二聚体。 在具体方面，GIP激动剂肽是天然人胰高血糖素的类似物。 在具体方面，胰高血糖素拮抗剂肽是天然人胰高血糖素的类似物。 在一些实施方案中，GIP激动剂肽通过接头共价连接到胰高血糖素拮抗剂肽。 进一步提供治疗疾病例如代谢紊乱（例如糖尿病和肥胖症）的方法，其包括施用本文所述的肽组合物。
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公开(公告)号：US09447162B2
公开(公告)日：2016-09-20
申请号：US14535853
申请日：2014-11-07
发明人： Jonathan Day , James Patterson , Joseph Chabenne , Maria DiMarchi , David L. Smiley , Richard D. DiMarchi
IPC分类号： C07K14/605 , A61K38/26 , A61K47/48 , A61K38/00 , C07K16/00
CPC分类号： C07K14/605 , A61K38/00 , A61K38/26 , A61K47/60 , C07K16/00 , C07K2317/52 , C07K2319/30
摘要： Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. Further modification of the glucagon peptides by forming lactam bridges or the substitution of the terminal carboxylic acid with an amide group produces peptides exhibiting glucagon/GLP-1 receptor co-agonist activity. The solubility and stability of these high potency glucagon analogs can be further improved by modification of the polypeptides by pegylation, substitution of carboxy terminal amino acids, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) and SEQ ID NO: 28 (KRNR).
摘要翻译： 公开了相对于天然胰高血糖素在胰高血糖素受体上具有增强的效力的改良的胰高血糖素肽。 通过形成内酰胺桥或用酰胺基取代末端羧酸对胰高血糖素肽进一步修饰产生显示胰高血糖素/ GLP-1受体共激动剂活性的肽。 这些高效胰高血糖素类似物的溶解度和稳定性可以通过聚乙二醇化，多肽羧基末端氨基酸的取代或加入选自SEQ ID NO：26（GPSSGAPPPS ），SEQ ID NO：27（KRNRNNIA）和SEQ ID NO：28（KRNR）。
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公开(公告)号：US10233225B2
公开(公告)日：2019-03-19
申请号：US15229942
申请日：2016-08-05
发明人： Richard D. DiMarchi , Yulia Azriel , Zachary Kaur , Jonathan Meyers , Todd Parody , Yan Zhao
摘要： Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.
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公开(公告)号：US09587005B2
公开(公告)日：2017-03-07
申请号：US14981187
申请日：2015-12-28
发明人： Richard D. DiMarchi , Brian P. Ward
IPC分类号： A61K38/00 , A61K38/26 , C07K14/605
CPC分类号： C07K14/605 , A61K38/00
摘要： Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.
摘要翻译： 本文提供了在GIP受体上表现出有效活性的胰高血糖素类似物，并且因此被预期用于治疗糖尿病和肥胖症。 在示例性实施方案中，本公开的胰高血糖素类似物在GIP受体下显示EC50，其在纳摩尔或皮摩尔范围内。
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公开(公告)号：US08900593B2
公开(公告)日：2014-12-02
申请号：US13737232
申请日：2013-01-09
发明人： Jonathan Day , James Patterson , Joseph Chabenne , Maria DiMarchi , David L. Smiley , Richard D. DiMarchi
IPC分类号： A61K38/26 , C07K14/605 , A61K38/00
CPC分类号： C07K14/605 , A61K38/00 , A61K38/26 , A61K47/60 , C07K16/00 , C07K2317/52 , C07K2319/30
摘要： Modified glucagon peptides are disclosed having enhanced potency at the glucagon receptor relative to native glucagon. Further modification of the glucagon peptides by forming lactam bridges or the substitution of the terminal carboxylic acid with an amide group produces peptides exhibiting glucagon/GLP-1 receptor co-agonist activity. The solubility and stability of these high potency glucagon analogs can be further improved by modification of the polypeptides by pegylation, substitution of carboxy terminal amino acids, or the addition of a carboxy terminal peptide selected from the group consisting of SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) and SEQ ID NO: 28 (KRNR).
摘要翻译： 公开了相对于天然胰高血糖素在胰高血糖素受体上具有增强的效力的改良的胰高血糖素肽。 通过形成内酰胺桥或用酰胺基取代末端羧酸对胰高血糖素肽进一步修饰产生显示胰高血糖素/ GLP-1受体共激动剂活性的肽。 这些高效胰高血糖素类似物的溶解度和稳定性可以通过聚乙二醇化，多肽羧基末端氨基酸的取代或加入选自SEQ ID NO：26（GPSSGAPPPS ），SEQ ID NO：27（KRNRNNIA）和SEQ ID NO：28（KRNR）。
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公开(公告)号：US10696726B2
公开(公告)日：2020-06-30
申请号：US15846485
申请日：2017-12-19
发明人： Richard D. DiMarchi , Todd Parody , Jie Han , Pengyun Li
IPC分类号： A61K38/28 , C07K14/62 , C07K14/605
摘要： Disclosed herein are insulin agonist peptides conjugated to a glucagon analog wherein the insulin/glucagon conjugate is targeted to liver tissues upon administration to a patient.
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