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公开(公告)号：US10584156B2
公开(公告)日：2020-03-10
申请号：US15558030
申请日：2016-03-14
发明人： Michael Weiss
摘要： A two-chain insulin analogue contains an A chain modified by (i) a monomeric glucose-binding element at or near its N terminus and (ii) a B chain modified by at or near its C terminus by an element that reversibly binds to the monomeric glucose-binding element such that this linkage is displaceable by glucose. The monomeric glucose-binding element may be phenylboronic acid derivative (optionally halogenated). The B chain may be modified by a diol-containing element derived from a monosaccharide, disaccharide or oligosaccharide, a non-saccharide diol-containing moiety or a α-hydroxycarboxylate-containing moiety. The analogue can be manufactured by trypsin-mediated semi-synthesis. Formulations can be at strengths U-10 to U-1000 in soluble solutions at pH 7.0-8.0 with or without zinc ions at a molar ratio of 0.0-3.0 ions per insulin analogue monomer. A patient with diabetes mellitus may be treated with subcutaneous, intraperitoneal, or oral administration of a physiologically effective amount of the insulin analogue.
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公开(公告)号：US20150299287A1
公开(公告)日：2015-10-22
申请号：US14416022
申请日：2013-07-17
发明人： Michael Weiss
IPC分类号： C07K14/62
摘要： An insulin analogue comprises an insulin B-chain polypeptide modified with an O-linked monosaccaride pyranoside adduct at the side chain of residue B27 or an O-linked monosaccaride pyranoside adduct at the side chain of residue B30, or both, where the positions are recited relative to human insulin. The monosaccaride may be a manopyranoside, an N-acetyl-galactopyranoside, or a glucopyranoside. The insulin analogue may additionally comprise containing a foreshortened B-chain polypeptide lacking residues B1-B3, an extension of 1 or 2 Glu residues on the carboxy terminal end of the B-chain polypeptide, an extension of ornithine at the carboxy-terminal end of the B-chain, the substitutions Lys at position B28 and Pro at position B29, an ornithine substitution at position B29, or combinations thereof. The analogue may be an analogue of a mammalian insulin, such as human insulin. A method of treating a patient comprises administering a physiologically effective amount of the insulin analogue.
摘要翻译： 胰岛素类似物包含在残基B27的侧链上与O-连接的单糖吡喃糖苷加合物修饰的胰岛素B链多肽或残基B30的侧链的O-连接的单糖吡喃糖苷加合物或两者，其中所述的位置被列举 相对于人胰岛素。 单糖可以是芒果糖苷，N-乙酰基 - 吡喃半乳糖苷或吡喃葡萄糖苷。 胰岛素类似物还可以包含含有缺失B1-B3残基的缩短的B链多肽，在B链多肽的羧基末端延伸1或2个Glu残基，在羧基末端延伸鸟氨酸 B链，位置B28处的取代Lys和位置B29的Pro，位置B29的鸟氨酸取代，或其组合。 类似物可以是哺乳动物胰岛素的类似物，例如人胰岛素。 治疗患者的方法包括施用生理有效量的胰岛素类似物。
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公开(公告)号：US11583572B2
公开(公告)日：2023-02-21
申请号：US16065596
申请日：2016-12-23
发明人： Michael Weiss , Jonathan Pokorski
摘要： An insulin composition comprises an insulin analogue and polymer blend. The insulin analogue contains cysteine substitutions at positions B4 and A10 (to form cystine B4-A10), and one or more additional substitutions selected from the group consisting of: a connecting domain of 5-11 amino acids between insulin A- and B domains; a non-beta-branched amino-acid substitution at position A8; a non-beta-branched acidic or polar side chain at position A14; a halogenic modification of PheB24 at the ortho position; and substitution of lysine at position B29 by Glu, Ala, Val, Ile, Leu, amino-propionic acid, amino-butryic acid, or Norleucine. The insulin analogue is compatible with a process of manufacture that includes one or more steps within the temperature range 90-120° C. The encapsulated insulin analogue may optionally contain free PEG or be PEGylated. The insulin analogue-encapsulated polymer blend may be cast as a microneedle patch for topical administration or as micropellets for subcutaneous injection.
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公开(公告)号：US10472406B2
公开(公告)日：2019-11-12
申请号：US15545189
申请日：2016-01-20
发明人： Michael Weiss
摘要： A two-chain insulin analog contains Aspartic Acid at position B10 and penta-fluoro-Phenylalanine at position B24, optionally Histidine or Glutamic Acid at position A8, optionally additional substitutions or modifications at positions A13 and/or A14 and/or B28 and/or B29. The analog may be an analog of a mammalian insulin, such as human insulin, may optionally include (i) N-terminal deletion of one, two or three residues from the B chain, (ii) a mono-peptide or dipeptide C-terminal extension of the B-chain containing at least one acidic residue, and (iii) other modifications known in the art to enhance the stability of insulin. Formulations of the above analogs at successive strengths U-100 to U-1000 in soluble solutions at least pH value in the range 7.0-8.0 in the absence or presence of zinc ions at a molar ratio of 0.00-0.10 zinc ions per insulin analog monomer.
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公开(公告)号：US20180057559A1
公开(公告)日：2018-03-01
申请号：US15558030
申请日：2016-03-14
发明人： Michael Weiss
IPC分类号： C07K14/62
CPC分类号： C07K14/62 , A61K38/00 , C07K14/622 , C07K2319/20 , C07K2319/70 , Y02A50/473
摘要： A two-chain insulin analogue contains an A chain modified by (i) a monomeric glucose-binding element at or near its N terminus and (ii) a B chain modified by at or near its C terminus by an element that reversibly binds to the monomeric glucose-binding element such that this linkage is displaceable by glucose. The monomeric glucose-binding element may be phenylboronic acid derivative (optionally halogenated). The B chain may be modified by a diol-containing element derived from a monosaccharide, disaccharide or oligosaccharide, a non-saccharide diol-containing moiety or a α-hydroxycarboxylate-containing moiety. The analogue can be manufactured by trypsin-mediated semi-synthesis. Formulations can be at strengths U-10 to U-1000 in soluble solutions at pH 7.0-8.0 with or without zinc ions at a molar ratio of 0.0-3.0 ions per insulin analogue monomer. A patient with diabetes mellitus may be treated with subcutaneous, intraperitoneal, or oral administration of a physiologically effective amount of the insulin analogue.
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公开(公告)号：US20170137488A1
公开(公告)日：2017-05-18
申请号：US15358977
申请日：2016-11-22
发明人： Michael Weiss
IPC分类号： C07K14/62
摘要： A single-chain insulin analogue containing a basic side chain at position A8 (Arginine, Histidine, Lysine, or Ornithine), a basic side chain at position B29 (Arginine, Histidine, Lysine, or Ornithine), and a foreshortened C-domain of length 6-11 residues is provided. Residues C1 and C2 of the C-domain have a net negative charge of −1 or −2; C3 is chosen from a group consisting of Gly, Ala, Pro, or Ser; and the remaining C-domain segment is successively derived from the C-domain of IGF-II (RRSR, SRRSR, VSRRSR, RVSRRSR, or SRVSRRSR; SEQ ID NO: 13). A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient.
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公开(公告)号：US09499600B2
公开(公告)日：2016-11-22
申请号：US14440540
申请日：2013-11-05
发明人： Michael Weiss
摘要： A single-chain insulin analog containing a basic side chain at position A8 (Arginine, Histidine, Lysine, or Ornithine), a basic side chain at position B29 (Arginine, Histidine, Lysine, or Ornithine), and a foreshortened C-domain of length 6-11 residues is provided. Residues C1 and C2 of the C-domain have a net negative charge of −1 or −2; C3 is chosen from a group consisting of Gly, Ala, Pro, or Ser; and the remaining C-domain segment is successively derived from the C-domain of IGF-II (RRSR (SEQ ID NO: 18), SRRSR (SEQ ID NO: 17), VSRRSR (SEQ ID NO: 16), RVSRRSR (SEQ ID NO: 15), or SRVSRRSR SEQ ID NO: 13). A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analog or a physiologically acceptable salt thereof to a patient.
摘要翻译： 位置A8（精氨酸，组氨酸，赖氨酸或鸟氨酸）的碱性侧链，位置B29的碱性侧链（精氨酸，组氨酸，赖氨酸或鸟氨酸）的单链胰岛素类似物和缩短的C结构域 提供长度为6-11的残留物。 C域的残基C1和C2具有-1或-2的净负电荷; C3选自Gly，Ala，Pro或Ser组成的组; （RRSR（SEQ ID NO：18），SRRSR（SEQ ID NO：17），VSRRSR（SEQ ID NO：16），RVSRRSR（SEQ ID NO：16））的C-结构域 SEQ ID NO：15）或SRVSRRSR SEQ ID NO：13）。 治疗患有糖尿病或肥胖的患者的方法包括向患者施用生理有效量的胰岛素类似物或其生理上可接受的盐。
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8.发明授权公开(公告)号：US09200053B2
公开(公告)日：2015-12-01
申请号：US14046620
申请日：2013-10-04
发明人： Michael Weiss
摘要： An insulin analog comprises a B-chain polypeptide incorporating a halogenated phenylalanine at position B24, B25 or B26. The halogenated phenylalanine may be ortho-monofluoro-phenylalanine, ortho-monobromo-phenylalanine, ortho-monochloro-phenylalanine, or para-monochloro-phenylalanine or penta-fluoro-Phenylalanine at position B24 alone or in combination with an acidic substitution (Aspartic Acid or Glutamic Acid) at position B10. The analog may be of a mammalian insulin, such as human insulin. A nucleic acid encodes such an insulin analog. The halogenated insulin analogs retain significant activity. A method of treating a patient comprises administering a physiologically effective amount of the insulin analog or a physiologically acceptable salt thereof to a patient. Halogen substitution-based stabilization of insulin may enhance the treatment of diabetes mellitus in regions of the developing world lacking refrigeration.
摘要翻译： 胰岛素类似物包含在B24，B25或B26位置掺入卤代苯丙氨酸的B链多肽。 卤代苯丙氨酸可以单独或与酸性取代（天冬氨酸或天冬氨酸）组合使用位置B24的邻位一氟 - 苯丙氨酸，邻位一溴 - 苯丙氨酸，邻 - 一氯 - 苯丙氨酸或对 - 一氯 - 苯丙氨酸或五氟 - 苯丙氨酸 位置B10处的谷氨酸）。 类似物可以是哺乳动物胰岛素，例如人胰岛素。 核酸编码这样的胰岛素类似物。 卤化胰岛素类似物保留显着的活性。 治疗患者的方法包括向患者施用生理有效量的胰岛素类似物或其生理上可接受的盐。 基于卤素替代的胰岛素稳定可以增强在缺乏制冷的发展中国家地区的糖尿病治疗。
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公开(公告)号：US20150274803A1
公开(公告)日：2015-10-01
申请号：US14440540
申请日：2013-11-05
发明人： Michael Weiss
IPC分类号： C07K14/62
摘要： A single-chain insulin analogue containing a basic side chain at position A8 (Arginine, Histidine, Lysine, or Ornithine), a basic side chain at position B29 (Arginine, Histidine, Lysine, or Ornithine), and a foreshortened C-domain of length 6-11 residues is provided. Residues C1 and C2 of the C-domain have a net negative charge of −1 or −2; C3 is chosen from a group consisting of Gly, Ala, Pro, or Ser; and the remaining C-domain segment is successively derived from the C-domain of IGF-II (RRSR, SRRSR, VSRRSR, RVSRRSR, or SRVSRRSR; SEQ ID NO: 13). A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient.
摘要翻译： 含有位置A8的碱性侧链（精氨酸，组氨酸，赖氨酸或鸟氨酸），位置B29的碱性侧链（精氨酸，组氨酸，赖氨酸或鸟氨酸）的单链胰岛素类似物和缩短的C结构域 提供长度为6-11的残留物。 C域的残基C1和C2具有-1或-2的净负电荷; C3选自Gly，Ala，Pro或Ser组成的组; 并且其余C-结构域片段依次从IGF-II（RRSR，SRRSR，VSRRSR，RVSRRSR或SRVSRRSR; SEQ ID NO：13）的C-结构域得到。 治疗患有糖尿病或肥胖的患者的方法包括向患者施用生理有效量的胰岛素类似物或其生理上可接受的盐。
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公开(公告)号：US10822386B2
公开(公告)日：2020-11-03
申请号：US15539450
申请日：2015-12-24
发明人： Michael Weiss
摘要： A polypeptide comprises an insulin B-chain sequence having the substitutions: Asp at position B10, Ala at position B12, and Glu at position B29, relative to wild type insulin. The polypeptide may additionally comprise a substitution of a halogenated phenylalanine at position B24, such as ortho-fluoro-phenylalanine. Optionally, the polypeptide may additionally comprise a C-terminal dipeptide extension wherein at least one amino acid in the dipeptide contains an acidic side chain, such as Glu-Glu, and/or an N-terminal deletion of one, two or three residues from the B chain. An insulin analogue may comprise any of these polypeptides with an insulin A-chain polypeptide that optionally contains a Glu A8 substitution. The A-chain sequence may be a separate polypeptide or it may be joined to the B-chain polypeptide by a two amino acid linker. The linker may be Trp-Lys or Ala-Lys. The insulin analogue may be used to treat a patient with diabetes mellitus.
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