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公开(公告)号：US20220112262A1
公开(公告)日：2022-04-14
申请号：US17562435
申请日：2021-12-27
发明人： Michael A. WEISS
摘要： A two-chain insulin analogue contains a modified A-chain polypeptide and a modified B-chain polypeptide. The A-chain polypeptide comprises one or more of: a His or Glu substitution at position A8, a Glu substitution at position A14; and a Gln or Arg substitution at position A17. The B-chain polypeptide comprises one or more of: a deletion of the amino acids at position B1, B1-B2, B1-B3, B30 or a combination thereof; an Ala or Glu substitution at position B2; a Glu substitution at position B3. The analogue exhibits thermodynamic stability in a zinc-free solution, decreased self-association, maintains biological potency, and no increased mitogenicity. The analogue exhibits resistance to chemical degradation and physical degradation. 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：US20210371489A1
公开(公告)日：2021-12-02
申请号：US17277979
申请日：2019-09-23
发明人： Michael A. WEISS
IPC分类号： C07K14/62
摘要： A single-chain insulin analogues may comprise an insulin B-chain polypeptide sequence connected by a connecting polypeptide (or C-domain) sequence to an insulin A-chain polypeptide sequence. The connecting polypeptide sequence may be Glu-Xaa-Gly-Pro-Arg-Arg where Xaa is Glu or Ala. The insulin analogues may additionally comprise Glu or His substitutions at the position corresponding to A8 of human insulin and/or a Glu substitution at the position corresponding to A14 of human insulin. In some embodiments, the insulin analogues may additionally comprise either a Pro or Glu at the positions corresponding to B28 and B29 of wild-type insulin. Additional substitutions may comprise Phe or Trp at the position corresponding to A13 of wild type insulin and/or Gln, Arg, Phe, or Glu at the position corresponding to A17 of wild type insulin. In some embodiments, a Glu substitution at the position corresponding to B16 of wild type insulin may be present. In other embodiments, a Cys substitution may be present at the positions corresponding to A10 and/or B4 of wild-type insulin. In addition or in the alternative, the analogue may comprise a His or Ala substitution at the position corresponding to B22 of wild-type insulin and/or the connecting polypeptide sequence may be Glu-Glu-Gly-Pro-Ala-His. A method of treating a patient with diabetes mellitus comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient by means of intravenous, intraperitoneal, or subcutaneous injection.
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公开(公告)号：US20200055914A1
公开(公告)日：2020-02-20
申请号：US16425906
申请日：2019-05-29
发明人： Michael A. WEISS , Nelson PHILLIPS , Nischay REGE
IPC分类号： C07K14/62
摘要： An insulin analogue comprises an insulin B-chain polypeptide containing a Trp substitution at position B26 relative to the sequence of wild-type insulin. The insulin analogue may additionally comprise an OrnB29 substitution, a C-terminal extension of one or two basic amino acids such as Arg-Arg, a GlnB13 substitution, a GlyA21 substitution, a HisA8 or ArgA8 substitution, or a combination thereof. The insulin analogue may be formulated in the presence of zinc ions at a molar ratio of 2.2-10 zinc ions per six insulin analogue monomers. The molecular design is believed to stabilize the dimer interface of insulin (and its stable formulation as a zinc insulin hexamer) by means of aromatic amino-acid substitutions at position B26 of the B chain. The insulin analogs of the present invention may have two chains (A and B) as in mammalian insulins or may be engineered with a C domain (4-12 amino acids in length) to provide a single-chain. The TrpB26-stabilized zinc insulin hexamers complement and extend other molecular strategies to achieve protracted action on subcutaneous injection.
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公开(公告)号：US20190144520A1
公开(公告)日：2019-05-16
申请号：US16198815
申请日：2018-11-22
发明人： Michael A. WEISS
IPC分类号： C07K14/62
摘要： An insulin analogue comprises a B-chain polypeptide containing a cyclohexanylalanine substitution at position B24 and optionally containing additional amino-acid substitutions at positions A8, B28, and/or B29. A proinsulin analogue or single-chain insulin analogue contains a B domain containing a cyclohexanylalanine substitution at position B24 and optionally contains additional amino-acid substitutions at positions A8, B28, and/or B29. The analogue may be an analogue of a mammalian insulin, such as human insulin. A nucleic acid encoding such an insulin analogue is also provided. A method of lowering the blood sugar of a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient. A method of semi-synthesis using an unprotected octapeptide by means of modification of an endogenous tryptic site by non-standard amino-acid substitutions.
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公开(公告)号：US20230088546A1
公开(公告)日：2023-03-23
申请号：US17909054
申请日：2021-03-02
IPC分类号： A61K38/28 , A61K31/5578 , A61K31/194 , A61K31/198 , A61K33/42 , A61P3/10
摘要： A pharmaceutical composition comprises an effective amount of an insulin analogue comprising modified A-chain and B-chain polypeptides. The modified A chain comprises one or more substitutions relative to wild-type human insulin A-chain selected from a Gln, His or Glu substitution at position A8, a Glu or Ala substitution at position A14, and an Ala, Gln, Gly, or Thr substitution at position A21. The modified B-chain polypeptide comprises one or more modifications relative to wild-type human insulin B-chain selected from a deletion of the amino acid or amino acids at position B1, B1 and B2, or B1-B3, an Ala or Glu substitution at position B2, a Glu or Ala substitution at position B3, an Ala substitution at position B4; and a Glu or Lys substitution at position B29. The composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound. The composition may be used to treat diabetes.
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公开(公告)号：US20220235111A1
公开(公告)日：2022-07-28
申请号：US17612047
申请日：2020-05-18
摘要： A single-chain insulin analogue containing (i) diverse amino-acid substitutions at position A14; (ii) wild-type or variant residues at positions A8 and A14; and (ii) an engineered C-domain segment of lengths 4-6 containing a specific set of Alanine substitutions and/or deletions derived from the prototype C-domain sequence Glu-Glu-Gly-Pro-Arg-Arg. The analogue may otherwise be an analogue of a mammalian insulin, such as human insulin, may optionally include standard or non-standard modifications that (i) augment the stability of insulin, (ii) cause a shift in the isoelectric point to enhance or impair the solubility of the protein at neutral pH or (iii) reduce cross-binding of the protein to the Type I IGF receptor. Formulations of the above analogues at successive strengths U-100 to U-1000 in soluble solutions under acidic or neutral pH values (e.g., pH 3.0-4.2 and 6.5-7.8, respectively) and optionally in the presence of zinc ions at a molar ratio of 2.2-10 zinc ions per six insulin analogue monomers. A method of treating a patient with diabetes mellitus comprising the administration of a physiologically effective amount of the protein or a physiologically acceptable salt thereof to a patient. Use of a single-chain insulin analogue of the present invention in an insulin delivery device (such as a pump or pen) is envisioned.
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公开(公告)号：US20190375813A1
公开(公告)日：2019-12-12
申请号：US16521969
申请日：2019-07-25
发明人： Michael A. WEISS
IPC分类号： C07K14/62
摘要： A two-chain insulin analogue 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 analogue may be an analogue 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 analogues at successive strengths U-100 to U-1000 in soluble solutions at 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 analogue monomer.
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公开(公告)号：US20240043493A1
公开(公告)日：2024-02-08
申请号：US18265616
申请日：2021-12-07
摘要： A single-chain insulin analogue comprises the insulin B-chain polypeptide sequence, the insulin A-chain polypeptide sequence, and a connecting polypeptide sequence of 5-11 amino acids linking the C-terminal amino acid of the B-chain polypeptide to the N-terminal amino acid of the A-chain polypeptide. The analogue comprises an acetylated Lys at a location selected from the group consisting of any of the amino acids in the connecting polypeptide, B0-B3, B28-B29 or A14, relative to wild type insulin, or comprises an acetylated amino acid at the N-terminal amino acid of the single-chain insulin analogue. The single-chain insulin analogue may be acylated with a C6-C21 fatty acid, which may be attached to the e-amino group of a unique Lysine residue or the a-amino group of the N-terminal amino acid of the single-chain insulin analogue. The insulin analogue may be used to lower the blood sugar of a patient in need thereof.
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公开(公告)号：US20220280614A1
公开(公告)日：2022-09-08
申请号：US17632193
申请日：2020-08-03
摘要： A premixed acidic solution contains two single-chain insulin analogues. One has isoelectric point between 6.5 and 8.0 (SCI-A) and the other has isoelectric point between 4.5 and 6.0 (SCI-B), such that biphasic basal and prandial insulin activity is provided on subcutaneous injection. Each protein is an analogue of a mammalian insulin, such as human insulin, with insertion of engineered C domain of length 5-11 residues; the respective C domains of SCI-A and SCI-B may be different. SCI-A contains a Glycine, Alanine, Serine or Glutamine substitution at position A21 and may contain a basic residue at position A8 and Glutamine at position B13. SCI-B may contain a non-beta-branched substitution at position A8, either Alanine or Glutamic Acid at position A14, and substitutions at positions B28 and/or B29 to confer rapid action. A method of treating a patient comprises administering the insulin analogue or a physiologically acceptable salt thereof to a patient.
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公开(公告)号：US20220002373A1
公开(公告)日：2022-01-06
申请号：US17294948
申请日：2019-11-19
发明人： Michael A. WEISS
IPC分类号： C07K14/62
摘要： A single-chain insulin analogue containing an engineered C-domain segment of lengths 4-11 conforming to the sequence pattern [Asp/Glu]-Ala-An-Ala-Xaa where An designates a sub-segment of 0-7 Alanine residues and where Xaa designates an amino-acid residue selected from the amino acids Alanine, Arginine, Asparagine, Aspartic Acid, Glutamic Acid, Histine, Lysine and Serine. The analogue may be an analogue of a mammalian insulin, such as human insulin, may optionally include standard or non-standard modifications that (i) augment the stability of insulin, (ii) cause a shift in the isoelectric point to enhance or impair the solubilty of the protein at neutral pH or (iii) reduce cross-binding of the protein to the Type I IGF receptor. A method of treating a patient with diabetes mellitus comprising the administration of a physiologically effective amount of the protein or a physiologically acceptable salt thereof to a patient.
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