Rapid-acting insulin analogues of enhanced stability
Inventors
Assignees
Case Western Reserve University
Publication Number
US-12312390-B2
Publication Date
2025-05-27
Expiration Date
2037-11-21
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Abstract
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.
Core Innovation
The invention concerns insulin analogues comprising a modified A-chain polypeptide and a modified B-chain polypeptide, in which specific substitutions and deletions are introduced to enhance thermodynamic stability, reduce self-association, and enable zinc-free pharmaceutical formulations. The A-chain polypeptide includes a Glu substitution at position A8 and a Glu substitution at position A14, with optional substitutions at A17 (such as Gln, Ala, His, Leu, Phe, Tyr, or Arg) and A21 (Ala, Gly, or Glu). The B-chain polypeptide may include modifications such as deletion of B30 or a Glu substitution at B29. These modifications collectively enable the insulin analogue to maintain rapid pharmacological action even at high protein concentrations and in the absence of zinc ions.
The problem addressed is that existing rapid-acting insulin analogues show delayed absorption and impaired efficacy when formulated at high strengths (U-200 and above), primarily due to self-association mediated by zinc ions and the molecular structure of wild-type insulin. These drawbacks hamper glycemic control, particularly in subcutaneous injection and pump-based infusion, and can prolong pharmacokinetic and pharmacodynamic profiles, which is undesirable for optimal diabetes management.
This innovation provides insulin analogues that avoid the use of AspB10 (which is associated with increased mitogenicity and cancer risk) and unnatural amino acids, instead employing carefully selected natural amino acid substitutions and chain modifications. The resulting analogues resist chemical and physical degradation, have biological activity of at least 20% that of wild-type insulin, exhibit no increased mitogenicity, and can be formulated over a wide concentration range in zinc-free solutions. This enables the development of stable, rapid-acting insulin products suitable for high-strength formulations and broader excipient compatibility, especially beneficial for advanced delivery methods like insulin pumps.
Claims Coverage
There are two independent claims in this patent: one to the insulin analogue itself, and one to a method of lowering blood sugar using the insulin analogue.
Insulin analogue with modified A-chain and B-chain sequences
An insulin analogue comprising: - A modified A-chain polypeptide having the amino acid sequence of SEQ ID NO: 2 with a Glu substitution at position A8 and a Glu substitution at position A14 relative to SEQ ID NO: 2. - The modified A-chain further includes at least one substitution selected from: - A substitution at position A17 chosen from Gln, Ala, His, Leu, Phe, Tyr, or Arg. - A substitution at position A21 chosen from Ala, Gly, or Glu. - A modified B-chain polypeptide, which in dependent claims may comprise a deletion at B30 or a Glu substitution at B29. - The amino acid substitutions provide enhanced thermodynamic stability, enable zinc-free formulation, and preserve at least 20% biological potency.
Method of lowering blood sugar with the insulin analogue
A method of lowering blood sugar in a patient by administering a physiologically effective amount of an insulin analogue or its physiologically acceptable salt, wherein: - The insulin analogue comprises a modified A-chain polypeptide (as described above, with Glu substitutions at A8 and A14, and possible substitutions at A17 and/or A21). - The B-chain may optionally include a deletion at B30 or a Glu substitution at B29. - This method results in effective blood glucose control in patients.
The claims provide coverage for both the structure of the novel insulin analogues (with defined A and B chain modifications) and their therapeutic use in lowering blood sugar.
Stated Advantages
Enhanced thermodynamic stability of the insulin analogue in a zinc-free solution, enabling high-concentration formulations.
Decreased self-association at higher protein concentrations, which allows for rapid pharmacological action even at strengths up to U-1000.
Analogues maintain at least 20% of the biological potency of wild-type insulin on a nanomolar basis.
No increased mitogenicity compared to existing rapid-acting analogues, with potential for reduced mitogenicity.
Resistance to chemical and physical degradation enhances the pharmaceutical stability and shelf-life of the formulations.
Permits stable formulation in the absence of zinc ions, enabling broader compatibility with a range of excipients and facilitating rapid absorption.
Excludes AspB10 and unnatural amino acids, avoiding increased cancer risk and manufacturing complexity.
Particularly benefits patients using continuous subcutaneous infusion via insulin pumps and supports potential miniaturization of pump devices.
Documented Applications
Treatment of diabetes mellitus by administration of the insulin analogue via subcutaneous injection, syringe, or pen device.
Use in high-concentration (U-200 to U-1000) insulin formulations designed for patients with marked insulin resistance.
Application in continuous subcutaneous insulin infusion pumps and compatibility with closed-loop systems.
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