IGF-1 Polypeptide Mutations for Yield and Hypoglycemia Control
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Solution Overview
Problem
Existing IGF-1 precursor variants fused to a human immunoglobulin Fc region face challenges such as low production yield in mammalian systems and increased binding affinity to the insulin receptor, leading to hypoglycemia as a therapeutic concern.
Innovation Solution
Modifying the human IGF-1 protein by deleting or substituting the amino acid glycine at position 42, combined with additional mutations at specific amino acids, to improve production yield and receptor specificity, and incorporating a peptide hinge region between the IGF-1 precursor and Fc region to modulate binding to Fc receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If IGF-1 precursor variants are fused to a human immunoglobulin Fc region to increase half-life, then serum half-life is improved, but production yield in mammalian systems decreases
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the IGF-1 precursor sequence (positions 1-3 and 71-77) to optimize both production yield and serum half-life. These sequence modifications enable the fusion protein to be produced efficiently in mammalian systems while maintaining extended circulation half-life through Fc region fusion.
Solution Approach 2:
The patent creates a composite fusion protein combining the IGF-1 precursor sequence with a human immunoglobulin Fc region. This composite structure leverages the biological activity of IGF-1 while utilizing the Fc region's long half-life properties, achieving both improved pharmacokinetics and manufacturability through optimized sequence design.
2Duration of action of stationary object
If IGF-1 precursor variants are fused to a human immunoglobulin Fc region to increase half-life, then serum half-life is improved, but binding affinity to insulin receptor increases leading to hypoglycemia
Solution Approach 1:
The patent modifies specific parameters of the IGF-1 precursor sequence (amino acid positions 1-3 and 71-77) to fine-tune insulin receptor binding affinity. These targeted sequence changes reduce excessive binding that would cause hypoglycemia while preserving the desired extended half-life through Fc fusion, achieving a balanced pharmacological profile.
Solution Approach 2:
The patent applies local quality changes by making site-specific amino acid modifications at particular positions (1-3 and 71-77) within the precursor sequence. These localized changes selectively modulate insulin receptor interaction without affecting other functional properties, enabling precise control over binding affinity and hypoglycemia risk.
3Productivity
If additional mutations are introduced to improve production yield and reduce degradation, then manufacturing efficiency is improved, but protein structure complexity increases
Solution Approach 1:
The patent systematically modifies specific amino acid parameters at defined positions (1-3 and 71-77) to enhance production yield and reduce degradation. These targeted parameter changes improve manufacturing efficiency while maintaining relatively simple sequence modifications that do not substantially increase structural complexity.
Data Source
Figure 1
Figure 2A~2C
Figure 2D
AI summary
This invention is in the field of IGF-1 modifications. In particular, it relates to modified IGF- polypeptides and modified IGF-1 precursor polypeptides wherein the cleavage of E-peptide is prevented. The invention also relates to the use of such polypeptides for treating muscle diseases and disorders.