FGF21 Variants Amino Acid Substitutions Stability
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Solution Overview
Problem
Human wild type FGF21 and existing variants suffer from low pharmacological potency and pharmaceutical stability, including susceptibility to proteolytic degradation, oxidation, aggregation, and post-translational modifications, which limits their effectiveness in treating type 2 diabetes, obesity, dyslipidemia, and metabolic syndrome.
Innovation Solution
Development of FGF21 variants with specific amino acid substitutions such as D127K, S167R, G174L, R175L, A180L, A31C, G43C, L98D, Y179F, and G170E that enhance pharmacological potency, stability, and compatibility with preservatives, reducing proteolytic degradation and aggregation, while maintaining biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If human wild type FGF21 is used, then biological activity is maintained, but pharmacological potency and pharmaceutical stability are low
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid substitutions at defined positions (e.g., A31C, G43C, L98D, Y179F, G170E) to modify the protein's physicochemical properties. These substitutions alter the protein's stability, potency, and resistance to degradation, transforming wild type FGF21 into engineered variants with improved therapeutic characteristics while maintaining biological activity.
Solution Approach 2:
The patent creates composite protein structures by combining multiple amino acid substitutions into a single FGF21 variant sequence. Each substitution contributes specific functional improvements, and their combination produces a synergistic effect that simultaneously enhances pharmacological potency, stability, and resistance to proteolytic degradation, achieving a comprehensive improvement over wild type.
2Stability of the object's composition
If FGF21 variants are engineered to improve stability, then pharmaceutical stability increases, but manufacturing complexity increases
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions at specific positions in the protein sequence rather than redesigning the entire protein. Each substitution is localized to a specific region where it provides specific functional improvement (e.g., A31C and G43C for stability, L98D for aggregation resistance, Y179F for reduced immunogenicity). This localized approach maintains overall protein structure while improving specific properties, simplifying manufacturing compared to complete protein redesign.
3Reliability
If FGF21 is administered at high concentrations to improve efficacy, then therapeutic effect increases, but aggregation increases
Solution Approach 1:
The patent applies preliminary anti-action by introducing the L98D amino acid substitution, which preemptively prevents aggregation before it occurs. The Asp98 residue creates electrostatic repulsion or steric hindrance that counteracts the tendency of FGF21 molecules to aggregate at high concentrations. This preliminary protective measure allows the protein to be administered at therapeutic concentrations without suffering from aggregation-related loss of efficacy or increased immunogenicity.
Data Source
AI summary
This present invention relates to pharmacologically potent and/or stable variants of human fibroblast growth factor 21 (FGF21), pharmaceutical compositions comprising FGF21 variants, and methods for treating type 2 diabetes, obesity, dyslipidemia, or metabolic syndrome, or any combination thereof, using such variants.