FGF23 Fusion Polypeptides Reducing Aggregation and Cleavage
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Solution Overview
Problem
Current treatments for age-related conditions and metabolic disorders often require separate administration of Klotho and fibroblast growth factors, which may not effectively activate FGF receptors due to potential interference or misorientation, limiting their therapeutic efficacy.
Innovation Solution
Development of fusion polypeptides combining a Klotho protein or its active fragment with a fibroblast growth factor, such as FGF23, and a modified Fc fragment, which are operatively linked to enhance serum half-life and reduce aggregation, allowing for effective activation of FGF receptors when administered as a single therapeutic entity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If separate Klotho and FGF polypeptides are administered, then the therapeutic composition is simpler to manufacture, but the activation of FGF receptors is insufficient due to potential interference or misorientation
Solution Approach 1:
The patent combines separate Klotho and FGF polypeptides into a single fusion polypeptide where the Klotho extracellular domain is fused to the FGF polypeptide. This merging ensures proper spatial orientation and proximity of both components for effective FGF receptor activation, resolving the insufficiency of separate administration while maintaining manufacturing simplicity through a single recombinant expression system.
2Reliability
If wild-type FGF23 is used in fusion polypeptides, then the polypeptide structure is simpler, but aggregation and protease-mediated cleavage occur frequently reducing therapeutic efficacy
Solution Approach 1:
The patent applies local quality changes by introducing specific amino acid substitutions at particular positions within the FGF23 sequence (e.g., hydrophobic to hydrophilic substitutions at aggregation-prone regions). These localized modifications reduce aggregation and protease susceptibility without altering the overall fusion polypeptide structure or requiring complex multi-component systems, thereby improving therapeutic efficacy while maintaining structural simplicity.
3Reliability
If FGF23 mutations are introduced to reduce aggregation, then therapeutic efficacy is improved, but the manufacturing process becomes more complex
Solution Approach 1:
The patent employs parameter changes by systematically modifying amino acid substitution patterns, glycosylation sites, and linker lengths to optimize protein stability and reduce aggregation. These controlled parameter adjustments are implemented through standardized molecular cloning protocols and expressed in established mammalian cell lines, achieving improved therapeutic efficacy without significantly complicating the manufacturing process.
Data Source
AI summary
The present disclosure is directed to methods, kits and compositions for preventing or treating age-related conditions or metabolic disorders. The fusion polypeptides of the disclosure include FGF23 or an active fragment thereof. In one embodiment, the fusion polypeptide comprises (a) a polypeptide comprising fibroblast growth factor 23 (FGF23), or a functionally active variant or derivative thereof, wherein FGF23 has a mutation at one or more of the positions Q156, C206 and C244; and (b) either a modified Fe fragment having decreased affinity for Fc-gamma-receptor and/or increased serum half-life, or a polypeptide comprising at least one extracellular subdomain of a Klotho protein, or a functionally active variant or derivative thereof; and, optionally (c) a linker. In another embodiment, the fusion polypeptide comprises a FGF (such as FGF23), or a functionally active variant or derivative thereof; and a modified Fe fragment, or a functionally active variant or derivative thereof. In various embodiments of the fusion polypeptides, FGF23 has mutations which decrease aggregation and protease-mediated cleavage.