Mutant FGF21 Polypeptides for β-Klotho Binding Modulation

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Solution Overview

Problem

There is a need to modulate the activity of FGF receptors and the signaling pathways activated by endocrine FGFs, such as FGF19 and FGF21, to treat or prevent diseases associated with these factors, particularly metabolic diseases and cancer, as existing methods are inadequate.

Innovation Solution

Development of a non-natural soluble construct that prevents or minimizes the binding of FGF receptors, FGF19, and FGF21 to β-Klotho, using antibodies, recombinant proteins, or small molecules that recognize specific amino acid residues to interfere with their interaction, thereby modulating their activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing methods are used to modulate FGF receptor activity, then treatment of metabolic diseases and cancer is attempted, but the methods are inadequate and fail to effectively prevent or treat these diseases

Engineering Contradiction:

Improveeffectiveness of disease treatmentVSAvoidadequacy of existing methods

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the amino acid sequence of FGF21 to create mutant variants with altered properties. Specifically, mutations are introduced to enhance binding affinity to β-Klotho receptor while maintaining or improving metabolic activity, thereby creating more effective therapeutic agents for diabetes and obesity treatment

Inventive Principle:

Principle #35Parameter changes

2Productivity

If FGF21 is used to treat metabolic diseases, then beneficial effects on insulin sensitivity and energy expenditure are achieved, but the need for more effective modulation methods arises due to limitations of existing approaches

Engineering Contradiction:

Improvemetabolic benefit efficiencyVSAvoidadequacy of current treatment approaches

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent creates FGF21 mutant polypeptides with modified amino acid sequences designed to improve metabolic activity and binding characteristics. These mutants are engineered to have enhanced ability to stimulate insulin sensitivity, energy expenditure, and weight loss compared to native FGF21

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent combines FGF21 mutant polypeptides with albumin or Fc regions to create fusion proteins. This composite structure extends circulating half-life and improves pharmacokinetic properties, making the therapeutic more effective and longer-lasting for treating metabolic diseases

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS12534503B2Mutant fibroblast growth factor 21 (FGF21) polypeptides

Publication Date: 2026.01.27 YALE UNIVERSITY

AI summary

Described herein soluble polypeptide comprising a FGF21 variant. The FGF21 variant comprises amino acid residues 29-209 of SEQ ID NO: 3, except that two or more amino acid residues in 29-209 of SEQ ID NO: 3 are mutated with respect to SEQ ID NO:3. The FGF21 variant comprises at least mutations L194F and R203W with respect to SEQ ID NO:3. Also described is a method of treating or ameliorating an endocrine FGF-related disease or disorder using the soluble polypeptide.