Agonistic β-Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions

Area of Science:

• Metabolic signaling pathways
• Protein-protein interactions
• Antibody engineering

Background:

• Fibroblast Growth Factor 21 (FGF21) is a key regulator of metabolic homeostasis and a therapeutic target for metabolic diseases.
• FGF21 exerts its effects via a receptor complex involving FGF receptor (FGFR) and the co-receptor β-Klotho.

Purpose of the Study:

• To identify and characterize a novel agonistic antibody, 39F7, targeting β-Klotho.
• To elucidate the mechanism by which 39F7 mimics FGF21 function and activates the FGF21 signaling pathway.
• To assess the therapeutic potential of 39F7 for metabolic diseases.

Main Methods:

• Biochemical and structural characterization of the 39F7 antibody and its interaction with β-Klotho.
• Co-crystal structure determination of the β-Klotho KL1 domain with 39F7 Fab.
• In vitro assays to assess receptor activation and antibody bivalency requirements.
• Negative stain electron microscopy (EM) for full-length β-Klotho analysis.

Main Results:

• 39F7 is a high-affinity agonistic monoclonal antibody against β-Klotho that mimics FGF21 activity.
• The co-crystal structure reveals 39F7 binds to β-Klotho independently of FGF21 binding site, centered on Trp-295.
• 39F7 specifically activates the β-Klotho/FGFR1c complex in a bivalent-dependent manner, suggesting it promotes receptor dimerization.
• A molecular model proposes 39F7 mimics FGF21 by facilitating β-Klotho and FGFR1c interaction.

Conclusions:

• The antibody 39F7 effectively mimics FGF21 activity by promoting β-Klotho and FGFR1c dimerization.
• 39F7 represents a promising therapeutic strategy for metabolic diseases, offering an antibody-based alternative to FGF21 analogs.