β-Klotho (KLB)

Class

recombinant fully human monoclonal antibody (anti-β-Klotho agonist)

Pathway

Agonizes the β-Klotho/FGFR1c co-receptor complex (the FGF21 receptor pathway) to lower triglyceride levels in hypertriglyceridemia

β-Klotho is a single-pass membrane protein that functions as an obligate co-receptor, pairing with fibroblast growth factor receptor 1c (FGFR1c) to form the receptor complex for the metabolic hormone FGF21. FGF21 is produced mainly by the liver in response to metabolic stress (such as fasting or high carbohydrate/low protein intake) and acts on this complex in liver, adipose tissue, and other organs to coordinate lipid handling, glucose uptake, and energy expenditure. Because native FGF21 has a short circulating half-life and modest receptor affinity, one therapeutic strategy is to bypass the natural ligand altogether and use an antibody that directly engages β-Klotho to activate the FGFR1c complex, producing FGF21-like signaling with greater stability and more predictable dosing. Activating this pathway reduces circulating triglycerides by shifting fat metabolism away from storage and toward oxidation, and by dampening hepatic production of triglyceride-rich lipoproteins. This mechanism is of interest across a range of metabolic diseases characterized by dyslipidemia and insulin resistance, including severe hypertriglyceridemia, fatty liver disease, and type 2 diabetes, where restoring or amplifying the body's endogenous FGF21 signal is thought to correct multiple aspects of metabolic dysfunction simultaneously rather than targeting a single lipid or glucose parameter in isolation.