Transferrin receptor binding valency determines the circulating half-life and weight-loss efficacy of Fc-FGF21 in TfR-humanized mice

In homozygous hTfR-humanized mice, Fc(TV35)-FGF21 fails to induce weight loss because its markedly shortened circulating half-life limits systemic exposure.

• Why it matters: Low receptor abundance in the brain creates a transport-efficacy gap for FGF21, and TfR-based brain shuttles may compromise systemic exposure through altered clearance.
• What they did: The authors engineered Fc(TV35)-FGF21 to bind human transferrin receptor, tested it in wild-type diet-induced obese mice versus homozygous hTfR-humanized mice, then converted it from a homodimer to a bispecific Fc with one hTfR-binding arm; they also compared homozygous versus heterozygous hTfR zygosity.
• The result: Bispecific Fc(TV35)-FGF21 partially restored circulating half-life and weight-loss efficacy, while reducing hTfR zygosity to heterozygous did not substantially improve half-life or weight loss.

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