Discovery of an antagonist nanobody targeting the oxytocin receptor with tocolytic effect in mice.

Preterm birth, defined as delivery before 37 completed weeks of gestation, poses significant risks to maternal and neonatal health. These risks include neonatal respiratory distress syndrome, intraventricular hemorrhage, long-term developmental challenges, and in severe cases, mortality. Addressing these issues, G protein-coupled receptor (GPCR)-mediated tocolysis has become a focal strategy in pharmaceutical research to mitigate preterm labor risks. Most GPCR drugs are small molecules, yet their tendency to cross the placental barrier and induce fetal toxicity presents a significant challenge. Antibody drugs, with minimal cell membrane permeability, offer a promising alternative. In this study, we leverage AI-driven protein design to enable nanobody screening and identify several nanobodies with antagonist activity against the oxytocin receptor, a key target for preterm birth therapeutics. One of these nanobodies demonstrates antagonist activity comparable to Atosiban, a commonly used clinical drug, while exhibiting higher subtype selectivity. Pharmacological and structural analyses reveal mechanisms distinct from small molecule antagonists. These findings expand the pharmacological potential of antibody drugs and introduce useful tools and perspectives for developing effective tocolytic agents.