The pharmacokinetics, bio-distribution and therapeutic efficacy of a trimeric nanobody against SARS-CoV-2 in the golden Syrian hamster COVID-19 model

Nanobodies are promising medical countermeasures against respiratory viruses, but their local pharmacokinetics and therapeutic window remain incompletely defined. We evaluated the pharmacokinetics, biodistribution and efficacy of a SARS-CoV-2-neutralising trimeric nanobody (A8) in golden Syrian hamsters. Following intranasal administration, A8 concentrations were quantified in nasal wash, bronchoalveolar lavage, lung and serum, and tissue distribution was assessed immunohistologically. Therapeutic efficacy was examined after intranasal treatment before or following challenge with SARS-CoV-2 B.1.351. Intranasal administration of A8 produced sustained respiratory exposure with minimal systemic absorption, whereas intraperitoneal dosing generated transient serum exposure and limited pulmonary delivery. A8 was detected within airway lining material, respiratory epithelial cells, type II pneumocytes and alveolar macrophages. Prophylactic administration 2 h before infection prevented weight loss, while treatment 24 h post infection accelerated recovery and reduced viral subgenomic RNA in respiratory tissues. Doses as low as 0.1 mg/kg were effective when administered at 24 h post infection, with no clear dose response relationship. Treatment delayed until 48 h post infection was less effective. These findings demonstrate that intranasal A8 achieves favourable compartmentalised exposure and that therapeutic efficacy depends principally on early respiratory delivery rather than dose magnitude, supporting further development of inhaled nanobody therapeutics against SARS-CoV-2.