Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming.

I. Hmila (1) , B. Cosyns (2) , H. Tounsi (3) , B. Roosens (2) , V. Caveliers (2) , R Ben Abderrazek (1) , S. Boubaker (4) , S. Muyldermans (5) , M. El Ayeb (1) , B. Bouhaouala-Zahar (1) , T. Lahoutte (2)

1 Laboratoire des Venins et Toxines, Institut Pasteur de Tunis
2 Laboratory of In Vivo Cellular and Molecular Imaging
3 Laboratoire d’Anatomie Pathologique Humaine et Expérimentale
4 Institut Pasteur de Tunis
5 Department of Structural Biology

Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab'(2) based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of (99m)Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab'(2) product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab'(2) based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10.

Domaines: Toxicologie

I. Hmila, B. Cosyns, H. Tounsi, B. Roosens, V. Caveliers, et al.. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming.. Toxicology and Applied Pharmacology, 2012, epub ahead of print. ⟨10.1016/j.taap.2012.07.033⟩. ⟨pasteur-00734381⟩