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

Journal Article · Mon Oct 15 04:00:00 EDT 2012 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2012.07.033· OSTI ID:22215941

Hmila, Issam ^[1]; Cosyns, Bernard ^[2]; Tounsi, Hayfa ^[3]; Roosens, Bram; Caveliers, Vicky ^[2]; Abderrazek, Rahma Ben ^[1]; Boubaker, Samir ^[3]; Muyldermans, Serge ^[4]; El Ayeb, Mohamed ^[1]; Bouhaouala-Zahar, Balkiss ^[1]; Lahoutte, Tony ^[2]

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1. Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)
2. Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)
3. Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)
4. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium)

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′{sub 2} based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of {sup 99m}Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab′{sub 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′{sub 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. -- Highlights: ► Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ► Late injection of Nanobody restores hemodynamic parameters to baseline values. ► Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ► Labeled Nanobody and Fab’2 pharmacokinetics curves reach plateau in favour of Nanobody.

• OSTI ID: 22215941
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 264; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMINO ACIDS
BLOOD PRESSURE
HEART
HISTOLOGY
IN VIVO
INJECTION
LETHAL DOSES
LUNGS
MICE
RATS
SCORPIONS
SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY
TECHNETIUM 99
THERAPY
TOXINS
VENOMS