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

Abstract

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 amore » 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.« less

Authors:
 [1];  [2];  [3]; ;  [2];  [1];  [3];  [4];  [1];  [1];  [2]
  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)
Publication Date:
OSTI Identifier:
22215941
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 264; Journal Issue: 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
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

Citation Formats

Hmila, Issam, Cosyns, Bernard, Tounsi, Hayfa, Roosens, Bram, Caveliers, Vicky, Abderrazek, Rahma Ben, Boubaker, Samir, Muyldermans, Serge, Department of Structural Biology, VIB, Brussels, El Ayeb, Mohamed, Bouhaouala-Zahar, Balkiss, Faculté de Médecine de Tunis, Université de Tunis-El Manar, and Lahoutte, Tony. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.07.033.
Hmila, Issam, Cosyns, Bernard, Tounsi, Hayfa, Roosens, Bram, Caveliers, Vicky, Abderrazek, Rahma Ben, Boubaker, Samir, Muyldermans, Serge, Department of Structural Biology, VIB, Brussels, El Ayeb, Mohamed, Bouhaouala-Zahar, Balkiss, Faculté de Médecine de Tunis, Université de Tunis-El Manar, & Lahoutte, Tony. Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming. United States. https://doi.org/10.1016/J.TAAP.2012.07.033
Hmila, Issam, Cosyns, Bernard, Tounsi, Hayfa, Roosens, Bram, Caveliers, Vicky, Abderrazek, Rahma Ben, Boubaker, Samir, Muyldermans, Serge, Department of Structural Biology, VIB, Brussels, El Ayeb, Mohamed, Bouhaouala-Zahar, Balkiss, Faculté de Médecine de Tunis, Université de Tunis-El Manar, and Lahoutte, Tony. 2012. "Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming". United States. https://doi.org/10.1016/J.TAAP.2012.07.033.
@article{osti_22215941,
title = {Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming},
author = {Hmila, Issam and Cosyns, Bernard and Tounsi, Hayfa and Roosens, Bram and Caveliers, Vicky and Abderrazek, Rahma Ben and Boubaker, Samir and Muyldermans, Serge and Department of Structural Biology, VIB, Brussels and El Ayeb, Mohamed and Bouhaouala-Zahar, Balkiss and Faculté de Médecine de Tunis, Université de Tunis-El Manar and Lahoutte, Tony},
abstractNote = {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.},
doi = {10.1016/J.TAAP.2012.07.033},
url = {https://www.osti.gov/biblio/22215941}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 264,
place = {United States},
year = {2012},
month = {10}
}