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Production of recombinant scorpion antivenoms in E. coli: current state and perspectives

Authors:
Susana Alonso at National Institute for Applied Sciences Tolouse
Susana Alonso
Hazar Kraïem-Ghezal
Hazar Kraïem-Ghezal
Hazar Kraïem-Ghezal
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Balkiss Bouhaouala-Zahar at Pasteur Network
Balkiss Bouhaouala-Zahar
Carine Bideaux at French National Centre for Scientific Research
Carine Bideaux
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Abstract and Figures

Scorpion envenomation is a serious health problem in tropical and subtropical zones. The access to scorpion antivenom is sometimes limited in availability and specificity. The classical production process is cumbersome, from the hyper-immunization of the horses to the IgG digestion and purification of the F(ab)′2 antibody fragments. The production of recombinant antibody fragments in Escherichia coli is a popular trend due to the ability of this microbial host to produce correctly folded proteins. Small recombinant antibody fragments, such as single-chain variable fragments (scFv) and nanobodies (VHH), have been constructed to recognize and neutralize the neurotoxins responsible for the envenomation symptoms in humans. They are the focus of interest of the most recent studies and are proposed as potentially new generation of pharmaceuticals for their use in immunotherapy against scorpion stings of the Buthidae family. This literature review comprises the current status on the scorpion antivenom market and the analyses of cross-reactivity of commercial scorpion anti-serum against non-specific scorpion venoms. Recent studies on the production of new recombinant scFv and nanobodies will be presented, with a focus on the Androctonus and Centruroides scorpion species. Protein engineering-based technology could be the key to obtaining the next generation of therapeutics capable of neutralizing and cross-reacting against several types of scorpion venoms. Key points • Commercial antivenoms consist of predominantly purified equine F(ab)′2fragments. • Nanobody-based antivenom can neutralize Androctonus venoms and have a low immunogenicity. • Affinity maturation and directed evolution are used to obtain potent scFv families against Centruroides scorpions.
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Vol.:(0123456789)
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Applied Microbiology and Biotechnology (2023) 107:4133–4152
https://doi.org/10.1007/s00253-023-12578-1
MINI-REVIEW
Production ofrecombinant scorpion antivenoms inE. coli: current
state andperspectives
SusanaMaríaAlonsoVillela1 · HazarKraïem‑Ghezal2 · BalkissBouhaouala‑Zahar2,3 · CarineBideaux1 ·
CésarArturoAcevesLara1 · LucFillaudeau1
Received: 29 December 2022 / Revised: 5 May 2023 / Accepted: 9 May 2023 / Published online: 18 May 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
Scorpion envenomation is a serious health problem in tropical and subtropical zones. The access to scorpion antivenom is
sometimes limited in availability and specificity. The classical production process is cumbersome, from the hyper-immuni-
zation of the horses to the IgG digestion and purification of the F(ab)′2 antibody fragments. The production of recombinant
antibody fragments in Escherichia coli is a popular trend due to the ability of this microbial host to produce correctly folded
proteins. Small recombinant antibody fragments, such as single-chain variable fragments (scFv) and nanobodies (VHH), have
been constructed to recognize and neutralize the neurotoxins responsible for the envenomation symptoms in humans. They
are the focus of interest of the most recent studies and are proposed as potentially new generation of pharmaceuticals for their
use in immunotherapy against scorpion stings of the Buthidae family. This literature review comprises the current status on
the scorpion antivenom market and the analyses of cross-reactivity of commercial scorpion anti-serum against non-specific
scorpion venoms. Recent studies on the production of new recombinant scFv and nanobodies will be presented, with a focus
on the Androctonus and Centruroides scorpion species. Protein engineering-based technology could be the key to obtain-
ing the next generation of therapeutics capable of neutralizing and cross-reacting against several types of scorpion venoms.
Key points
• Commercial antivenoms consist of predominantly purified equine F(ab)′2fragments.
• Nanobody-based antivenom can neutralize Androctonus venoms and have a low immunogenicity.
• Affinity maturation and directed evolution are used to obtain potent scFv families against Centruroides scorpions.
Keywords Antibody fragments· Buthidae scorpions· Scorpion antivenom· Recombinant protein
Introduction
According to the World Health Organization (WHO), scor-
pion envenomation is a neglected health problem, mainly in
tropical and subtropical zones, such as the northern parts of
Africa, Middle-East, Central and South America (Warrell
etal. 2007). About 2.5 billion people live in at-risk zones
(Chippaux and Goyffon 2008), with children under 7years
old and elders over 60years old being the most vulnerable
to the effects of the scorpion venom (Carmo etal. 2015).
From the approximately 1500 species of scorpions in the
world, less than a dozen are responsible for serious enveno-
mation or death in humans (Chippaux and Goyffon 2008).
They all belong to the Buthidae scorpion family, and include
the scorpion genera Androctonus, Buthus, Centruroides,
Leiurus, and Tityus. Most of these scorpions of medical
* Susana María Alonso Villela
salonsovillela@gmail.com
* Balkiss Bouhaouala-Zahar
balkiss.bouhaouala@fmt.utm.tn
1 TBI, Université de Toulouse, CNRS, INRAE, INSA,
Toulouse, France
2 Laboratoire Des Venins Et Molécules Thérapeutiques,
Institut Pasteur de Tunis, Université de Tunis El Manar, 13
Place Pasteur BP74, 1002Tunis, Tunisia
3 Faculté de Médecine de Tunis, Université de Tunis El Manar,
Tunis, Tunisia
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... They are more thermostable and production is achieved using microbial cell hosts making them a more cost-effective alternative to monoclonal antibodies [3]. The bacteria Escherichia coli has been engineered as the preferred host for the efficient production of antivenom proteins, leveraging its scalability and cost-effectiveness [4,5]. ...
... The bioreactor is assumed to be an infinitely mixed culture without any transfer limitation. The mass balances for biomass, glucose, proteins and volume are given by Eq. (1) - (4). ...
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... Additionally, it risks the depletion of snake and scorpion populations in nature. The identification and characterization of specific venom components, such as PLA2, can serve as alternatives to whole venom extraction, reducing the dependency on these traditional practices [49][50][51] . Antivenom production centers typically rely on carefully breeding and maintaining snakes, spiders, and scorpions in captivity to extract venom without euthanizing the animals. ...
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The structure and function of phospholipase A2 (PLA2) in scorpion venom are relatively unexplored, making further study crucial. This research aims to pave the way for a better understanding of scorpion venom, including the biochemical identification and characterization of PLA2 from Iranian Hemiscorpius lepturus, expressed in E. coli, as well as the in vivo study of polyclonal antibodies against PLA2. The PLA2 gene was cloned into pET-26b (+), expressed in E. coli BL21 (DE3) pLysS, and purified by affinity chromatography. The secondary structure of the recombinant protein was analyzed using CD spectroscopy. Biochemical identification included phospholipase activity, temperature, pH, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) methods. New Zealand Albino male rabbits were immunized with 100 µg/ml at 10–12-day intervals using Complete and Incomplete Freund’s Adjuvant. Specific rabbit anti-PLA2 polyclonal antibodies were detected using ELISA. CD spectroscopy analysis revealed the recombinant proteins’ unique composition: 45.1% beta-sheet, 36.6% random coil, 10.3% turn, and 8.1% alpha helix. The highest PLA2 activity was at 250 µg/ml. Phospholipase activity peaked at 25 °C (over 70%) and decreased to about 62% at 37 °C. MIC and MBC tests showed antibacterial and lethal properties at 31.25 µg/ml and 0.5 mg/ml, respectively. This enzymatic protein shows promise as a drug or vaccine candidate against H. lepturus envenomation in future clinical studies.
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... Buthus martensii Karsch antitumor-analgesic peptide's analgesic effect was proven in hot-plate and mouse twisting tests. 52 Ehrlich and S-180 fibrosarcoma were used to illustrate the in vivo anticancer activity. Recombinant rBmK AGAP (rAGAP) inhibited the development and proliferation of glioma cells by causing cell cycle arrest in the G1 phase and blocking the action of proteins involved in growth and cell cycle regulation. ...
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... Whole-cell patch-clamp electrophysiology is a valuable tool for preliminary characterisation of AV efficacy, and it has the advantage of reducing dependence on experimental animals. Production of AV is transitioning towards E. coli-derived manufacturing systems (Alonso Villela et al., 2023), running in tandem with the rise of phage displayselected antibodies (Roncolato et al., 2015), recombinant monoclonal antibodies (Laustsen, 2018), and the recombinant expression of venom toxins as antigens for AV production (Rimbault et al., 2023). Evidently, the dependence on animals throughout the last century of AV development is waning, and efficacy investigations should follow suit. ...
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... From the characterization of the toxic components of any given venom, it is possible, through scFv affinity maturation, to implement rational strategies to achieve a good neutralization of each of the toxic components [40][41][42][43]. The scFvs 10FG2 and HV evaluated in this work show a good level of interaction with the evaluated toxins similar to those that have already been neutralized [27,33]. ...
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In the pharmaceutical industry, nanobodies show promising properties for its application in serotherapy targeting the highly diffusible scorpion toxins. The production of recombinant nanobodies in Escherichia coli has been widely studied in shake flask cultures in rich medium. However, there are no upstream bioprocess studies of nanobody production in defined minimal medium and the effect of the induction temperature on the production kinetics. In this work, the effect of the temperature during the expression of the chimeric bispecific nanobody CH10-12 form, showing high scorpion antivenom potential, was studied in bioreactor cultures of E. coli. High biomass concentrations (25 g cdw/L) were achieved in fed-batch mode, and the expression of the CH10-12 nanobody was induced at temperatures 28, 29, 30, 33, and 37°C with a constant glucose feed. For the bispecific form NbF12-10, the induction was performed at 29°C. Biomass and carbon dioxide yields were reported for each culture phase, and the maintenance coefficient was obtained for each strain. Nanobody production in the CH10-12 strain was higher at low temperatures (lower than 30°C) and declined with the increase of the temperature. At 29°C, the CH10-12, NbF12-10, and WK6 strains were compared. Strains CH10-12 and NbF12-10 had a productivity of 0.052 and 0.021 mg/L/h of nanobody, respectively, after 13 h of induction. The specific productivity of the nanobodies was modeled as a function of the induction temperature and the specific growth rates. Experimental results confirm that low temperatures increase the productivity of the nanobody. Key points • Nanobodies with scorpion antivenom activity produced using two recombinant strains.• Nanobodies production was achieved in fed-batch cultures at different induction temperatures.• Low induction temperatures result in high volumetric productivities of the nanobody CH10-12.
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The venom of the scorpion Centruroides limpidus, which causes the highest number of stings in Mexico, is neutralized by two recombinant antibody fragments
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  • Sep 2021
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Phage display and directed evolution have made it possible to generate recombinant antibodies in the format of single chain variable fragments (scFvs) capable of neutralizing different toxins and venoms of Mexican scorpions. Despite having managed to neutralize a significant number of venoms, some others have not yet been completely neutralized, due to the diversity of the toxic components present in them. An example is the venom of the scorpion Centruroides limpidus, which contains three toxins of medical importance, called Cll1, Cll2 and Cl13. The first two are neutralized by scFv 10FG2, while Cl13, due to its sequence divergence, was not even recognized. For this reason, the aim of the present work was the generation of a new scFv capable of neutralizing Cl13 toxin and thereby helping to neutralize the whole venom of this scorpion. By hybridoma technology, a monoclonal antibody (mAb B7) was generated, which was able to recognize and partially neutralize Cl13 toxin. From mAb B7, its scFv format was obtained, named scFv B7 and subjected to three cycles of directed evolution. At the end of these processes, scFv 11F which neutralized Cl13 toxin was obtained. This scFv, administered in conjunction with scFv 10FG2, allowed to fully neutralize the whole venom of Centruroides limpidus scorpion.
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