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Compared to conventional antisera strategies, monoclonal antibodies (mAbs) represent an alternative and safer way to treat botulism, a fatal flaccid paralysis due to botulinum neurotoxins (BoNTs). In addition, mAbs offer the advantage to be produced in a reproducible manner. We previously identified a unique and potent mouse mAb (TA12) targeting BoNT/A1 with high affinity and neutralizing activity. In this study, we characterized the molecular basis of TA12 neutralization by combining Hydrogen/Deuterium eXchange Mass Spectrometry (HDX‐MS) with site‐directed mutagenesis and functional studies. We found that TA12 recognizes a conformational epitope located at the interface between the HCN and HCC subdomains of the BoNT/A1 receptor‐binding domain (HC). The TA12‐binding interface shares common structural features with the ciA‐C2 VHH epitope and lies on the face opposite recognized by ciA‐C2‐ and the CR1/CR2‐neutralizing mAbs. The single substitution of N1006 was sufficient to affect TA12 binding to HC confirming the position of the epitope. We further uncovered that the TA12 epitope overlaps with the BoNT/A1‐binding site for both the neuronal cell surface receptor synaptic vesicle glycoprotein 2 isoform C (SV2C) and the GT1b ganglioside. Hence, TA12 potently blocks the entry of BoNT/A1 into neurons by interfering simultaneously with the binding of SV2C and to a lower extent GT1b. Our study reveals the unique neutralization mechanism of TA12 and emphasizes on the potential of using single mAbs for the treatment of botulism type A.
Sébastien Brier; Christine Rasetti‐Escargueil; Anne Wijkhuisen; Stéphanie Simon; Maud Marechal; Emmanuel Lemichez; Michel R. Popoff. Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A. The FASEB Journal 2021, 35, e21540 .
AMA StyleSébastien Brier, Christine Rasetti‐Escargueil, Anne Wijkhuisen, Stéphanie Simon, Maud Marechal, Emmanuel Lemichez, Michel R. Popoff. Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A. The FASEB Journal. 2021; 35 (5):e21540.
Chicago/Turabian StyleSébastien Brier; Christine Rasetti‐Escargueil; Anne Wijkhuisen; Stéphanie Simon; Maud Marechal; Emmanuel Lemichez; Michel R. Popoff. 2021. "Characterization of a highly neutralizing single monoclonal antibody to botulinum neurotoxin type A." The FASEB Journal 35, no. 5: e21540.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Antibodies and vaccines against botulinum toxins: Available measures and novel approaches. Toxicon 2021, 190, S62 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Antibodies and vaccines against botulinum toxins: Available measures and novel approaches. Toxicon. 2021; 190 ():S62.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2021. "Antibodies and vaccines against botulinum toxins: Available measures and novel approaches." Toxicon 190, no. : S62.
Botulinum neurotoxins (BoNTs) show increasing therapeutic applications ranging from treatment of locally paralyzed muscles to cosmetic benefits. At first, in the 1970s, BoNT was used for the treatment of strabismus, however, nowadays, BoNT has multiple medical applications including the treatment of muscle hyperactivity such as strabismus, dystonia, movement disorders, hemifacial spasm, essential tremor, tics, cervical dystonia, cerebral palsy, as well as secretory disorders (hyperhidrosis, sialorrhea) and pain syndromes such as chronic migraine. This review summarizes current knowledge related to engineering of botulinum toxins, with particular emphasis on their potential therapeutic applications for pain management and for retargeting to non-neuronal tissues. Advances in molecular biology have resulted in generating modified BoNTs with the potential to act in a variety of disorders, however, in addition to the modifications of well characterized toxinotypes, the diversity of the wild type BoNT toxinotypes or subtypes, provides the basis for innovative BoNT-based therapeutics and research tools. This expanding BoNT superfamily forms the foundation for new toxins candidates in a wider range of therapeutic options.
Christine Rasetti-Escargueil; Michel R. Popoff. Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development. Toxins 2020, 13, 1 .
AMA StyleChristine Rasetti-Escargueil, Michel R. Popoff. Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development. Toxins. 2020; 13 (1):1.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Michel R. Popoff. 2020. "Engineering Botulinum Neurotoxins for Enhanced Therapeutic Applications and Vaccine Development." Toxins 13, no. 1: 1.
Human botulism is a severe disease characterized by flaccid paralysis and inhibition of certain gland secretions, notably salivary secretions, caused by inhibition of neurotransmitter release. Naturally acquired botulism occurs in three main forms: food-borne botulism by ingestion of preformed botulinum neurotoxin (BoNT) in food, botulism by intestinal colonization (infant botulism and intestinal toxemia botulism in infants above one year and adults), and wound botulism. A rapid laboratory confirmation of botulism is required for the appropriate management of patients. Detection of BoNT in the patient’s sera is the most direct way to address the diagnosis of botulism. Based on previous published reports, botulinum toxemia was identified in about 70% of food-borne and wound botulism cases, and only in about 28% of infant botulism cases, in which the diagnosis is mainly confirmed from stool sample investigation. The presence of BoNT in serum depends on the BoNT amount ingested with contaminated food or produced locally in the intestine or wound, and the delay between serum sampling and disease onset. BoNT levels in patient’s sera are most frequently low, requiring a highly sensitive method of detection. Mouse bioassay is still the most used method of botulism identification from serum samples. However, in vitro methods based on BoNT endopeptidase activity with detection by mass spectrometry have been developed and depending on BoNT type, are more sensitive than the mouse bioassay. These new assays show high specificity for individual BoNT types and allow the differentiation between positive toxin sera from botulism and autoimmune neuropathy patients.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Toxemia in Human Naturally Acquired Botulism. Toxins 2020, 12, 716 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Toxemia in Human Naturally Acquired Botulism. Toxins. 2020; 12 (11):716.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2020. "Toxemia in Human Naturally Acquired Botulism." Toxins 12, no. 11: 716.
Botulism is a rare but severe disease which is characterized by paralysis and inhibition of secretions. Only a few cases had been reported at the end of the 19th century in France. The disease was frequent during the second world war, and then the incidence decreased progressively. However, human botulism is still present in France with 10–25 cases every year. Food-borne botulism was the main form of botulism in France, whereas infant botulism (17 cases between 2004 and 2016) was rare, and wound and inhalational botulism were exceptional. Type B was the prevalent botulism type and was mainly due to consumption of home-made or small-scale preparations of cured ham and to a lesser extent other pork meat products. In the recent period (2000–2016), a wider diversity of botulism types from various food origin including industrial foods was reported. Severe cases of type A and F botulism as well as type E botulism were more frequent. Albeit rare, the severity of botulism justifies its continued surveillance and recommendations to food industry and consumers regarding food hygiene and preservation practices.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Human Botulism in France, 1875–2016. Toxins 2020, 12, 338 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Human Botulism in France, 1875–2016. Toxins. 2020; 12 (5):338.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2020. "Human Botulism in France, 1875–2016." Toxins 12, no. 5: 338.
Botulism is a rare but severe neurological disease in man and animals that is caused by botulinum neurotoxins (BoNTs) produced by Clostridium botulinum and atypical strains from other Clostridium and non-Clostridium species. BoNTs are divided into more than seven toxinotypes based on neutralization with specific corresponding antisera, and each toxinotype is subdivided into subtypes according to amino acid sequence variations. Animal species show variable sensitivity to the different BoNT toxinotypes. Thereby, naturally acquired animal botulism is mainly due to BoNT/C, D and the mosaic variants CD and DC, BoNT/CD being more prevalent in birds and BoNT/DC in cattle, whereas human botulism is more frequently in the types A, B and E, and to a lower extent, F. Botulism is not a contagious disease, since there is no direct transmission from diseased animals or man to a healthy subject. Botulism occurs via the environment, notably from food contaminated with C. botulinum spores and preserved in conditions favorable for C. botulinum growth and toxin production. The high prevalence of botulism types C, D and variants DC and CD in farmed and wild birds, and to a lower extent in cattle, raises the risk of transmission to human beings. However, human botulism is much rarer than animal botulism, and botulism types C and D are exceptional in humans. Only 15 cases or suspected cases of botulism type C and one outbreak of botulism type D have been reported in humans to date. In contrast, animal healthy carriers of C. botulinum group II, such as C. botulinum type E in fish of the northern hemisphere, and C. botulinum B4 in pigs, represent a more prevalent risk of botulism transmission to human subjects. Less common botulism types in animals but at risk of transmission to humans, can sporadically be observed, such as botulism type E in farmed chickens in France (1998–2002), botulism type B in cattle in The Netherlands (1977–1979), botulism types A and B in horses, or botulism type A in dairy cows (Egypt, 1976). In most cases, human and animal botulisms have distinct origins, and cross transmissions between animals and human beings are rather rare, accidental events. But, due to the severity of this disease, human and animal botulism requires a careful surveillance.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Public Health Risk Associated with Botulism as Foodborne Zoonoses. Toxins 2019, 12, 17 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Public Health Risk Associated with Botulism as Foodborne Zoonoses. Toxins. 2019; 12 (1):17.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2019. "Public Health Risk Associated with Botulism as Foodborne Zoonoses." Toxins 12, no. 1: 17.
Botulinum neurotoxin (BoNT) is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum. As one of the most poisonous toxins known and a potential bioterrosism agent, BoNT is characterized by a complex mode of action comprising: internalization, translocation and proteolytic cleavage of a substrate, which inhibits synaptic exocytotic transmitter release at neuro-muscular nerve endings leading to peripheral neuroparalysis of the skeletal and autonomic nervous systems. There are seven major serologically distinct toxinotypes (A–G) of BoNT which act on different substrates. Human botulism is generally caused by BoNT/A, B and E. Due to its extreme lethality and potential use as biological weapon, botulism remains a global public health concern. Vaccination against BoNT, although an effective strategy, remains undesirable due to the growing expectation around therapeutic use of BoNTs in various pathological conditions. This review focuses on the current approaches for botulism control by immunotherapy, highlighting the future challenges while the molecular underpinnings among subtypes variants and BoNT sequences found in non-clostridial species remain to be elucidated.
Christine Rasetti-Escargueil; Michel R. Popoff; Rasetti- Escargueil. Antibodies and Vaccines Against Botulinum Toxins: Available Measures and Novel Approaches. Toxins 2019, 11, 528 .
AMA StyleChristine Rasetti-Escargueil, Michel R. Popoff, Rasetti- Escargueil. Antibodies and Vaccines Against Botulinum Toxins: Available Measures and Novel Approaches. Toxins. 2019; 11 (9):528.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Michel R. Popoff; Rasetti- Escargueil. 2019. "Antibodies and Vaccines Against Botulinum Toxins: Available Measures and Novel Approaches." Toxins 11, no. 9: 528.
Botulinum neurotoxins (BoNTs) are the most potent known toxins, and are therefore classified as extremely harmful biological weapons. However, BoNTs are therapeutic drugs that are widely used and have an increasing number of applications. BoNTs show a high diversity and are divided into multiple types and subtypes. Better understanding of the activity at the molecular and clinical levels of the natural BoNT variants as well as the development of BoNT-based chimeric molecules opens the door to novel medical applications such as silencing the sensory neurons at targeted areas and dermal restoration. This short review is focused on BoNTs’ variability and the opportunities or challenges posed for future clinical applications.
Christine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. Variability of Botulinum Toxins: Challenges and Opportunities for the Future. Toxins 2018, 10, 374 .
AMA StyleChristine Rasetti-Escargueil, Emmanuel Lemichez, Michel R. Popoff. Variability of Botulinum Toxins: Challenges and Opportunities for the Future. Toxins. 2018; 10 (9):374.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Emmanuel Lemichez; Michel R. Popoff. 2018. "Variability of Botulinum Toxins: Challenges and Opportunities for the Future." Toxins 10, no. 9: 374.
The goal of the AntiBotABE Program was the development of recombinant antibodies that neutralize botulinum neurotoxins (BoNT) A, B and E. These serotypes are lethal and responsible for most human botulinum cases. To improve therapeutic efficacy, the heavy and light chains (HC and LC) of the three BoNT serotypes were targeted to achieve a synergistic effect (oligoclonal antibodies). For antibody isolation, macaques were immunized with the recombinant and non-toxic BoNT/A, B or E, HC or LC, followed by the generation of immune phage-display libraries. Antibodies were selected from these libraries against the holotoxin and further analyzed in in vitro and ex vivo assays. For each library, the best ex vivo neutralizing antibody fragments were germline-humanized and expressed as immunoglobulin G (IgGs). The IgGs were tested in vivo, in a standardized model of protection, and challenged with toxins obtained from collections of Clostridium strains. Protective antibody combinations against BoNT/A and BoNT/B were evidenced and for BoNT/E, the anti-LC antibody alone was found highly protective. The combination of these five antibodies as an oligoclonal antibody cocktail can be clinically and regulatorily developed while their high “humanness” predicts a high tolerance in humans.
Christine Rasetti-Escargueil; Arnaud Avril; Sebastian Miethe; Christelle Mazuet; Yagmur Derman; Katja Selby; Philippe Thullier; Thibaut Pelat; Remi Urbain; Alexandre Fontayne; Hannu Korkeala; Dorothea Sesardic; Michael Hust; Michel R. Popoff. The European AntibotABE Framework Program and Its Update: Development of Innovative Botulinum Antibodies. Toxins 2017, 9, 309 .
AMA StyleChristine Rasetti-Escargueil, Arnaud Avril, Sebastian Miethe, Christelle Mazuet, Yagmur Derman, Katja Selby, Philippe Thullier, Thibaut Pelat, Remi Urbain, Alexandre Fontayne, Hannu Korkeala, Dorothea Sesardic, Michael Hust, Michel R. Popoff. The European AntibotABE Framework Program and Its Update: Development of Innovative Botulinum Antibodies. Toxins. 2017; 9 (10):309.
Chicago/Turabian StyleChristine Rasetti-Escargueil; Arnaud Avril; Sebastian Miethe; Christelle Mazuet; Yagmur Derman; Katja Selby; Philippe Thullier; Thibaut Pelat; Remi Urbain; Alexandre Fontayne; Hannu Korkeala; Dorothea Sesardic; Michael Hust; Michel R. Popoff. 2017. "The European AntibotABE Framework Program and Its Update: Development of Innovative Botulinum Antibodies." Toxins 9, no. 10: 309.
Botulinum neurotoxins (BoNTs) cause botulism and are the deadliest naturally-occurring substances known to humans. BoNTs have been classified as one of the category A agents by the Centers for Disease Control and Prevention, indicating their potential use as bioweapons. To counter bio-threat and naturally-occurring botulism cases, well-tolerated antibodies by humans that neutralize BoNTs are relevant. In our previous work, we showed the neutralizing potential of macaque (Macaca fascicularis)-derived scFv-Fc (scFv-Fc ELC18) by in vitro endopeptidase immunoassay and ex vivo mouse phrenic nerve-hemidiaphragm assay by targeting the light chain of the botulinum neurotoxin type E (BoNT/E). In the present study, we germline-humanized scFv-Fc ELC18 into a full IgG hu8ELC18 to increase its immunotolerance by humans. We demonstrated the protection and prophylaxis capacity of hu8ELC18 against BoNT/E in a mouse model. A concentration of 2.5 ng/mouse of hu8ELC18 protected against 5 mouse lethal dose (MLD) in a mouse protection assay and complete neutralization of 1 LD50 of pure BoNT/E toxin was achieved with 8 ng of hu8ELC18 in mouse paralysis assay. Furthermore, hu8ELC18 protected mice from 5 MLD if injected up to 14 days prior to intraperitoneal BoNT/E administration. This newly-developed humanized IgG is expected to have high tolerance in humans.
Yağmur Derman; Katja Selby; Sebastian Miethe; André Frenzel; Yvonne Liu; Christine Rasetti-Escargueil; Arnaud Avril; Thibaut Pelat; Remi Urbain; Alexandre Fontayne; Philippe Thullier; Dorothea Sesardic; Miia Lindström; Michael Hust; Hannu Korkeala. Neutralization of Botulinum Neurotoxin Type E by a Humanized Antibody. Toxins 2016, 8, 257 .
AMA StyleYağmur Derman, Katja Selby, Sebastian Miethe, André Frenzel, Yvonne Liu, Christine Rasetti-Escargueil, Arnaud Avril, Thibaut Pelat, Remi Urbain, Alexandre Fontayne, Philippe Thullier, Dorothea Sesardic, Miia Lindström, Michael Hust, Hannu Korkeala. Neutralization of Botulinum Neurotoxin Type E by a Humanized Antibody. Toxins. 2016; 8 (9):257.
Chicago/Turabian StyleYağmur Derman; Katja Selby; Sebastian Miethe; André Frenzel; Yvonne Liu; Christine Rasetti-Escargueil; Arnaud Avril; Thibaut Pelat; Remi Urbain; Alexandre Fontayne; Philippe Thullier; Dorothea Sesardic; Miia Lindström; Michael Hust; Hannu Korkeala. 2016. "Neutralization of Botulinum Neurotoxin Type E by a Humanized Antibody." Toxins 8, no. 9: 257.
A series of α‐hydroxyamides of type (VII) and (VIII) are prepared and evaluated as antagonists of the M3 muscarinic receptor in guinea pig ileum.
Kenneth J. Broadley; Robin H. Davies; Christine Escargueil; Alan T. L. Lee; Peter Penson; Eric J. Thomas. ChemInform Abstract: Synthesis of Antagonists of Muscarinic (M3) Receptors. ChemInform 2011, 42, 1 .
AMA StyleKenneth J. Broadley, Robin H. Davies, Christine Escargueil, Alan T. L. Lee, Peter Penson, Eric J. Thomas. ChemInform Abstract: Synthesis of Antagonists of Muscarinic (M3) Receptors. ChemInform. 2011; 42 (43):1.
Chicago/Turabian StyleKenneth J. Broadley; Robin H. Davies; Christine Escargueil; Alan T. L. Lee; Peter Penson; Eric J. Thomas. 2011. "ChemInform Abstract: Synthesis of Antagonists of Muscarinic (M3) Receptors." ChemInform 42, no. 43: 1.
Several α-hydroxyamides with (2,6-dialkoxyphenoxy)methyl substituents have been prepared and their activities as antagonists of the M3 muscarinic receptor in guinea pig ileum have been evaluated. N-{1-[(Phenyl)methyl]piperidin-4-yl}-2-{2-[(2,6-dimethoxyphenoxy)-methyl]phenyl}-2-hydroxypropanamide and N-(1-[{6-amino-4-[(1-propylpiperidin-4-yl)methyl]pyridin-2-yl}methyl]piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide were the most potent compounds prepared, the micromolar potency of the latter indicating that it may be worth further investigation.
Kenneth J. Broadley; Robin H. Davies; Christine Escargueil; Alan T. L. Lee; Peter Penson; Eric J. Thomas. Synthesis of antagonists of muscarinic (M3) receptors. Collection of Czechoslovak Chemical Communications 2011, 76, 781 -801.
AMA StyleKenneth J. Broadley, Robin H. Davies, Christine Escargueil, Alan T. L. Lee, Peter Penson, Eric J. Thomas. Synthesis of antagonists of muscarinic (M3) receptors. Collection of Czechoslovak Chemical Communications. 2011; 76 (7):781-801.
Chicago/Turabian StyleKenneth J. Broadley; Robin H. Davies; Christine Escargueil; Alan T. L. Lee; Peter Penson; Eric J. Thomas. 2011. "Synthesis of antagonists of muscarinic (M3) receptors." Collection of Czechoslovak Chemical Communications 76, no. 7: 781-801.