First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E

Raja, Shruti; Guptill, Jeffrey T.; Juel, Vern C.; Walter, Emmanuel B.; Cohen‐Wolkowiez, Michael; Hill, Heather; Sendra, Eli A.; Hauser, B.; Jackson, Paul J.; Tomic, Milan T.; Espinoza, Yero; Swamy, Geeta K.

doi:10.1128/aac.01732-21

Cited by 6 publications

(6 citation statements)

References 21 publications

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“…Such antibodies can be GMP manufactured and combined as three-mAb combinations. When studied in Phase 1 clinical trials, they showed no serious drug-related adverse events for mAb combinations against serotype A [ 24 ], serotype B [ 25 ], serotypes C and D [ 26 ], or serotype E [ 27 ]. In contrast, the current FDA-approved therapy, equine-derived BAT ® [ 20 ] is immunogenic, and hypersensitivity reactions have been reported, including cardiac arrest and serum sickness.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, we have developed safe and effective monoclonal antibody (mAb) based countermeasures for BoNT/A, B, C, D, and E, which have all completed Phase 1 clinical trials with no drug-related serious adverse effects [ 24 , 25 , 26 , 27 ] and have developed a recombinant mAb-based antitoxin for BoNT/F which is in preclinical development [ 28 ]. In the current work, we report the identification of mAbs against BoNT/G that, when combined, potently neutralize BoNT/G and thus could be used in the diagnosis, prevention, and treatment of BoNT/G-induced botulism.…”

Section: Introductionmentioning

confidence: 99%

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A Three-Monoclonal Antibody Combination Potently Neutralizes BoNT/G Toxin in Mice

Fan¹,

Lou²,

Tam

et al. 2023

Toxins

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Equine-derived antitoxin (BAT®) is the only treatment for botulism from botulinum neurotoxin serotype G (BoNT/G). BAT® is a foreign protein with potentially severe adverse effects and is not renewable. To develop a safe, more potent, and renewable antitoxin, humanized monoclonal antibodies (mAbs) were generated. Yeast displayed single chain Fv (scFv) libraries were prepared from mice immunized with BoNT/G and BoNT/G domains and screened with BoNT/G using fluorescence-activated cell sorting (FACS). Fourteen scFv-binding BoNT/G were isolated with KD values ranging from 3.86 nM to 103 nM (median KD 20.9 nM). Five mAb-binding non-overlapping epitopes were humanized and affinity matured to create antibodies hu6G6.2, hu6G7.2, hu6G9.1, hu6G10, and hu6G11.2, with IgG KD values ranging from 51 pM to 8 pM. Three IgG combinations completely protected mice challenged with 10,000 LD50s of BoNT/G at a total mAb dose of 6.25 μg per mouse. The mAb combinations have the potential for use in the diagnosis and treatment of botulism due to serotype G and, along with antibody combinations to BoNT/A, B, C, D, E, and F, provide the basis for a fully recombinant heptavalent botulinum antitoxin to replace the legacy equine product.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Three-Monoclonal Antibody Combination Potently Neutralizes BoNT/G Toxin in Mice

Fan¹,

Lou²,

Tam

et al. 2023

Toxins

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“…В данном исследовании было показано, что период полувыведения препаратов антител составляет в среднем от 6,5 до 10 суток. Позднее с использованием данных антител был произведен ряд экспериментальных исследований по оценке их протективной эффективности на животных моделях, а также клинические исследования по оценке фармакокинетических характеристик, которые показали их высокую эффективность и безопасность [17][18][19][20][21].…”

Section: Biological Security and Protection Against Biological Threat...unclassified

Humanized Antibodies. Modern Developments and Prospects for the Creation of Medical Protectors Against Biological Threads and Hazards

Gorshkov,

Pechenkin,

Kuznetsovskiy

et al. 2024

jour

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Passive immunization is the variant of the immunization, in which antibodies are introduced into the body in quantities, sufficient to provide a therapeutic effect. One of the «windows of opportunity» for passive immunization is an urgent post-exposure prophylaxis of infectious diseases and their preventive therapy, especially in the absence of chemotherapy drugs suitable for these purposes or their insufficient effectiveness. The existing heterologous drugs based on hyperimmune sera are highly reactogenic, and obtaining donor human immunoglobulins is associated with a number of ethical and technical restrictions. Therefore, biotechnologies that make it possible to obtain, on an industrial scale, low-reactogenic preparations of chimeric monoclonal antibodies with partially human specificity, as well as recombinant antibodies with fully human specificity, have enormous prospects. This trend is called «humanization of antibodies.» The purpose of this article is to analyze modern developments and to show the prospects for creating humanized antibodies specific to antigens of pathogens of especially dangerous infections and toxins as medical biological protection agents. The sources of the research are English-language studies and the scientific literature available via the Internet. The research method is an analysis of scientific sources on the topic being studied from the general to the specific. Results and discussion. The history of the creation of specific prevention drugs based on heterologous and homologous sera/immunoglobulins and monoclonal antibodies is presented. It has been shown in the article, that humanized specific monoclonal antibodies are widely used currently for the treatment of a number of severe chronic diseases (for example, rheumatoid arthritis, psoriasis, immunoinflammatory bowel diseases, malignant tumors). Conclusion. Recently, there has been an increase in numbers of both scientific research and developments, and drugs of recombinant antibodies already approved for use in clinical practice, specific to antigens of pathogens of especially dangerous infections and toxins - potential agents of bioterrorism, such as the anthrax microbe, botulinum toxins of various types, plant toxins ricin and abrin, ebolaviruses, coronaviruses. Such drugs can also be used as medical protectors against biological threats and hazards.

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“…Genetically engineered monoclonal antibodies are also in the development stage (Raja et al 2022;Rasetti-Escargueil et al 2017;Tomic et al 2021). However, technologically, equine-derived BAT is the most mature BAT available to date (Kim et al 2019;Rasseti-Escargueil and Popoff 2019;Richardson et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a novel tetravalent botulism antitoxin based on receptor-binding domain of BoNTs

Shi¹,

Lu²,

Mao³

et al. 2023

Appl Microbiol Biotechnol

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Botulinum neurotoxin (BoNTs; serotypes A, B, E, and F) cause botulism disease in humans, which could be effectively treated using antitoxins. Herein, we established a novel receptor-binding domain (RBD)-based antitoxin using recombinant C terminal heavy chain (Hc) domains of BoNTs as immunogens. Immunization of horses with these recombinant Hc domains allowed the purification and digestion of IgGs from hyper-immune sera to produce high-quality and high-efficiency monovalent botulism antitoxin F(ab′) 2 against each BoNT (M-BATs). However, these M-BATs could not bind or neutralize other serotypes of BoNTs, and that there were no cross-protective effects among these M-BATs. This suggested the need to prepare tetravalent antitoxins to neutralize the four BoNTs simultaneously. Thus, these M-BATs were formulated into a novel tetravalent botulism antitoxin (T-BAT), in which a 10-ml volume contained 10000 IU of BoNT/A and 5000 IU of BoNT/B, BoNT/E, and BoNT/F antitoxins. The novel antitoxin preparation could prevent and treat the four mixed botulinum neurotoxins simultaneously in vivo, representing strong efficacy in an animal poisoning model. Moreover, these antibodies in T-BAT could bind the RBD, whereas conventional antitoxins based on inactivated toxins mainly bind the light chain or heavy chain translocation domain (HN) and weakly bind the important RBD in current experimental conditions. The high levels of RBD-specific novel antitoxins can efficiently bind the RBD and neutralize natural or recombinant toxins containing this RBD. The findings of the present study experimentally support the use of RBD-specific antitoxins to treat BoNT serotype A, B, E, and F-mediated botulism. This study demonstrated the concept of developing potent novel multivalent antitoxins against all BoNTs or other toxins, using the RBD of these toxins as an alternative antigen to inactivated toxins. Key points • Antitoxins based on the receptor-binding domains of botulinum neurotoxins were made. • Novel antitoxin binds RBD; traditional antitoxin mainly binds light chain or HN domain. • A tetravalent antitoxin could prevent and treat the four mixed neurotoxins in vivo. Supplementary Information The online version contains supplementary material available at 10.1007/s00253-023-12515-2.

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First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E

Abstract: Botulism is a rare, life-threatening paralytic disease caused by botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given postexposure and challenging to produce and administer.

Cited by 6 publications

References 21 publications

A Three-Monoclonal Antibody Combination Potently Neutralizes BoNT/G Toxin in Mice

A Three-Monoclonal Antibody Combination Potently Neutralizes BoNT/G Toxin in Mice

Humanized Antibodies. Modern Developments and Prospects for the Creation of Medical Protectors Against Biological Threads and Hazards

Characterization of a novel tetravalent botulism antitoxin based on receptor-binding domain of BoNTs

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