Current technology for the industrial manufacture of snake antivenoms

León, Guillermo; Vargas, Mariángela; Segura, Álvaro; Herrera, María; Villalta, Mauren; Sánchez, Andrés; Solano, Gabriela; Gómez, Aarón; Sánchez, Melvin; Estrada, Ricardo; Gutiérrez, José Marı́a

doi:10.1016/j.toxicon.2018.06.084

Cited by 72 publications

(49 citation statements)

References 112 publications

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“…Another important stage in the production phase is the stabilization process of antivenoms, known as the freeze-drying technique. In this process, because of the structural changes that the toxins are subjected to due to the stress, the effectiveness of the two venoms with the same toxicity profile may differ 12 . In addition, as a result of the batch-to-batch variation out from the factory, there may be differences between the antivenom success and effectiveness even in antivenoms produced at different times in the same production facility.…”

Section: Discussionmentioning

confidence: 99%

Comparison of two types of polyvalent snake antivenom used in treatment

Gülen¹,

Satar²,

Yeşiloğlu³

et al. 2020

Cukurova Medical Journal

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Öz Purpose: In this study; we aimed to compare the effectiveness of the two types of polyvalent snake antivenom and to determine the possible local and systemic reactions in patients who admitted to the emergency department with snake bite. Materials and Methods: We performed this retrospective study on 30 patients who complained of snakebite. We grouped the patients according to the antivenom type (PoliseraTM or Polivalan TM) which they received. Demographic characteristics of the patients, vital signs, local tissue findings, and laboratory parameters were recorded in the standard data form. The following data were also recorded; the number of vials of snake antivenom used in each group, additional doses of venom were administered, and whether any local or systemic reaction to antivenom has developed or not. Results: Thirty patients were included in the study. 16 patients were administered PoliseraTM (Group 1) snake antivenom and 14 patients were administered Polivalan TM (Group 2) snake antivenom. Patients in Group 1 were given an average of 9.1±7.3 vials, while patients in Group 2 were given an average of 11.6±12.7 vials. More allergic reactions-urticaria, fever, and cellulite were observed in the group receiving PolivalanTM antivenom. Conclusion: Different methodologies arising from the production of antivenom, pyrogen contamination, and differences in packaging can cause different effects and side effects even in products with the same dose and antivenom content. Amaç: Bu çalışmada; acil servise yılan ısırması ile başvuran hastalarda kullanılan iki tip polivalan yılan antivenomun etkinliğinin karşılaştırılması ve olası lokal ve sistemik yan etkilerin belirlenmesi amaçlanmıştır. Gereç ve Yöntem: Bu retrospektif çalışmaya yılan ısırması şikayeti olan 30 hasta dahil edildi. Hastalar aldıkları antivenom tipine (PoliseraTM veya PolivalanTM) göre gruplandırıldı. Hastaların demografik özelliklerinin yanı sıra, vital bulguları, lokal doku bulguları ve laboratuvar parametreleri standart veri formuna kaydedildi. Her grupta kaç vial yılan anti serumu kullanıldığı, kaç kez ek doz venom ihtiyacı olduğu; antivenoma karşı herhangi bir reaksiyon gelişip gelişmediği kaydedildi. Bulgular: Çalışmaya 30 hasta dahil edildi. 16 hastaya Polisera TM (Grup 1) yılan antivenomu, 14 hastaya PolivalanTM (Grup 2) yılan antivenomu verildi. Grup 1'deki hastalara ortalama 9.1±7.3 vial antivenom verilirken, Grup 2'deki hastalara ortalama 11.6±12.7 vial verildi. PolivalanTM antivenom alan grupta daha fazla alerjik reaksiyon-ürtiker, ateş ve selülitgözlendi. Sonuç: Pirojen kontaminasyonu, üretimden kaynaklanan farklı metodolojiler ve ambalaj farklılıkları aynı doz ve içeriğe sahip antivenom ürünlerinde bile farklı etkilere ve yan etkilere neden olabilir.

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Section: Discussionmentioning

confidence: 99%

Comparison of two types of polyvalent snake antivenom used in treatment

Gülen¹,

Satar²,

Yeşiloğlu³

et al. 2020

Cukurova Medical Journal

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“…Aside from the doubtful role of the Fc fraction in adverse reactions [ 18 , 19 , 22 , 23 ], its removal reduces the quantity of foreign material in the product intended for use in humans, thus increasing specific activity and at least partially contributing to safety improvement. Although both F(ab') 2 and Fab antivenoms are currently involved in snakebite management [ 20 ], fewer laboratories have adopted the production of the latter ones for commercial purposes [ 24 ]. Specifically, in vast majority of cases F(ab') 2 antivenoms have been considered more efficacious in a clinical setting owing to their pharmacokinetic properties, which are valid for longer retention in systemic circulation, and possession of two antigen-binding sites, mediating the venom-neutralization activity through formation of large, stable and precipitable complexes [ 20 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…Additional procedures, most notably ion-exchange chromatography, have been introduced to increase the product's purity after an initial processing step, such as salting-out or caprylic acid fractionation of pepsin-digested plasma [ 16 , 24 ]. The anion-exchange approach is favored for pragmatic reasons, since contaminants bind to the column, whereas IgGs or their fragments, present at much higher concentrations, remain unhindered [ 24 , 26 ]. Affinity chromatography for the purification of F(ab') 2 fragments has also been suggested [ 27 ], although its application for industrial manufacture is largely impractical from the standpoint of cost [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…The anion-exchange approach is favored for pragmatic reasons, since contaminants bind to the column, whereas IgGs or their fragments, present at much higher concentrations, remain unhindered [ 24 , 26 ]. Affinity chromatography for the purification of F(ab') 2 fragments has also been suggested [ 27 ], although its application for industrial manufacture is largely impractical from the standpoint of cost [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Streamlined downstream process for efficient and sustainable (Fab')2 antivenom preparation

Kurtović

Brgles

Balija

et al. 2020

J. Venom. Anim. Toxins incl. Trop. Dis

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Background: Antivenoms are the only validated treatment against snakebite envenoming. Numerous drawbacks pertaining to their availability, safety and efficacy are becoming increasingly evident due to low sustainability of current productions. Technological innovation of procedures generating therapeutics of higher purity and better physicochemical characteristics at acceptable cost is necessary. The objective was to develop at laboratory scale a compact, feasible and economically viable platform for preparation of equine F(ab') 2 antivenom against Vipera ammodytes ammodytes venom and to support it with efficiency data, to enable estimation of the process cost-effectiveness. Methods: The principle of simultaneous caprylic acid precipitation and pepsin digestion has been implemented into plasma downstream processing. Balance between incomplete IgG breakdown, F(ab') 2 over-digestion and loss of the active drug's protective efficacy was achieved by adjusting pepsin to a 1:30 substrate ratio ( w / w ) and setting pH at 3.2. Precipitation and digestion co-performance required 2 h-long incubation at 21 °C. Final polishing was accomplished by a combination of diafiltration and flow-through chromatography. In vivo neutralization potency of the F(ab') 2 product against the venom's lethal toxicity was determined. Results: Only three consecutive steps, performed under finely tuned conditions, were sufficient for preservation of the highest process recovery with the overall yield of 74%, comparing favorably to others. At the same time, regulatory requirements were met. Final product was aggregate- and pepsin-free. Its composition profile was analyzed by mass spectrometry as a quality control check. Impurities, present in minor traces, were identified mostly as IgG/IgM fragments, contributing to active drug. Specific activity of the F(ab') 2 preparation with respect to the plasma was increased 3.9-fold. Conclusion: A highly streamlined mode for production of equine F(ab') 2 antivenom was engineered. In addition to preservation of the highest process yield and fulfillment of the regulatory demands, performance simplicity and rapidity in the laboratory setting were demonstrated. Suitability for large-scale manufacturing appears promising.

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“…Antivenom production involves the repeated immunization (for months to years) of large mammals (mostly horses and sheep), followed by purification of the immunoglobulin G (IgG) antibodies from the hyper-immunized plasma. IgG purification is typically carried out by salting-out procedures using either caprylic acid or ammonium sulfate [ 9 , 14 , 17 , 18 , 19 ]. Additionally, most manufacturers produce F(ab’) 2 antivenoms by introducing a pepsin digestion step [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Innovative Immunization Strategies for Antivenom Development

Bermúdez-Méndez

Fuglsang-Madsen

Føns

et al. 2018

Toxins

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Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with antivenom. Current antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation antivenoms.

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Current technology for the industrial manufacture of snake antivenoms

Cited by 72 publications

References 112 publications

Comparison of two types of polyvalent snake antivenom used in treatment

Comparison of two types of polyvalent snake antivenom used in treatment

Streamlined downstream process for efficient and sustainable (Fab')2 antivenom preparation

Innovative Immunization Strategies for Antivenom Development

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