How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

Laustsen, Andreas Hougaard

doi:10.1080/17460441.2019.1646723

Cited by 29 publications

(27 citation statements)

References 110 publications

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“…The choice of antivenom is not easy at central level, and should be targeted per regions for the moment, which is also complex. Next-generation monoclonal antibodies (mAbs) mixtures and PLA2 inhibitors (varespladib) are promising [25,26], but have not undergone clinical trials yet.…”

Section: Lack Of Antivenommentioning

confidence: 99%

Snakebite epidemiology and health-seeking behavior in Akonolinga health district, Cameroon: Cross-sectional study

et al. 2020

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Background Snakebite envenoming causes 81,000-138,000 annual human deaths and pain, terror, or disability in 4.5-5.4 million victims. Accurate community-based epidemiological data is scarce. Our objective was to assess snakebite incidence, mortality, and health-seeking behavior, in an affected health district of Cameroon. Methods We conducted a cross-sectional multicluster household survey in Akonolinga health district, Centre Region, Cameroon, from October to December 2016. Using probability-proportionalto-size, 20 villages were randomly selected, then, all inhabited households were systematically selected. Annual incidence and adjusted odds-ratio for predictors were estimated. Findings Among the 9,924 participants, 66 suffered a snakebite during the past year: the resulting incidence is 665 (95%CI: 519-841) per 100,000 inhabitants per year. Victims were aged 5-75y (median: 34y), 53% were male and 57% farmer-cultivators. Two children died (casefatality rate: 3%); 39 (59%) presented severity signs, including 2 (3%) neurotoxic syndromes, 20 (30%) systemic digestive syndromes, and 17 (26%) severe cytotoxic syndromes. Non-severe cases included 20 (30%) mild cytotoxic syndromes and 7 (11%) dry bites. Only two victims (3%) received antivenom. 59 (89%) used family traditional practices, 25 (38%) traditional healers, and 31 (47%) consulted health facilities. Median delays to these three care-options were 5, 45, and 60 minutes, respectively. Traditional treatments included incisions (n = 57; 86%), tourniquets (n = 51; 77%) and black-stones (n = 44; 67%).

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Section: Lack Of Antivenommentioning

confidence: 99%

Snakebite epidemiology and health-seeking behavior in Akonolinga health district, Cameroon: Cross-sectional study

et al. 2020

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“…Recently, the case for discovering mAbs for neglected tropical and other infectious diseases was reviewed [34]. This work took a broad, category-wide approach (viruses, bacteria, parasites) and also included venoms.…”

Section: Challenges To Developing Mabs Against Infectious Diseasesmentioning

confidence: 99%

“…Snake bites, and the challenge of envenoming, represent a serious health problem, resulting in 81,000 to 138,000 deaths yearly [35], and were recently included in the World Health Organization (WHO) list of neglected tropical diseases. The discovery of mAbs in this area logically follows the long-standing therapeutic successes with passive immunization [36], and the costs and feasibility of developing mAbs were recently reviewed [34,37][38], including specific clinical development and regulatory challenges [39]. In this Review, we selected diseases prioritized by the Global Health Innovative Technology (GHIT) Fund, an international collaboration between the public and private sectors, supporting collaborations between Japanese and non-Japanese entities to advance global health research and development [40,41].…”

Section: Challenges To Developing Mabs Against Infectious Diseasesmentioning

confidence: 99%

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Reassessing therapeutic antibodies for neglected and tropical diseases

et al. 2020

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In the past two decades there has been a significant expansion in the number of new therapeutic monoclonal antibodies (mAbs) that are approved by regulators. The discovery of these new medicines has been driven primarily by new approaches in inflammatory diseases and oncology, especially in immuno-oncology. Other recent successes have included new antibodies for use in viral diseases, including HIV. The perception of very high costs associated with mAbs has led to the assumption that they play no role in prophylaxis for diseases of poverty. However, improvements in antibody-expression yields and manufacturing processes indicate this is a cost-effective option for providing protection from many types of infection that should be revisited. Recent technology developments also indicate that several months of protection could be achieved with a single dose. Moreover, new methods in B cell sorting now enable the systematic identification of high-quality antibodies from humanized mice, or patients. This Review discusses the potential for passive immunization against schistosomiasis, fungal infections, dengue, and other neglected diseases.PLOS Neglected Tropical Diseases | https://doi.interactions have proved difficult to block. In addition, there has been great progress in the development of technology. Early generations of antibodies for human use were developed from mAbs developed in mice, antibodies that were then humanized. Recently, the technology used peptide and antibody display on phages, for which part of the 2018 Nobel Prize in Chemistry was awarded to Sir Gregory P. Winter [6]. More recently, new technologies have been developed to clone antibodies from memory B cells [7] or plasma B cells [8, 9], allowing the isolation of individual antibodies from patients with viral infections-approaches that can be applied to any infectious disease.A second reason for the popularity of antibodies in recent years is their success rate in clinical development. Once an antibody reaches testing in humans, it has a success rate of 17% to 25% for approval as a new medicine [10], compared with 5% to 10% for small molecules. This success rate is partly due to the exquisite selectivity of mAbs, enabling them to distinguish between closely related molecular targets. In the case of infectious disease, this selectivity can be absolute, since antibodies can be generated that are specific for the invading pathogen and do not cross-react with host tissues. This lack of cross-reactivity with human tissue can be confirmed by immunohistochemistry on both adult and embryonic tissues prior to the start of clinical trials. This is in stark contrast to small molecules, in which sometimes unexpected onand off-target safety signals are frequently seen in the later stages of clinical development, resulting in expensive late-stage attrition. In addition, antibodies show a relatively narrow range of variation in pharmacokinetic exposure, facilitating early estimation of the human effective dose. This is unlike true xenobiotics, whose metabolism an...

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“…Additionally, recombinant antivenoms have also been hypothesized to be manufacturable at low cost ( Laustsen et al, 2016 , 2017 ), which is an important parameter for therapies against neglected tropical diseases. However, one of the challenges that sets snakebite envenoming aside from other indications that are treatable with antibodies is that exceptionally high amounts of antibodies are needed for effective treatment ( Laustsen, 2019 ). Therefore, the cost of manufacture should be a key focal point for recombinant antivenom developers ( Laustsen and Dorrestijn, 2018 ; Knudsen et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Cost of Manufacturing for Recombinant Snakebite Antivenoms

Jenkins

Laustsen

2020

Front. Bioeng. Biotechnol.

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Snakebite envenoming is a neglected tropical disease that affects millions of people across the globe. It has been suggested that recombinant antivenoms based on mixtures of human monoclonal antibodies, which target key toxins of medically important snake venom, could present a promising avenue toward the reduction of morbidity and mortality of envenomated patients. However, since snakebite envenoming is a disease of poverty, it is pivotal that next-generation therapies are affordable to those most in need; this warrants analysis of the cost dynamics of recombinant antivenom manufacture. Therefore, we present, for the first time, a bottom-up analysis of the cost dynamics surrounding the production of future recombinant antivenoms based on available industry data. We unravel the potential impact that venom volume, abundance of medically relevant toxins in a venom, and the molecular weight of these toxins may have on the final product cost. Furthermore, we assess the roles that antibody molar mass, manufacturing and purification strategies, formulation, antibody efficacy, and potential cross-reactivity play in the complex cost dynamics of recombinant antivenom manufacture. Notably, according to our calculations, it appears that such next-generation antivenoms based on cocktails of monoclonal immunoglobulin Gs (IgGs) could be manufacturable at a comparable or lower cost to current plasma-derived antivenoms, which are priced at USD 13-1120 per treatment. We found that monovalent recombinant antivenoms based on IgGs could be manufactured for USD 20-225 per treatment, while more complex polyvalent recombinant antivenoms based on IgGs could be manufactured for USD 48-1354 per treatment. Finally, we investigated the prospective cost of manufacturing for recombinant antivenoms based on alternative protein scaffolds, such as DARPins and nanobodies, and highlight the potential utility of such scaffolds in the context of low-cost manufacturing. In conclusion, the development of recombinant antivenoms not only holds a promise for improving therapeutic parameters, such as safety and efficacy, but could possibly also lead to a more competetive cost of manufacture of antivenom products for patients worldwide.

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How can monoclonal antibodies be harnessed against neglected tropical diseases and other infectious diseases?

Cited by 29 publications

References 110 publications

Snakebite epidemiology and health-seeking behavior in Akonolinga health district, Cameroon: Cross-sectional study

Snakebite epidemiology and health-seeking behavior in Akonolinga health district, Cameroon: Cross-sectional study

Reassessing therapeutic antibodies for neglected and tropical diseases

Cost of Manufacturing for Recombinant Snakebite Antivenoms

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