Development of an inhibiting antibody against equine interleukin 5 to treat insect bite hypersensitivity of horses

Langreder, Nora; Schäckermann, Dorina; Meier, Doris; Becker, Marlies; Schubert, Maren; Dübel, Stefan; Reinard, Thomas; Figge-Wegener, Stefanie; Roßbach, Kristine; Bäumer, Wolfgang; Ladel, Simone; Hust, Michael

doi:10.1038/s41598-023-31173-y

Cited by 4 publications

(4 citation statements)

References 60 publications

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“…Interestingly, despite the high molecular weight of the protein (~130 kDa), four to five consecutive panning rounds were needed to significantly increase the hit-rate. This is in contrast to other antibody selections ( 41 , 46 , 48 , 52 , 64 , 65 ) and most likely explained by a low representation of anti α-LTX scFv in the naïve library. The most efficient strategy was using a mix of both libraries and panning in MTP.…”

Section: Discussioncontrasting

confidence: 63%

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Human antibodies neutralizing the alpha-latrotoxin of the European black widow

Ruschig,

Nerlich,

Becker

et al. 2024

Front. Immunol.

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Poisoning by widow-spider (genus Latrodectus) bites occurs worldwide. The illness, termed latrodectism, can cause severe and persistent pain and can lead to muscle rigidity, respiratory complications, and cardiac problems. It is a global health challenge especially in developing countries. Equine serum-derived polyclonal anti-sera are commercially available as a medication for patients with latrodectism, but the use of sera imposes potential inherent risks related to its animal origin. The treatment may cause allergic reactions in humans (serum sickness), including anaphylactic shock. Furthermore, equine-derived antivenom is observed to have batch-to-batch variability and poor specificity, as it is always an undefined mix of antibodies. Because latrodectism can be extremely painful but is rarely fatal, the use of antivenom is controversial and only a small fraction of patients is treated. In this work, recombinant human antibodies were selected against alpha-latrotoxin of the European black widow (Latrodectus tredecimguttatus) by phage display from a naïve antibody gene library. Alpha-Latrotoxin (α-LTX) binding scFv were recloned and produced as fully human IgG. A novel alamarBlue assay for venom neutralization was developed and used to select neutralizing IgGs. The human antibodies showed in vitro neutralization efficacy both as single antibodies and antibody combinations. This was also confirmed by electrophysiological measurements of neuronal activity in cell culture. The best neutralizing antibodies showed nanomolar affinities. Antibody MRU44–4-A1 showed outstanding neutralization efficacy and affinity to L. tredecimguttatus α-LTX. Interestingly, only two of the neutralizing antibodies showed cross-neutralization of the venom of the Southern black widow (Latrodectus mactans). This was unexpected, because in the current literature the alpha-latrotoxins are described as highly conserved. The here-engineered antibodies are candidates for future development as potential therapeutics and diagnostic tools, as they for the first time would provide unlimited supply of a chemically completely defined drug of constant quality and efficacy, which is also made without the use of animals.

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Section: Discussioncontrasting

confidence: 63%

“…Lastly, antibodies generated here can be improved to increase affinity against other Latrodectus species, e.g. by affinity maturation ( 64 , 74 ).…”

Section: Discussionmentioning

confidence: 99%

Human antibodies neutralizing the alpha-latrotoxin of the European black widow

Ruschig,

Nerlich,

Becker

et al. 2024

Front. Immunol.

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“…The TB had many ROHs and these contained over 300 annotated genes (see Additional file 4 : Table S3), including genes that were previously associated with memory formation ( FSTL4 ), bone formation, lung function and development ( WNT2B ), muscle cell proliferation and regulation of myogenesis ( KCNRG, MSTN ), and hip conformation ( IRX2 ) [ 61 ]. The ROH islands contained several interleukin genes ( IL4, IL5, IL13 ), which, together with their associated receptors, have been implicated in inflammatory processes such as recurrent airway obstruction and summer-pasture associated obstructive pulmonary disease ( IL4, IL13 [ 62 – 64 ]) or insect bite hypersensitivity ( IL5 [ 65 – 67 ]). There were also three Insulin-like growth factor binding protein genes ( IGFBP1, IGFBP3, and IGFBP6 ), which are involved in somatic cell growth and muscle cell distribution, and were previously identified in breed-specific ROH islands including German and Swedish WB horses [ 13 , 19 ] as well as French Trotters [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Using high-density SNP data to unravel the origin of the Franches-Montagnes horse breed

Gmel,

Mikko,

Ricard

et al. 2024

Genet Sel Evol

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Background The Franches-Montagnes (FM) is the last native horse breed of Switzerland, established at the end of the 19th century by cross-breeding local mares with Anglo-Norman stallions. We collected high-density SNP genotype data (Axiom™ 670 K Equine genotyping array) from 522 FM horses, including 44 old-type horses (OF), 514 European Warmblood horses (WB) from Sweden and Switzerland (including a stallion used for cross-breeding in 1990), 136 purebred Arabians (AR), 32 Shagya Arabians (SA), and 64 Thoroughbred (TB) horses, as introgressed WB stallions showed TB origin in their pedigrees. The aim of the study was to ascertain fine-scale population structures of the FM breed, including estimation of individual admixture levels and genomic inbreeding (FROH) by means of Runs of Homozygosity. Results To assess fine-scale population structures within the FM breed, we applied a three-step approach, which combined admixture, genetic contribution, and FROH of individuals into a high-resolution network visualization. Based on this approach, we were able to demonstrate that population substructures, as detected by model-based clustering, can be either associated with a different genetic origin or with the progeny of most influential sires. Within the FM breed, admixed horses explained most of the genetic variance of the current breeding population, while OF horses only accounted for a small proportion of the variance. Furthermore, we illustrated that FM horses showed high TB admixture levels and we identified inconsistencies in the origin of FM horses descending from the Arabian stallion Doktryner. With the exception of WB, FM horses were less inbred compared to the other breeds. However, the relatively few but long ROH segments suggested diversity loss in both FM subpopulations. Genes located in FM- and OF-specific ROH islands had known functions involved in conformation and behaviour, two traits that are highly valued by breeders. Conclusions The FM remains the last native Swiss breed, clearly distinguishable from other historically introgressed breeds, but it suffered bottlenecks due to intensive selection of stallions, restrictive mating choices based on arbitrary definitions of pure breeding, and selection of rare coat colours. To preserve the genetic diversity of FM horses, future conservation managements strategies should involve a well-balanced selection of stallions (e.g., by integrating OF stallions in the FM breeding population) and avoid selection for rare coat colours.

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“…Currently, the large size and weight of horses precludes the economical use of viruslike particle (VLP)-based therapeutic vaccines targeting IL-5 and 31 in horses [18,56]. The next step now in exploring this technology would involve in vivo studies on affected horses.…”

Section: Virus-like Particle (Vlp)-based Therapeutic Vaccines Targeti...mentioning

confidence: 99%

Insect Bite Hypersensitivity in Horses: Causes, Diagnosis, Scoring and New Therapies

Cox

Stewart

2023

Animals

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Insect Bite Hypersensitivity (IBH, Queensland itch, sweet itch, equine summer eczema) is the most common pruritic disease of horses. It is most often caused by sensitivity to the saliva of Culicoides spp. of biting midges; however, it can also be caused by hypersensitivity to other insect species. The prevalence of IBH in horses is reported to be as high as 60% in some parts of the world. Due to the severe pruritus and effects of secondary self-trauma, IBH has animal welfare concerns, and there is currently no cure. Management of this condition is life-long, time consuming and costly. New grading systems to document disease severity are being validated, which will allow the comparison of clinical trial results of new and existing therapies. Management involves the minimisation of insect bites by use of stabling, fans, rugs and repellents. Symptomatic therapy involves the administration of systemic or topical corticosteroids, systemic antihistamines, and creams and sprays to promote skin healing and decrease inflammation. New immune-mediated therapeutics including vaccines, in addition to desensitisation procedures, show promise at controlling hypersensitivity reactions. This article will review aetiologic agents, pathophysiology, scoring systems and current and new therapies.

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Development of an inhibiting antibody against equine interleukin 5 to treat insect bite hypersensitivity of horses

Cited by 4 publications

References 60 publications

Human antibodies neutralizing the alpha-latrotoxin of the European black widow

Human antibodies neutralizing the alpha-latrotoxin of the European black widow

Using high-density SNP data to unravel the origin of the Franches-Montagnes horse breed

Insect Bite Hypersensitivity in Horses: Causes, Diagnosis, Scoring and New Therapies

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