VHH, bivalent domains and chimeric Heavy chain-only antibodies with high neutralizing efficacy for scorpion toxin AahI′

Hmila, Issam; R, Ben Abderrazek Ben Abdallah; Saerens, Dirk; Benlasfar, Zakaria; Conrath, Katja; Ayeb, Mohamed El; Muyldermans, Serge; Bouhaouala‐Zahar, Balkiss

doi:10.1016/j.molimm.2008.04.011

Cited by 126 publications

(105 citation statements)

References 47 publications

(66 reference statements)

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“…15 Due to an increased avidity, the construction of bivalent VHHs typically improves the neutralization potency of VHHs. 16,17 The increased molecular size may also contribute to this effect by extending the half-life of the construct, as has been observed by comparison of the neutralizing activity of glycosylated and deglycosylated VHHs against the heat-labile toxin of E. coli produced in yeast. 18 The half-life of VHHs has also been prolonged via interaction with the neonatal Fc receptor by fusing them to Fc fragments, 19 or to a second VHH with affinity for host immunoglobulins 11 or albumin.…”

Section: Introductionmentioning

confidence: 95%

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Increasing the potency of neutralizing single-domain antibodies by functionalization with a CD11b/CD18 binding domain

Rossotti

González-Techera

Guarnaschelli

et al. 2015

mAbs

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Recombinant single domain antibodies (nanobodies) constitute an attractive alternative for the production of neutralizing therapeutic agents. Their small size warrants rapid bioavailability and fast penetration to sites of toxin uptake, but also rapid renal clearance, which negatively affects their performance. In this work, we present a new strategy to drastically improve the neutralizing potency of single domain antibodies based on their fusion to a second nanobody specific for the complement receptor CD11b/CD18 (Mac-1). These bispecific antibodies retain a small size (»30 kDa), but acquire effector functions that promote the elimination of the toxin-immunocomplexes. The principle was demonstrated in a mouse model of lethal toxicity with tetanus toxin. Three anti-tetanus toxin nanobodies were selected and characterized in terms of overlapping epitopes and inhibition of toxin binding to neuron gangliosides. Bispecific constructs of the most promising monodomain antibodies were built using anti Mac-1, CD45 and MHC II nanobodies. When co-administered with the toxin, all bispecific antibodies showed higher toxin-neutralizing capacity than the monomeric ones, but only their fusion to the anti-endocytic receptor Mac-1 nanobody allowed the mice to survive a 10-fold lethal dose. In a model of delayed neutralization of the toxin, the anti-Mac-1 bispecific antibodies outperformed a sheep anti-toxin polyclonal IgG that had shown similar neutralization potency in the co-administration experiments. This strategy should have widespread application in the development of nanobody-based neutralizing therapeutics, which can be produced economically and more safely than conventional antisera.

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Section: Introductionmentioning

confidence: 95%

“…16,17 To this end we combined VH T5 with VHH T3 using the flexible spacer -GGGSGGGS-; having non-overlapping epitopes, this could allow the simultaneously binding of these 2 nanobodies to the toxin. Indeed, the increased avidity of the bivalent antibody was reflected by the kinetic measurements performed by biolayer…”

Section: Selection Of Tetc Specific Vh/vhhsmentioning

confidence: 99%

Increasing the potency of neutralizing single-domain antibodies by functionalization with a CD11b/CD18 binding domain

Rossotti

González-Techera

Guarnaschelli

et al. 2015

mAbs

View full text Add to dashboard Cite

show abstract

“…Кро-ме того, антитела используются в лечении вирус-ных инфекций [103,122] и для нейтрализации токсинов [63,64,126]. Появление цитокин-ней-трализующих антител совершило переворот в те-рапии ревматоидного артрита, псориаза и других хронических воспалительных заболеваний [1].…”

Section: применение наноантител в терапииunclassified

“…С этой целью в том числе используется восстановление генно-инженерных наноантител до полноразмерной формы путем добавления Fc-области, что продлевает время пребывания наноантител в кровотоке за счет увеличения раз-мера молекулы [63]. Используется также сшивка наноантител с сывороточным альбумином.…”

Section: применение наноантител в терапииunclassified