Monoclonal human IgGs capable of neutralizing elapid neurotoxins in vivo

Urska Pus, Andreas Hougaard Laustsen, Aneesh Karatt-Vellatt, Daniel T. Griffiths, Saioa Oscoz, Mikael Rørdam Andersen, Robert Harrison, Nicholas Casewell, Bruno Lomonte, John McCafferty, José María Gutiérrez

Research output: Contribution to journalConference abstract in journalResearchpeer-review

Abstract

The two elapids, the black mamba (Dendroaspis polylepis) and the monocled cobra (Naja kaouthia) are notorious for their bite, which each year causes a substantial share of the severe envenomings that occur in sub Saharan Africa and Southeast Asia, respectively. Through a combined toxicovenomics and the phage display selection approach, monoclonal fully human IgGs were discovered and assessed for their ability to neutralize medically relevant toxins from the aforementioned snakes in vivo. The discovered monoclonal human IgGs were expressed in mammalian Expi-293 cells and tested in CD-1 mice using two different routes of administration. Initially, IgGs were incubated for 30 min at 37°C together with their target toxins in different molar ratios (mol toxin: mol IgG of 1:3 to 1:8) and then administered either intracerebroventricularly (i.c.v.) (dendrotoxins) using a toxin dose of 0.5 μg or intravenously (i.v.) (α-cobratoxin) using a toxin dose of 4 μg to evaluate the neutralization potential of the IgGs. The survival of mice administered with lethal doses of elapid toxins was substantially prolonged by the monoclonal human IgGs. Hence, we report the discovery of monoclonal fully human IgGs that are able to neutralize snake toxins in vivo. Additionally, one of the tested human IgGs was able to prolong survival both against its cognate toxin (α-cobratoxin) and against whole venom from N. kaouthia. This demonstrates the applicability of the Toxicity Score for identifying medically relevant toxins in a venom and that α-cobratoxin is one of the key toxic components of N. kaouthia venom.
Original languageEnglish
Article number145
JournalToxicon
Volume158
Issue numberSuppl. 1
Pages (from-to)S44-S44
Number of pages1
ISSN0041-0101
DOIs
Publication statusPublished - 2019

Cite this

Pus, U., Laustsen, A. H., Karatt-Vellatt, A., Griffiths, D. T., Oscoz, S., Andersen, M. R., ... Gutiérrez, J. M. (2019). Monoclonal human IgGs capable of neutralizing elapid neurotoxins in vivo. Toxicon, 158(Suppl. 1), S44-S44. [145]. https://doi.org/10.1016/j.toxicon.2018.10.154
Pus, Urska ; Laustsen, Andreas Hougaard ; Karatt-Vellatt, Aneesh ; Griffiths, Daniel T. ; Oscoz, Saioa ; Andersen, Mikael Rørdam ; Harrison, Robert ; Casewell, Nicholas ; Lomonte, Bruno ; McCafferty, John ; Gutiérrez, José María. / Monoclonal human IgGs capable of neutralizing elapid neurotoxins in vivo. In: Toxicon. 2019 ; Vol. 158, No. Suppl. 1. pp. S44-S44.
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title = "Monoclonal human IgGs capable of neutralizing elapid neurotoxins in vivo",
abstract = "The two elapids, the black mamba (Dendroaspis polylepis) and the monocled cobra (Naja kaouthia) are notorious for their bite, which each year causes a substantial share of the severe envenomings that occur in sub Saharan Africa and Southeast Asia, respectively. Through a combined toxicovenomics and the phage display selection approach, monoclonal fully human IgGs were discovered and assessed for their ability to neutralize medically relevant toxins from the aforementioned snakes in vivo. The discovered monoclonal human IgGs were expressed in mammalian Expi-293 cells and tested in CD-1 mice using two different routes of administration. Initially, IgGs were incubated for 30 min at 37°C together with their target toxins in different molar ratios (mol toxin: mol IgG of 1:3 to 1:8) and then administered either intracerebroventricularly (i.c.v.) (dendrotoxins) using a toxin dose of 0.5 μg or intravenously (i.v.) (α-cobratoxin) using a toxin dose of 4 μg to evaluate the neutralization potential of the IgGs. The survival of mice administered with lethal doses of elapid toxins was substantially prolonged by the monoclonal human IgGs. Hence, we report the discovery of monoclonal fully human IgGs that are able to neutralize snake toxins in vivo. Additionally, one of the tested human IgGs was able to prolong survival both against its cognate toxin (α-cobratoxin) and against whole venom from N. kaouthia. This demonstrates the applicability of the Toxicity Score for identifying medically relevant toxins in a venom and that α-cobratoxin is one of the key toxic components of N. kaouthia venom.",
author = "Urska Pus and Laustsen, {Andreas Hougaard} and Aneesh Karatt-Vellatt and Griffiths, {Daniel T.} and Saioa Oscoz and Andersen, {Mikael R{\o}rdam} and Robert Harrison and Nicholas Casewell and Bruno Lomonte and John McCafferty and Guti{\'e}rrez, {Jos{\'e} Mar{\'i}a}",
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doi = "10.1016/j.toxicon.2018.10.154",
language = "English",
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Pus, U, Laustsen, AH, Karatt-Vellatt, A, Griffiths, DT, Oscoz, S, Andersen, MR, Harrison, R, Casewell, N, Lomonte, B, McCafferty, J & Gutiérrez, JM 2019, 'Monoclonal human IgGs capable of neutralizing elapid neurotoxins in vivo', Toxicon, vol. 158, no. Suppl. 1, 145, pp. S44-S44. https://doi.org/10.1016/j.toxicon.2018.10.154

Monoclonal human IgGs capable of neutralizing elapid neurotoxins in vivo. / Pus, Urska; Laustsen, Andreas Hougaard; Karatt-Vellatt, Aneesh; Griffiths, Daniel T.; Oscoz, Saioa; Andersen, Mikael Rørdam; Harrison, Robert; Casewell, Nicholas; Lomonte, Bruno; McCafferty, John; Gutiérrez, José María.

In: Toxicon, Vol. 158, No. Suppl. 1, 145, 2019, p. S44-S44.

Research output: Contribution to journalConference abstract in journalResearchpeer-review

TY - ABST

T1 - Monoclonal human IgGs capable of neutralizing elapid neurotoxins in vivo

AU - Pus, Urska

AU - Laustsen, Andreas Hougaard

AU - Karatt-Vellatt, Aneesh

AU - Griffiths, Daniel T.

AU - Oscoz, Saioa

AU - Andersen, Mikael Rørdam

AU - Harrison, Robert

AU - Casewell, Nicholas

AU - Lomonte, Bruno

AU - McCafferty, John

AU - Gutiérrez, José María

PY - 2019

Y1 - 2019

N2 - The two elapids, the black mamba (Dendroaspis polylepis) and the monocled cobra (Naja kaouthia) are notorious for their bite, which each year causes a substantial share of the severe envenomings that occur in sub Saharan Africa and Southeast Asia, respectively. Through a combined toxicovenomics and the phage display selection approach, monoclonal fully human IgGs were discovered and assessed for their ability to neutralize medically relevant toxins from the aforementioned snakes in vivo. The discovered monoclonal human IgGs were expressed in mammalian Expi-293 cells and tested in CD-1 mice using two different routes of administration. Initially, IgGs were incubated for 30 min at 37°C together with their target toxins in different molar ratios (mol toxin: mol IgG of 1:3 to 1:8) and then administered either intracerebroventricularly (i.c.v.) (dendrotoxins) using a toxin dose of 0.5 μg or intravenously (i.v.) (α-cobratoxin) using a toxin dose of 4 μg to evaluate the neutralization potential of the IgGs. The survival of mice administered with lethal doses of elapid toxins was substantially prolonged by the monoclonal human IgGs. Hence, we report the discovery of monoclonal fully human IgGs that are able to neutralize snake toxins in vivo. Additionally, one of the tested human IgGs was able to prolong survival both against its cognate toxin (α-cobratoxin) and against whole venom from N. kaouthia. This demonstrates the applicability of the Toxicity Score for identifying medically relevant toxins in a venom and that α-cobratoxin is one of the key toxic components of N. kaouthia venom.

AB - The two elapids, the black mamba (Dendroaspis polylepis) and the monocled cobra (Naja kaouthia) are notorious for their bite, which each year causes a substantial share of the severe envenomings that occur in sub Saharan Africa and Southeast Asia, respectively. Through a combined toxicovenomics and the phage display selection approach, monoclonal fully human IgGs were discovered and assessed for their ability to neutralize medically relevant toxins from the aforementioned snakes in vivo. The discovered monoclonal human IgGs were expressed in mammalian Expi-293 cells and tested in CD-1 mice using two different routes of administration. Initially, IgGs were incubated for 30 min at 37°C together with their target toxins in different molar ratios (mol toxin: mol IgG of 1:3 to 1:8) and then administered either intracerebroventricularly (i.c.v.) (dendrotoxins) using a toxin dose of 0.5 μg or intravenously (i.v.) (α-cobratoxin) using a toxin dose of 4 μg to evaluate the neutralization potential of the IgGs. The survival of mice administered with lethal doses of elapid toxins was substantially prolonged by the monoclonal human IgGs. Hence, we report the discovery of monoclonal fully human IgGs that are able to neutralize snake toxins in vivo. Additionally, one of the tested human IgGs was able to prolong survival both against its cognate toxin (α-cobratoxin) and against whole venom from N. kaouthia. This demonstrates the applicability of the Toxicity Score for identifying medically relevant toxins in a venom and that α-cobratoxin is one of the key toxic components of N. kaouthia venom.

U2 - 10.1016/j.toxicon.2018.10.154

DO - 10.1016/j.toxicon.2018.10.154

M3 - Conference abstract in journal

VL - 158

SP - S44-S44

JO - Toxicon

JF - Toxicon

SN - 0041-0101

IS - Suppl. 1

M1 - 145

ER -