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Neutralizing human monoclonal antibodies binding multiple serotypes of botulinum neurotoxin.

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Title: Neutralizing human monoclonal antibodies binding multiple serotypes of botulinum neurotoxin.
Authors: Garcia-Rodriguez, C.1, Geren, I.N.1, Lou, J.1, Conrad, F.1, Forsyth, C.1, Wen, W.1, Chakraborti, S.1, Zao, H.1, Manzanarez, G.1, Smith, T.J.2, Brown, J.2, Tepp, W.H.3, Liu, N.4, Wijesuriya, S.4, Tomic, M.T.4, Johnson, E.A.3, Smith, L.A.2, Marks, J.D.1
Source: PEDS: Protein Engineering, Design & Selection. Mar2011, Vol. 24 Issue 3, p321-331. 11p. 3 Diagrams, 4 Charts, 4 Graphs.
Subjects: Monoclonal antibodies, Botulinum toxin, Paralysis, Etiology of diseases, Amino acids, Serotypes, Molecular evolution
Abstract: Botulism, a disease of humans characterized by prolonged paralysis, is caused by botulinum neurotoxins (BoNTs), the most poisonous substances known. There are seven serotypes of BoNT (A–G) which differ from each other by 34–64% at the amino acid level. Each serotype is uniquely recognized by polyclonal antibodies, which originally were used to classify serotypes. To determine if there existed monoclonal antibodies (mAbs) capable of binding two or more serotypes, we evaluated the ability of 35 yeast-displayed single-chain variable fragment antibodies generated from vaccinated humans or mice for their ability to bind multiple BoNT serotypes. Two such clonally related human mAbs (1B18 and 4E17) were identified that bound BoNT serotype A (BoNT/A) and B or BoNT/A, B, E and F, respectively, with high affinity. Using molecular evolution techniques, it proved possible to both increase affinity and maintain cross-serotype reactivity for the 4E17 mAb. Both 1B18 and 4E17 bound to a relatively conserved epitope at the tip of the BoNT translocation domain. Immunoglobulin G constructed from affinity matured variants of 1B18 and 4E17 were evaluated for their ability to neutralize BoNT/B and E, respectively, in vivo. Both antibodies potently neutralized BoNT in vivo demonstrating that this epitope is functionally important in the intoxication pathway. Such cross-serotype binding and neutralizing mAbs should simplify the development of antibody-based BoNT diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]
Copyright of PEDS: Protein Engineering, Design & Selection is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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  Data: Neutralizing human monoclonal antibodies binding multiple serotypes of botulinum neurotoxin.
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  Data: <searchLink fieldCode="AR" term="%22Garcia-Rodriguez%2C+C%2E%22">Garcia-Rodriguez, C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Geren%2C+I%2EN%2E%22">Geren, I.N.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lou%2C+J%2E%22">Lou, J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Conrad%2C+F%2E%22">Conrad, F.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Forsyth%2C+C%2E%22">Forsyth, C.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Wen%2C+W%2E%22">Wen, W.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Chakraborti%2C+S%2E%22">Chakraborti, S.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Zao%2C+H%2E%22">Zao, H.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Manzanarez%2C+G%2E%22">Manzanarez, G.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Smith%2C+T%2EJ%2E%22">Smith, T.J.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Brown%2C+J%2E%22">Brown, J.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Tepp%2C+W%2EH%2E%22">Tepp, W.H.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Liu%2C+N%2E%22">Liu, N.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Wijesuriya%2C+S%2E%22">Wijesuriya, S.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Tomic%2C+M%2ET%2E%22">Tomic, M.T.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Johnson%2C+E%2EA%2E%22">Johnson, E.A.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Smith%2C+L%2EA%2E%22">Smith, L.A.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Marks%2C+J%2ED%2E%22">Marks, J.D.</searchLink><relatesTo>1</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22PEDS%3A+Protein+Engineering%2C+Design+%26+Selection%22">PEDS: Protein Engineering, Design & Selection</searchLink>. Mar2011, Vol. 24 Issue 3, p321-331. 11p. 3 Diagrams, 4 Charts, 4 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22Monoclonal+antibodies%22">Monoclonal antibodies</searchLink><br /><searchLink fieldCode="DE" term="%22Botulinum+toxin%22">Botulinum toxin</searchLink><br /><searchLink fieldCode="DE" term="%22Paralysis%22">Paralysis</searchLink><br /><searchLink fieldCode="DE" term="%22Etiology+of+diseases%22">Etiology of diseases</searchLink><br /><searchLink fieldCode="DE" term="%22Amino+acids%22">Amino acids</searchLink><br /><searchLink fieldCode="DE" term="%22Serotypes%22">Serotypes</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+evolution%22">Molecular evolution</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Botulism, a disease of humans characterized by prolonged paralysis, is caused by botulinum neurotoxins (BoNTs), the most poisonous substances known. There are seven serotypes of BoNT (A–G) which differ from each other by 34–64% at the amino acid level. Each serotype is uniquely recognized by polyclonal antibodies, which originally were used to classify serotypes. To determine if there existed monoclonal antibodies (mAbs) capable of binding two or more serotypes, we evaluated the ability of 35 yeast-displayed single-chain variable fragment antibodies generated from vaccinated humans or mice for their ability to bind multiple BoNT serotypes. Two such clonally related human mAbs (1B18 and 4E17) were identified that bound BoNT serotype A (BoNT/A) and B or BoNT/A, B, E and F, respectively, with high affinity. Using molecular evolution techniques, it proved possible to both increase affinity and maintain cross-serotype reactivity for the 4E17 mAb. Both 1B18 and 4E17 bound to a relatively conserved epitope at the tip of the BoNT translocation domain. Immunoglobulin G constructed from affinity matured variants of 1B18 and 4E17 were evaluated for their ability to neutralize BoNT/B and E, respectively, in vivo. Both antibodies potently neutralized BoNT in vivo demonstrating that this epitope is functionally important in the intoxication pathway. Such cross-serotype binding and neutralizing mAbs should simplify the development of antibody-based BoNT diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of PEDS: Protein Engineering, Design & Selection is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1093/protein/gzq111
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