Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.

Most forms of chronic pain are inadequately treated by present therapeutic options. Compelling evidence has accumulated, demonstrating that Nerve Growth Factor (NGF) is a key modulator of inflammatory and nociceptive responses, and is a promising target for the treatment of human pathologies linked...

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Autores principales:	Sonia Covaceuszach, Sara Marinelli, Ivet Krastanova, Gabriele Ugolini, Flaminia Pavone, Doriano Lamba, Antonino Cattaneo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/863bba9b7db841b1a0914d87b29bdf05
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spelling	oai:doaj.org-article:863bba9b7db841b1a0914d87b29bdf052021-11-18T07:26:09ZSingle cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.1932-620310.1371/journal.pone.0032212https://doaj.org/article/863bba9b7db841b1a0914d87b29bdf052012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22403636/?tool=EBIhttps://doaj.org/toc/1932-6203Most forms of chronic pain are inadequately treated by present therapeutic options. Compelling evidence has accumulated, demonstrating that Nerve Growth Factor (NGF) is a key modulator of inflammatory and nociceptive responses, and is a promising target for the treatment of human pathologies linked to chronic and inflammatory pain. There is therefore a growing interest in the development of therapeutic molecules antagonising the NGF pathway and its nociceptor sensitization actions, among which function-blocking anti-NGF antibodies are particularly relevant candidates.In this respect, the rat anti-NGF αD11 monoclonal antibody (mAb) is a potent antagonist, able to effectively antagonize rodent and human NGF in a variety of in vitro and in vivo systems. Here we show that mAb αD11 displays a significant analgesic effect in two different models of persistent pain in mice, with a remarkable long-lasting activity. In order to advance αD11 mAb towards its clinical application in man, anti-NGF αD11 mAb was humanized by applying a novel single cycle strategy based on the a priori experimental determination of the crystal and molecular structure of the parental Fragment antigen-binding (Fab). The humanized antibody (hum-αD11) was tested in vitro and in vivo, showing that the binding mode and the NGF neutralizing biological activities of the parental antibody are fully preserved, with even a significant affinity improvement. The results firmly establish hum-αD11 as a lead candidate for clinical applications in a therapeutic area with a severe unmet medical need. More generally, the single-cycle structure-based humanization method represents a considerable improvement over the standard humanization methods, which are intrinsically empirical and require several refinement cycles.Sonia CovaceuszachSara MarinelliIvet KrastanovaGabriele UgoliniFlaminia PavoneDoriano LambaAntonino CattaneoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e32212 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sonia Covaceuszach Sara Marinelli Ivet Krastanova Gabriele Ugolini Flaminia Pavone Doriano Lamba Antonino Cattaneo Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.
description	Most forms of chronic pain are inadequately treated by present therapeutic options. Compelling evidence has accumulated, demonstrating that Nerve Growth Factor (NGF) is a key modulator of inflammatory and nociceptive responses, and is a promising target for the treatment of human pathologies linked to chronic and inflammatory pain. There is therefore a growing interest in the development of therapeutic molecules antagonising the NGF pathway and its nociceptor sensitization actions, among which function-blocking anti-NGF antibodies are particularly relevant candidates.In this respect, the rat anti-NGF αD11 monoclonal antibody (mAb) is a potent antagonist, able to effectively antagonize rodent and human NGF in a variety of in vitro and in vivo systems. Here we show that mAb αD11 displays a significant analgesic effect in two different models of persistent pain in mice, with a remarkable long-lasting activity. In order to advance αD11 mAb towards its clinical application in man, anti-NGF αD11 mAb was humanized by applying a novel single cycle strategy based on the a priori experimental determination of the crystal and molecular structure of the parental Fragment antigen-binding (Fab). The humanized antibody (hum-αD11) was tested in vitro and in vivo, showing that the binding mode and the NGF neutralizing biological activities of the parental antibody are fully preserved, with even a significant affinity improvement. The results firmly establish hum-αD11 as a lead candidate for clinical applications in a therapeutic area with a severe unmet medical need. More generally, the single-cycle structure-based humanization method represents a considerable improvement over the standard humanization methods, which are intrinsically empirical and require several refinement cycles.
format	article
author	Sonia Covaceuszach Sara Marinelli Ivet Krastanova Gabriele Ugolini Flaminia Pavone Doriano Lamba Antonino Cattaneo
author_facet	Sonia Covaceuszach Sara Marinelli Ivet Krastanova Gabriele Ugolini Flaminia Pavone Doriano Lamba Antonino Cattaneo
author_sort	Sonia Covaceuszach
title	Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.
title_short	Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.
title_full	Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.
title_fullStr	Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.
title_full_unstemmed	Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.
title_sort	single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/863bba9b7db841b1a0914d87b29bdf05
work_keys_str_mv	AT soniacovaceuszach singlecyclestructurebasedhumanizationofanantinervegrowthfactortherapeuticantibody AT saramarinelli singlecyclestructurebasedhumanizationofanantinervegrowthfactortherapeuticantibody AT ivetkrastanova singlecyclestructurebasedhumanizationofanantinervegrowthfactortherapeuticantibody AT gabrieleugolini singlecyclestructurebasedhumanizationofanantinervegrowthfactortherapeuticantibody AT flaminiapavone singlecyclestructurebasedhumanizationofanantinervegrowthfactortherapeuticantibody AT dorianolamba singlecyclestructurebasedhumanizationofanantinervegrowthfactortherapeuticantibody AT antoninocattaneo singlecyclestructurebasedhumanizationofanantinervegrowthfactortherapeuticantibody
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Single cycle structure-based humanization of an anti-nerve growth factor therapeutic antibody.

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