Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation

Abstract In clinical trials with early Alzheimer’s patients, administration of anti-amyloid antibodies reduced amyloid deposits, suggesting that immunotherapies may be promising disease-modifying interventions against Alzheimer’s disease (AD). Specific forms of amyloid beta (Aβ) peptides, for exampl...

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Autores principales:	Thore Hettmann, Stephen D. Gillies, Martin Kleinschmidt, Anke Piechotta, Koki Makioka, Cynthia A. Lemere, Stephan Schilling, Jens-Ulrich Rahfeld, Inge Lues
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Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dab5d0faf6364197a4d53ba697df7975
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spelling	oai:doaj.org-article:dab5d0faf6364197a4d53ba697df79752021-12-02T11:02:17ZDevelopment of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation10.1038/s41598-020-60319-52045-2322https://doaj.org/article/dab5d0faf6364197a4d53ba697df79752020-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-60319-5https://doaj.org/toc/2045-2322Abstract In clinical trials with early Alzheimer’s patients, administration of anti-amyloid antibodies reduced amyloid deposits, suggesting that immunotherapies may be promising disease-modifying interventions against Alzheimer’s disease (AD). Specific forms of amyloid beta (Aβ) peptides, for example post-translationally modified Aβ peptides with a pyroglutamate at the N-terminus (pGlu3, pE3), are attractive antibody targets, due to pGlu3-Aβ’s neo-epitope character and its propensity to form neurotoxic oligomeric aggregates. We have generated a novel anti-pGlu3-Aβ antibody, PBD-C06, which is based on a murine precursor antibody that binds with high specificity to pGlu3-Aβ monomers, oligomers and fibrils, including mixed aggregates of unmodified Aβ and pGlu3-Aβ peptides. PBD-C06 was generated by first grafting the murine antigen binding sequences onto suitable human variable light and heavy chains. Subsequently, the humanized antibody was de-immunized and site-specific mutations were introduced to restore original target binding, to eliminate complement activation and to improve protein stability. PBD-C06 binds with the same specificity and avidity as its murine precursor antibody and elimination of C1q binding did not compromise Fcγ-receptor binding or in vitro phagocytosis. Thus, PBD-C06 was specifically designed to target neurotoxic aggregates and to avoid complement-mediated inflammatory responses, in order to lower the risk for vasogenic edemas in the clinic.Thore HettmannStephen D. GilliesMartin KleinschmidtAnke PiechottaKoki MakiokaCynthia A. LemereStephan SchillingJens-Ulrich RahfeldInge LuesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thore Hettmann Stephen D. Gillies Martin Kleinschmidt Anke Piechotta Koki Makioka Cynthia A. Lemere Stephan Schilling Jens-Ulrich Rahfeld Inge Lues Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation
description	Abstract In clinical trials with early Alzheimer’s patients, administration of anti-amyloid antibodies reduced amyloid deposits, suggesting that immunotherapies may be promising disease-modifying interventions against Alzheimer’s disease (AD). Specific forms of amyloid beta (Aβ) peptides, for example post-translationally modified Aβ peptides with a pyroglutamate at the N-terminus (pGlu3, pE3), are attractive antibody targets, due to pGlu3-Aβ’s neo-epitope character and its propensity to form neurotoxic oligomeric aggregates. We have generated a novel anti-pGlu3-Aβ antibody, PBD-C06, which is based on a murine precursor antibody that binds with high specificity to pGlu3-Aβ monomers, oligomers and fibrils, including mixed aggregates of unmodified Aβ and pGlu3-Aβ peptides. PBD-C06 was generated by first grafting the murine antigen binding sequences onto suitable human variable light and heavy chains. Subsequently, the humanized antibody was de-immunized and site-specific mutations were introduced to restore original target binding, to eliminate complement activation and to improve protein stability. PBD-C06 binds with the same specificity and avidity as its murine precursor antibody and elimination of C1q binding did not compromise Fcγ-receptor binding or in vitro phagocytosis. Thus, PBD-C06 was specifically designed to target neurotoxic aggregates and to avoid complement-mediated inflammatory responses, in order to lower the risk for vasogenic edemas in the clinic.
format	article
author	Thore Hettmann Stephen D. Gillies Martin Kleinschmidt Anke Piechotta Koki Makioka Cynthia A. Lemere Stephan Schilling Jens-Ulrich Rahfeld Inge Lues
author_facet	Thore Hettmann Stephen D. Gillies Martin Kleinschmidt Anke Piechotta Koki Makioka Cynthia A. Lemere Stephan Schilling Jens-Ulrich Rahfeld Inge Lues
author_sort	Thore Hettmann
title	Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation
title_short	Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation
title_full	Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation
title_fullStr	Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation
title_full_unstemmed	Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation
title_sort	development of the clinical candidate pbd-c06, a humanized pglu3-aβ-specific antibody against alzheimer’s disease with reduced complement activation
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/dab5d0faf6364197a4d53ba697df7975
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Development of the clinical candidate PBD-C06, a humanized pGlu3-Aβ-specific antibody against Alzheimer’s disease with reduced complement activation

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