Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser 422 containing epitope on pathological tau

Jeroen van Ameijde, Rosa Crespo, Roosmarijn Janson, Jarek Juraszek, Berdien Siregar, Hanneke Verveen, Imke Sprengers, Tariq Nahar, Jeroen J. Hoozemans, Stefan Steinbacher, Roland Willems, Lore Delbroek, Marianne Borgers, Koen Dockx, Kristof van Kolen, Marc Mercken, Gabriel Pascual, Wouter Koudstaal, Adrian Apetri

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser 422 ) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cellbased immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1.
Original languageEnglish
Article number59
JournalActa Neuropathologica Communinications
Volume6
Issue number1
DOIs
Publication statusPublished - 2018

Cite this

van Ameijde, Jeroen ; Crespo, Rosa ; Janson, Roosmarijn ; Juraszek, Jarek ; Siregar, Berdien ; Verveen, Hanneke ; Sprengers, Imke ; Nahar, Tariq ; Hoozemans, Jeroen J. ; Steinbacher, Stefan ; Willems, Roland ; Delbroek, Lore ; Borgers, Marianne ; Dockx, Koen ; van Kolen, Kristof ; Mercken, Marc ; Pascual, Gabriel ; Koudstaal, Wouter ; Apetri, Adrian. / Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser 422 containing epitope on pathological tau. In: Acta Neuropathologica Communinications. 2018 ; Vol. 6, No. 1.
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title = "Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser 422 containing epitope on pathological tau",
abstract = "Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser 422 ) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cellbased immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1.",
keywords = "Tau, Nucleation, Aggregation, Phosphorylation, Monoclonal antibody, Intervention",
author = "{van Ameijde}, Jeroen and Rosa Crespo and Roosmarijn Janson and Jarek Juraszek and Berdien Siregar and Hanneke Verveen and Imke Sprengers and Tariq Nahar and Hoozemans, {Jeroen J.} and Stefan Steinbacher and Roland Willems and Lore Delbroek and Marianne Borgers and Koen Dockx and {van Kolen}, Kristof and Marc Mercken and Gabriel Pascual and Wouter Koudstaal and Adrian Apetri",
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journal = "Acta Neuropathologica Communinications",
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van Ameijde, J, Crespo, R, Janson, R, Juraszek, J, Siregar, B, Verveen, H, Sprengers, I, Nahar, T, Hoozemans, JJ, Steinbacher, S, Willems, R, Delbroek, L, Borgers, M, Dockx, K, van Kolen, K, Mercken, M, Pascual, G, Koudstaal, W & Apetri, A 2018, 'Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser 422 containing epitope on pathological tau' Acta Neuropathologica Communinications, vol. 6, no. 1, 59. https://doi.org/10.1186/s40478-018-0562-9, https://doi.org/10.1186/s40478-018-0562-9

Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser 422 containing epitope on pathological tau. / van Ameijde, Jeroen; Crespo, Rosa; Janson, Roosmarijn; Juraszek, Jarek; Siregar, Berdien; Verveen, Hanneke; Sprengers, Imke; Nahar, Tariq; Hoozemans, Jeroen J.; Steinbacher, Stefan; Willems, Roland; Delbroek, Lore; Borgers, Marianne; Dockx, Koen; van Kolen, Kristof; Mercken, Marc; Pascual, Gabriel; Koudstaal, Wouter; Apetri, Adrian.

In: Acta Neuropathologica Communinications, Vol. 6, No. 1, 59, 2018.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser 422 containing epitope on pathological tau

AU - van Ameijde, Jeroen

AU - Crespo, Rosa

AU - Janson, Roosmarijn

AU - Juraszek, Jarek

AU - Siregar, Berdien

AU - Verveen, Hanneke

AU - Sprengers, Imke

AU - Nahar, Tariq

AU - Hoozemans, Jeroen J.

AU - Steinbacher, Stefan

AU - Willems, Roland

AU - Delbroek, Lore

AU - Borgers, Marianne

AU - Dockx, Koen

AU - van Kolen, Kristof

AU - Mercken, Marc

AU - Pascual, Gabriel

AU - Koudstaal, Wouter

AU - Apetri, Adrian

PY - 2018

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N2 - Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser 422 ) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cellbased immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1.

AB - Aggregation of tau protein and spreading of tau aggregates are pivotal pathological processes in a range of neurological disorders. Accumulating evidence suggests that immunotherapy targeting tau may be a viable therapeutic strategy. We have previously described the isolation of antibody CBTAU-22.1 from the memory B-cell repertoire of healthy human donors. CBTAU-22.1 was shown to specifically bind a disease-associated phosphorylated epitope in the C-terminus of tau (Ser 422 ) and to be able to inhibit the spreading of pathological tau aggregates from P301S spinal cord lysates in vitro, albeit with limited potency. Using a combination of rational design and random mutagenesis we have derived a variant antibody with improved affinity while maintaining the specificity of the parental antibody. This affinity improved antibody showed greatly enhanced potency in a cellbased immunodepletion assay using paired helical filaments (PHFs) derived from human Alzheimer's disease (AD) brain tissue. Moreover, the affinity improved antibody limits the in vitro aggregation propensity of full length tau species specifically phosphorylated at position 422 produced by employing a native chemical ligation approach. Together, these results indicate that in addition to being able to inhibit the spreading of pathological tau aggregates, the matured antibody can potentially also interfere with the nucleation of tau which is believed to be the first step of the pathogenic process. Finally, the functionality in a P301L transgenic mice co-injection model highlights the therapeutic potential of human antibody dmCBTAU-22.1.

KW - Tau

KW - Nucleation

KW - Aggregation

KW - Phosphorylation

KW - Monoclonal antibody

KW - Intervention

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