Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 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 CB...
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| Format: | Article |
| Language: | English |
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BMC
2018-07-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0562-9 |
| _version_ | 1818215549918773248 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jeroen van Ameijde |
| collection | DOAJ |
| description | 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 (Ser422) 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 cell-based 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. |
| first_indexed | 2024-12-12T06:37:51Z |
| format | Article |
| id | doaj.art-953e8ff91c8e4f18bdde6ccba2569d9c |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-12T06:37:51Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-953e8ff91c8e4f18bdde6ccba2569d9c2022-12-22T00:34:25ZengBMCActa Neuropathologica Communications2051-59602018-07-016111410.1186/s40478-018-0562-9Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tauJeroen van Ameijde0Rosa Crespo1Roosmarijn Janson2Jarek Juraszek3Berdien Siregar4Hanneke Verveen5Imke Sprengers6Tariq Nahar7Jeroen J. Hoozemans8Stefan Steinbacher9Roland Willems10Lore Delbroek11Marianne Borgers12Koen Dockx13Kristof Van Kolen14Marc Mercken15Gabriel Pascual16Wouter Koudstaal17Adrian Apetri18Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonDepartment of Pathology, Amsterdam Neuroscience, VU University Medical CenterProteros Biostructures GmbHJanssen Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and JohnsonMolecular and Cellular Pharmacology, Discovery Sciences, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonJanssen Prevention Center, Janssen Pharmaceutical Companies of Johnson and JohnsonAbstract 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 (Ser422) 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 cell-based 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.http://link.springer.com/article/10.1186/s40478-018-0562-9TauNucleationAggregationPhosphorylationMonoclonal antibodyIntervention |
| spellingShingle | 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 Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau Acta Neuropathologica Communications Tau Nucleation Aggregation Phosphorylation Monoclonal antibody Intervention |
| title | Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau |
| title_full | Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau |
| title_fullStr | Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau |
| title_full_unstemmed | Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau |
| title_short | Enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated Ser422 containing epitope on pathological tau |
| title_sort | enhancement of therapeutic potential of a naturally occurring human antibody targeting a phosphorylated ser422 containing epitope on pathological tau |
| topic | Tau Nucleation Aggregation Phosphorylation Monoclonal antibody Intervention |
| url | http://link.springer.com/article/10.1186/s40478-018-0562-9 |
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