- Email: [email protected]
ANTI-TAU ANTIBODY PROFILING FOR PASSIVE IMMUNIZATION THERAPY: COMPARING SEEDS DERIVED FROM TRANSGENIC ANIMALS AND HUMAN BRAIN TISSUE
P1274
Poster Presentations: Wednesday, July 19, 2017
agents. Results: MAPTA will model the quantitative relationships between agents and processes leading to Tau neuropathology based on preclinical data of Tau neurobiology and clinical data on spatiotemporal tau progression. Similar to our amyloid aggregation model outcome, tau aggregation is driven by different pathological environments that reflect the nature of the tauopathies. The tau-site modification modeling is constrained by biomarker signature and allows to derive information regarding the different pathological processes for individual tauopathies. The NErvous SysTems Organized Reference (NESTOR) database, a one-stop website that captures annotated published information on tau pathology in a natural and logical format is an essential part of this project. Conclusions: The consortium engages pharma industries and patient foundation and is different from traditional data-gathering consortia in that the key deliverable is an actionable modeling platform that can be used for target validation and drug discovery support in tauopathies.
P4-046
PARTIAL VOLUME SUSCEPTIBILITY OF TAU PET: REGIONWISE ASSESSMENT AND COMPARISON WITH AMYLOID PET
Jungsu S. Oh1, Minyoung Oh1, Soo Jong Kim1, Sang Won Seo2, Jee Hoon Roh1, Sang Ju Lee1, Seung Jun Oh1, Jae Seung Kim1, 1Asan Medical Center, Seoul, Republic of South Korea; 2Samsung Medical Center, Seoul, Republic of South Korea. Contact e-mail: [email protected] Background: Although Tau PET became an emerging imaging
modality for investigating Alzheimer’s disease (AD), the impact of partial volume effect (PVE) and its correction (PVC) has not been sufficiently addressed thus far. We evaluated the partial volume susceptibility (PVS) of many cortical and subcortical regions on Tau PET comparing with amyloid PET. Methods: We recruited total 116 subjects including normal/subjective memory impairment (SMI), mild cognitive impairment (MCI), and AD. All subjects underwent Tau PET with F-18 THK5351 and amyloid PET with F-18 Florbetaben. 3D volumetric T1 images were also acquired for creating cortical volume of interests (VOIs) for both quantification and PVC. To this end, we used Freesurferbased cortical gray/white matter parcellation, i.e., a gyral parcellation based on Desikan atlas. Using geometric transfer matrix approach, we conducted region-based PVC, and using the ratio of it and its smoothed version, further conducted voxel-based PVC. We defined PVS as the ratio of VOI mean values of PV-corrected PET over that of original (PV-uncorrected) PET. We also conducted subgroup analysis: 1) amyloid positive and negative groups, and 2) AD/ MCI and normal/SMI groups. Results: In general, PVSs of Tau PET in cortical gray matter were significantly higher (1.6-1.7) than those of FBB PET (1.3-1.5). In particular, hippocampus and caudate in Tau PET exhibited high (1.5-1.6) PVS, whereas those in FBB PET exhibited no PVS (¼1.0) or mild overestimation (PVS<1.0). FBB PET shows significantly higher PVS in amyloid positive group than negative group and also AD/MCI groups than normal SMI groups, but there was no significant difference of PVS of Tau PET among subgroups. Conclusions: Tau PET exhibited much extensive and severe partial
volume susceptibility than amyloid PET. Therefore, we suggest appropriate PVC is needed for the accurate quantification of Tau PET.
P4-047
ANTI-TAU ANTIBODY PROFILING FOR PASSIVE IMMUNIZATION THERAPY: COMPARING SEEDS DERIVED FROM TRANSGENIC ANIMALS AND HUMAN BRAIN TISSUE
Marianne Borgers1, Koen Dockx2, Inez Van de Weyer2, Sofie Versweyveld1, Katja De Waepenaert2, Marc Vandermeeren1, Kristof Van Kolen1, Greet Vanhoof2, Andreas Ebneth3, Marc Mercken1, 1 Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium; 2Discovery Sciences, a division of Janssen Pharmaceutica NV, Beerse, Belgium; 3Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium. Contact e-mail: mborgers@its. jnj.com Background: Studies based on post-mortem staging of Tau
pathology in Alzheimer’s disease (AD) subjects have led to the hypothesis that the spread of Tau pathology may be due to transmission of toxic Tau species along synaptically connected brain regions. Passive immunization with anti-Tau antibodies targets this toxic Tau species that seeds aggregation in connected neurons to prevent further spread of Tau pathology and hence neurodegeneration. Monoclonal antibodies (mAbs) developed for passive immunization are often evaluated in Tau transgenic (Tg-) mice developing spontaneous aggregation of human mutated Tau with age. Since in these models it is unclear if a spreading component is present, this study investigates if seeds derived from Tg-mice or human AD brain can be used to evaluate efficacy of Tau mAbs. Methods: Over 100 mAbs spanning the complete Tau protein were developed in house by immunizing mice with paired helical filaments extracted from AD brain tissue. Different experimental setups were developed using a cellular seeding model to study the effectiveness of mAbs. Efficacy of mAbs to block seeding was compared employing seeds derived from two different sources; homogenates from spinal cord of P301S Tau Tg-mice and postmortem brain tissue of AD patients. Results: Co-incubation experiments using seeds derived from Tg-mice indicated that the majority of mAbs only partially antagonized seeding in the cellular model. This was shown to be unrelated to the targeted epitope and was not due to the absence of the respective epitope on a subset of Tau aggregates since all seeding capacity could be removed from this homogenate via immunodepletion. The latter indicates that at least one antibody epitope is present on each seed/Tau aggregate in homogenates derived from Tg-mice. Conversely, several mAbs were not able to fully immunodeplete all seeding capacity from human AD brain homogenates. This indicates that these seeds are different than those derived from Tg-mice. Conclusions: These results underline the importance of testing mAbs for passive immunization approaches against human brain derived Tau seeds both in vitro and in vivo using a seeding model with human AD derived seeds in the Tg-mice for prioritizing mAbs towards clinical development.
Poster Presentations: Wednesday, July 19, 2017
agents. Results: MAPTA will model the quantitative relationships between agents and processes leading to Tau neuropathology based on preclinical data of Tau neurobiology and clinical data on spatiotemporal tau progression. Similar to our amyloid aggregation model outcome, tau aggregation is driven by different pathological environments that reflect the nature of the tauopathies. The tau-site modification modeling is constrained by biomarker signature and allows to derive information regarding the different pathological processes for individual tauopathies. The NErvous SysTems Organized Reference (NESTOR) database, a one-stop website that captures annotated published information on tau pathology in a natural and logical format is an essential part of this project. Conclusions: The consortium engages pharma industries and patient foundation and is different from traditional data-gathering consortia in that the key deliverable is an actionable modeling platform that can be used for target validation and drug discovery support in tauopathies.
P4-046
PARTIAL VOLUME SUSCEPTIBILITY OF TAU PET: REGIONWISE ASSESSMENT AND COMPARISON WITH AMYLOID PET
Jungsu S. Oh1, Minyoung Oh1, Soo Jong Kim1, Sang Won Seo2, Jee Hoon Roh1, Sang Ju Lee1, Seung Jun Oh1, Jae Seung Kim1, 1Asan Medical Center, Seoul, Republic of South Korea; 2Samsung Medical Center, Seoul, Republic of South Korea. Contact e-mail: [email protected] Background: Although Tau PET became an emerging imaging
modality for investigating Alzheimer’s disease (AD), the impact of partial volume effect (PVE) and its correction (PVC) has not been sufficiently addressed thus far. We evaluated the partial volume susceptibility (PVS) of many cortical and subcortical regions on Tau PET comparing with amyloid PET. Methods: We recruited total 116 subjects including normal/subjective memory impairment (SMI), mild cognitive impairment (MCI), and AD. All subjects underwent Tau PET with F-18 THK5351 and amyloid PET with F-18 Florbetaben. 3D volumetric T1 images were also acquired for creating cortical volume of interests (VOIs) for both quantification and PVC. To this end, we used Freesurferbased cortical gray/white matter parcellation, i.e., a gyral parcellation based on Desikan atlas. Using geometric transfer matrix approach, we conducted region-based PVC, and using the ratio of it and its smoothed version, further conducted voxel-based PVC. We defined PVS as the ratio of VOI mean values of PV-corrected PET over that of original (PV-uncorrected) PET. We also conducted subgroup analysis: 1) amyloid positive and negative groups, and 2) AD/ MCI and normal/SMI groups. Results: In general, PVSs of Tau PET in cortical gray matter were significantly higher (1.6-1.7) than those of FBB PET (1.3-1.5). In particular, hippocampus and caudate in Tau PET exhibited high (1.5-1.6) PVS, whereas those in FBB PET exhibited no PVS (¼1.0) or mild overestimation (PVS<1.0). FBB PET shows significantly higher PVS in amyloid positive group than negative group and also AD/MCI groups than normal SMI groups, but there was no significant difference of PVS of Tau PET among subgroups. Conclusions: Tau PET exhibited much extensive and severe partial
volume susceptibility than amyloid PET. Therefore, we suggest appropriate PVC is needed for the accurate quantification of Tau PET.
P4-047
ANTI-TAU ANTIBODY PROFILING FOR PASSIVE IMMUNIZATION THERAPY: COMPARING SEEDS DERIVED FROM TRANSGENIC ANIMALS AND HUMAN BRAIN TISSUE
Marianne Borgers1, Koen Dockx2, Inez Van de Weyer2, Sofie Versweyveld1, Katja De Waepenaert2, Marc Vandermeeren1, Kristof Van Kolen1, Greet Vanhoof2, Andreas Ebneth3, Marc Mercken1, 1 Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium; 2Discovery Sciences, a division of Janssen Pharmaceutica NV, Beerse, Belgium; 3Janssen Research & Development, a division of Janssen Pharmaceutica, Beerse, Belgium. Contact e-mail: mborgers@its. jnj.com Background: Studies based on post-mortem staging of Tau
pathology in Alzheimer’s disease (AD) subjects have led to the hypothesis that the spread of Tau pathology may be due to transmission of toxic Tau species along synaptically connected brain regions. Passive immunization with anti-Tau antibodies targets this toxic Tau species that seeds aggregation in connected neurons to prevent further spread of Tau pathology and hence neurodegeneration. Monoclonal antibodies (mAbs) developed for passive immunization are often evaluated in Tau transgenic (Tg-) mice developing spontaneous aggregation of human mutated Tau with age. Since in these models it is unclear if a spreading component is present, this study investigates if seeds derived from Tg-mice or human AD brain can be used to evaluate efficacy of Tau mAbs. Methods: Over 100 mAbs spanning the complete Tau protein were developed in house by immunizing mice with paired helical filaments extracted from AD brain tissue. Different experimental setups were developed using a cellular seeding model to study the effectiveness of mAbs. Efficacy of mAbs to block seeding was compared employing seeds derived from two different sources; homogenates from spinal cord of P301S Tau Tg-mice and postmortem brain tissue of AD patients. Results: Co-incubation experiments using seeds derived from Tg-mice indicated that the majority of mAbs only partially antagonized seeding in the cellular model. This was shown to be unrelated to the targeted epitope and was not due to the absence of the respective epitope on a subset of Tau aggregates since all seeding capacity could be removed from this homogenate via immunodepletion. The latter indicates that at least one antibody epitope is present on each seed/Tau aggregate in homogenates derived from Tg-mice. Conversely, several mAbs were not able to fully immunodeplete all seeding capacity from human AD brain homogenates. This indicates that these seeds are different than those derived from Tg-mice. Conclusions: These results underline the importance of testing mAbs for passive immunization approaches against human brain derived Tau seeds both in vitro and in vivo using a seeding model with human AD derived seeds in the Tg-mice for prioritizing mAbs towards clinical development.