Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans
There are few treatments that slow neurodegeneration in Alzheimer’s disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood–brain barrier. This study investigates a bispecific mod...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2261509 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839619364712611840 |
|---|---|
| author | Hans Peter Grimm Vanessa Schumacher Martin Schäfer Sabine Imhof-Jung Per-Ola Freskgård Kevin Brady Carsten Hofmann Petra Rüger Tilman Schlothauer Ulrich Göpfert Maximilian Hartl Sylvia Rottach Adrian Zwick Shanon Seger Rachel Neff Jens Niewoehner Niels Janssen |
| author_facet | Hans Peter Grimm Vanessa Schumacher Martin Schäfer Sabine Imhof-Jung Per-Ola Freskgård Kevin Brady Carsten Hofmann Petra Rüger Tilman Schlothauer Ulrich Göpfert Maximilian Hartl Sylvia Rottach Adrian Zwick Shanon Seger Rachel Neff Jens Niewoehner Niels Janssen |
| author_sort | Hans Peter Grimm |
| collection | DOAJ |
| description | There are few treatments that slow neurodegeneration in Alzheimer’s disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood–brain barrier. This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aβ) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). In vitro, trontinemab showed a similar binding affinity to fibrillar Aβ40 and Aβ plaques in human AD brain sections to gantenerumab. A single intravenous administration of trontinemab (10 mg/kg) or gantenerumab (20 mg/kg) to non-human primates (NHPs, Macaca fascicularis), was well tolerated in both groups. Immunohistochemistry indicated increased trontinemab uptake into the brain endothelial cell layer and parenchyma, and more homogeneous distribution, compared with gantenerumab. Brain and plasma pharmacokinetic (PK) parameters for trontinemab were estimated by nonlinear mixed-effects modeling with correction for tissue residual blood, indicating a 4–18-fold increase in brain exposure. A previously developed clinical PK/pharmacodynamic model of gantenerumab was adapted to include a brain compartment as a driver of plaque removal and linked to the allometrically scaled above model from NHP. The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial. |
| format | Article |
| id | doaj-art-1e3d18094e0b44a99ca3a99a2f9d46b6 |
| institution | Matheson Library |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-1e3d18094e0b44a99ca3a99a2f9d46b62025-07-23T08:11:35ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2261509Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humansHans Peter Grimm0Vanessa Schumacher1Martin Schäfer2Sabine Imhof-Jung3Per-Ola Freskgård4Kevin Brady5Carsten Hofmann6Petra Rüger7Tilman Schlothauer8Ulrich Göpfert9Maximilian Hartl10Sylvia Rottach11Adrian Zwick12Shanon Seger13Rachel Neff14Jens Niewoehner15Niels Janssen16Roche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandRoche Pharmaceutical Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Munich, GermanyRoche Pharmaceutical Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, SwitzerlandThere are few treatments that slow neurodegeneration in Alzheimer’s disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood–brain barrier. This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aβ) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). In vitro, trontinemab showed a similar binding affinity to fibrillar Aβ40 and Aβ plaques in human AD brain sections to gantenerumab. A single intravenous administration of trontinemab (10 mg/kg) or gantenerumab (20 mg/kg) to non-human primates (NHPs, Macaca fascicularis), was well tolerated in both groups. Immunohistochemistry indicated increased trontinemab uptake into the brain endothelial cell layer and parenchyma, and more homogeneous distribution, compared with gantenerumab. Brain and plasma pharmacokinetic (PK) parameters for trontinemab were estimated by nonlinear mixed-effects modeling with correction for tissue residual blood, indicating a 4–18-fold increase in brain exposure. A previously developed clinical PK/pharmacodynamic model of gantenerumab was adapted to include a brain compartment as a driver of plaque removal and linked to the allometrically scaled above model from NHP. The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial.https://www.tandfonline.com/doi/10.1080/19420862.2023.2261509Alzheimer’s diseasegantenerumabBrainshuttle™monoclonal antibodyblood–brain barrierpharmacokinetics |
| spellingShingle | Hans Peter Grimm Vanessa Schumacher Martin Schäfer Sabine Imhof-Jung Per-Ola Freskgård Kevin Brady Carsten Hofmann Petra Rüger Tilman Schlothauer Ulrich Göpfert Maximilian Hartl Sylvia Rottach Adrian Zwick Shanon Seger Rachel Neff Jens Niewoehner Niels Janssen Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans mAbs Alzheimer’s disease gantenerumab Brainshuttle™ monoclonal antibody blood–brain barrier pharmacokinetics |
| title | Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans |
| title_full | Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans |
| title_fullStr | Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans |
| title_full_unstemmed | Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans |
| title_short | Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans |
| title_sort | delivery of the brainshuttle™ amyloid beta antibody fusion trontinemab to non human primate brain and projected efficacious dose regimens in humans |
| topic | Alzheimer’s disease gantenerumab Brainshuttle™ monoclonal antibody blood–brain barrier pharmacokinetics |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2261509 |
| work_keys_str_mv | AT hanspetergrimm deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT vanessaschumacher deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT martinschafer deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT sabineimhofjung deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT perolafreskgard deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT kevinbrady deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT carstenhofmann deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT petraruger deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT tilmanschlothauer deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT ulrichgopfert deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT maximilianhartl deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT sylviarottach deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT adrianzwick deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT shanonseger deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT rachelneff deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT jensniewoehner deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans AT nielsjanssen deliveryofthebrainshuttleamyloidbetaantibodyfusiontrontinemabtononhumanprimatebrainandprojectedefficaciousdoseregimensinhumans |