Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction
Intrathecal drug administration represents a promising method to deliver biologics effectively to the central nervous system (CNS). However, little is known about the tolerability and pharmacokinetics of intrathecally applied antibodies. Hence, the focus of this study was to evaluate the toxicity, p...
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Elsevier
2025-03-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747924001715 |
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| author | Pascal B. Kunz Michael A. Maurer Jannik Vollmer Matthias Machacek Oliver Weinmann Jelena Klisic Martin E. Schwab |
| author_facet | Pascal B. Kunz Michael A. Maurer Jannik Vollmer Matthias Machacek Oliver Weinmann Jelena Klisic Martin E. Schwab |
| author_sort | Pascal B. Kunz |
| collection | DOAJ |
| description | Intrathecal drug administration represents a promising method to deliver biologics effectively to the central nervous system (CNS). However, little is known about the tolerability and pharmacokinetics of intrathecally applied antibodies. Hence, the focus of this study was to evaluate the toxicity, pharmacokinetic, and pharmacodynamic properties of an intrathecally administered human monoclonal antibody against the growth inhibitory CNS membrane protein Nogo-A in the non-human primate (NHP). The antibody was repeatedly injected into the lumbar cerebrospinal fluid (CSF) sack of NHPs, Macaca fascicularis (N = 18), at three dose levels (placebo, 75 and 150 mg antibody/injection, n = 6/group). CSF and serum samples were collected for pharmacokinetic analysis. The health status was constantly monitored to detect any treatment-related abnormalities. After sacrifice, the CNS tissues were evaluated by immunohistochemistry and biochemistry to study the antibody distribution and target interaction in the spinal cord and brain. No treatment-related side effects were observed, and the treatment was well tolerated by NHPs. After administration, the antibody was rapidly cleared from the CSF with a half-life of 6.4 h and accumulated in the serum where it showed a half-life of 13.7 days. The antibody distributed over the spinal cord and brain, penetrated into the CNS parenchyma where it bound to Nogo-A expressing neurons and oligodendrocytes, and induced significant (P < 0.05) downregulation of the target antigen Nogo-A. Collectively, these results support the direct administration of therapeutic antibodies into the CSF and are of relevance for the antibody-based therapeutics currently in development for different CNS diseases. |
| format | Article |
| id | doaj-art-beaab7f7865d4ddebaa89afa23670557 |
| institution | DOAJ |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-beaab7f7865d4ddebaa89afa236705572025-08-20T02:54:30ZengElsevierNeurotherapeutics1878-74792025-03-01222e0048410.1016/j.neurot.2024.e00484Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interactionPascal B. Kunz0Michael A. Maurer1Jannik Vollmer2Matthias Machacek3Oliver Weinmann4Jelena Klisic5Martin E. Schwab6NovaGo Therapeutics AG, 8952 Zurich-Schlieren, SwitzerlandNovaGo Therapeutics AG, 8952 Zurich-Schlieren, SwitzerlandLYO-X AG, 4051 Basel, SwitzerlandLYO-X AG, 4051 Basel, SwitzerlandNovaGo Therapeutics AG, 8952 Zurich-Schlieren, SwitzerlandNovaGo Therapeutics AG, 8952 Zurich-Schlieren, SwitzerlandNovaGo Therapeutics AG, 8952 Zurich-Schlieren, Switzerland; Corresponding author.Intrathecal drug administration represents a promising method to deliver biologics effectively to the central nervous system (CNS). However, little is known about the tolerability and pharmacokinetics of intrathecally applied antibodies. Hence, the focus of this study was to evaluate the toxicity, pharmacokinetic, and pharmacodynamic properties of an intrathecally administered human monoclonal antibody against the growth inhibitory CNS membrane protein Nogo-A in the non-human primate (NHP). The antibody was repeatedly injected into the lumbar cerebrospinal fluid (CSF) sack of NHPs, Macaca fascicularis (N = 18), at three dose levels (placebo, 75 and 150 mg antibody/injection, n = 6/group). CSF and serum samples were collected for pharmacokinetic analysis. The health status was constantly monitored to detect any treatment-related abnormalities. After sacrifice, the CNS tissues were evaluated by immunohistochemistry and biochemistry to study the antibody distribution and target interaction in the spinal cord and brain. No treatment-related side effects were observed, and the treatment was well tolerated by NHPs. After administration, the antibody was rapidly cleared from the CSF with a half-life of 6.4 h and accumulated in the serum where it showed a half-life of 13.7 days. The antibody distributed over the spinal cord and brain, penetrated into the CNS parenchyma where it bound to Nogo-A expressing neurons and oligodendrocytes, and induced significant (P < 0.05) downregulation of the target antigen Nogo-A. Collectively, these results support the direct administration of therapeutic antibodies into the CSF and are of relevance for the antibody-based therapeutics currently in development for different CNS diseases.http://www.sciencedirect.com/science/article/pii/S1878747924001715Intrathecal administrationMonoclonal antibodyCNSSafety pharmacologyPharmacokineticsPharmacodynamics |
| spellingShingle | Pascal B. Kunz Michael A. Maurer Jannik Vollmer Matthias Machacek Oliver Weinmann Jelena Klisic Martin E. Schwab Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction Neurotherapeutics Intrathecal administration Monoclonal antibody CNS Safety pharmacology Pharmacokinetics Pharmacodynamics |
| title | Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction |
| title_full | Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction |
| title_fullStr | Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction |
| title_full_unstemmed | Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction |
| title_short | Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction |
| title_sort | intrathecal administration of anti nogo a antibody in macaque monkeys pharmacokinetics tissue penetration and target interaction |
| topic | Intrathecal administration Monoclonal antibody CNS Safety pharmacology Pharmacokinetics Pharmacodynamics |
| url | http://www.sciencedirect.com/science/article/pii/S1878747924001715 |
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