Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and target interaction.
| Autor: | Kunz PB; NovaGo Therapeutics AG, 8952 Zurich-Schlieren, Switzerland., Maurer MA; NovaGo Therapeutics AG, 8952 Zurich-Schlieren, Switzerland., Vollmer J; LYO-X AG, 4051 Basel, Switzerland., Machacek M; LYO-X AG, 4051 Basel, Switzerland., Weinmann O; NovaGo Therapeutics AG, 8952 Zurich-Schlieren, Switzerland., Klisic J; NovaGo Therapeutics AG, 8952 Zurich-Schlieren, Switzerland., Schwab ME; NovaGo Therapeutics AG, 8952 Zurich-Schlieren, Switzerland. Electronic address: martin@novagotx.com. |
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| Jazyk: | angličtina |
| Zdroj: | Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2024 Nov 20, pp. e00484. Date of Electronic Publication: 2024 Nov 20. |
| DOI: | 10.1016/j.neurot.2024.e00484 |
| Abstrakt: | 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. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Ernst Schwab reports a relationship with Novago Therapeutics AG that includes: board membership, employment, and equity or stocks. Pascal Benjamin Kunz reports a relationship with Novago Therapeutics AG that includes: employment. Michael Andreas Maurer reports a relationship with Novago Therapeutics AG that includes: employment. Jannik Vollmer reports a relationship with LYO-X AG that includes: employment. Matthias Machacek reports a relationship with LYO-X AG that includes: employment. Jelena Klisic reports a relationship with Novago Therapeutics AG that includes: employment. Oliver Weinmann reports a relationship with Novago Therapeutics AG that includes: employment. Michael Andreas Maurer has patent #WO 2021/079,002 A2 pending to NovaGo Therapeutics AG. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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