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Intrathecal administration of Anti-Nogo-A antibody in macaque monkeys: Pharmacokinetics, tissue penetration and
Pascal B Kunz1, Michael A Maurer1, Jannik Vollmer2
1NovaGo Therapeutics AG, 8952 Zurich-Schlieren, Switzerland.
Abstract:
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.
Insights
Intrathecal antibody administration for central nervous system (CNS) diseases is safe and effective. This study shows good tolerability and target engagement of an anti-Nogo-A antibody in non-human primates, supporting its therapeutic potential.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Intrathecal drug delivery offers targeted central nervous system (CNS) access for biologics.
- Limited data exists on the tolerability and pharmacokinetics of intrathecally administered antibodies.
Purpose of the Study:
- To assess the toxicity, pharmacokinetics, and pharmacodynamics of an intrathecally administered anti-Nogo-A monoclonal antibody in non-human primates (NHPs).
Main Methods:
- Repeated intrathecal injections of anti-Nogo-A antibody (placebo, 75, 150 mg) into Macaca fascicularis NHPs.
- Pharmacokinetic analysis of cerebrospinal fluid (CSF) and serum samples.
- CNS tissue evaluation via immunohistochemistry and biochemistry post-sacrifice.
Main Results:
- The intrathecal antibody treatment was well-tolerated with no observed adverse effects in NHPs.
- Rapid CSF clearance (6.4 h half-life) and serum accumulation (13.7 days half-life) of the antibody.
- Antibody distributed to CNS parenchyma, bound Nogo-A, and significantly downregulated its expression.
Conclusions:
- Direct intrathecal antibody administration is a viable strategy for CNS therapeutics.
- Results support the development of antibody-based therapies targeting Nogo-A for CNS diseases.
