Intranasal delivery of full-length anti-Nogo-A antibody: A potential alternative route for therapeutic antibodies to central nervous system targets

Correa, Daphne; Scheuber, Myriam I.; Shan, Hui-Min; Weinmann, Oliver; Baumgartner, Yves A.; Harten, Aliona; Wahl, Anna-Sophia; Skaar, Kirstin L.

doi:10.1073/pnas.2200057120

Cited by 16 publications

(14 citation statements)

References 86 publications

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“…Moreover, intranasal delivery of insulin improved cognitive functions in AD patients and human subjects with amnestic mild cognitive impairment [ 29 ]. These findings support the feasibility of passive immunotherapy in AD via intranasal administration [ 28 , 29 ]. Nevertheless, there are still several disadvantages of intranasal administration.…”

Section: Introductionsupporting

confidence: 76%

Passive immunotherapy for Alzheimer’s disease: challenges & future directions

Yi,

Tan,

Zhou

2024

J Transl Med

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Passive immunotherapy with specific antibodies targeting Amyloid β (Aβ) peptide or tubulin-associated unit (tau) protein has emerged as a promising therapeutic approach in Alzheimer’s disease (AD). However, in a recent phase III clinical study, Sperling et al. (N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aβ peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aβ antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects. In addition, three humanized antibodies targeting tau protein failed in their phase II trials. However, other anti-Aβ antibodies, such as lecanemab (a humanized mAb binds to soluble Aβ protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aβ peptides) and aducanumab (a human mAb binds to the aggregated form of Aβ), have been shown to slow the decline of cognitive functions in early stage AD patients. The specific targets used in passive immunotherapy in these clinical trials may explain the divergent clinical outcomes. There are several challenges and limitations of passive immunotherapy using anti-Aβ antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both anti-Aβ antibodies and other pharmaceutical agents should also be explored.

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Section: Introductionsupporting

confidence: 76%

Passive immunotherapy for Alzheimer’s disease: challenges & future directions

Yi,

Tan,

Zhou

2024

J Transl Med

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“…In contrast to previous studies, where large volumes of antibodies were applied in the whole nasal cavity [ 16 , 22 ], in the present study we used a more specific delivery mode by targeting the olfactory mucosa with relatively small volumes of antibody, and we followed antibody distribution in disease conditions. We observed that 11C7 administration onto the olfactory mucosa significantly reduces EAE-induced spinal cord motor symptoms and demyelination.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of intranasal 11C7 administration in chronic EAE is of particular interest for the development of new therapies for multiple sclerosis and CNS injuries such as stroke [ 22 ]. Indeed, the stabilization of neurological deficits in the chronic phase of EAE is due to permanent demyelination and axonal damage.…”

Section: Discussionmentioning

confidence: 99%

Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS

Pernet,

Joly,

Spiegel

et al. 2023

Cell Death Discov.

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Systemic administration of Nogo-A-neutralizing antibody ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the blood-brain barrier (BBB) is a major obstacle limiting the passage of systemically applied antibody to the CNS. To bypass the BBB, in the present study we tested the intranasal route of administration by targeting the olfactory mucosa with the Nogo-A-blocking antibody 11C7 mAb in myelin oligodendrocyte glycoprotein-induced EAE. Antibodies were specifically administered onto the olfactory mucosa using a microcatheter. Antibody distribution was examined in the CNS by ELISA and light-sheet microscopy. The effects of 11C7 mAb on Nogo-A signaling were assessed by Western blotting. EAE-induced deficits were monitored daily. Demyelination was observed on spinal cord histological sections. Gene expression changes were followed by trancriptomic analyses. A sensitive capture ELISA revealed a rapid and widespread distribution of 11C7 mAb in the CNS, including the olfactory bulb, the cerebellum and the lumbar spinal cord, but not in the CSF. Light-sheet microscopy allowed to observe antibody accumulation in the parenchyma, thus demonstrating nose-to-brain transfer of IgG. At the functional level, the widespread penetration of 11C7 mAb in the CNS, including the thoracolumbar spinal cord, resulted in the improvement of motor symptoms and in the preservation of myelin in the spinal cord of EAE mice. This was accompanied by Nogo-A signaling downregulation, as reflected by the decreased level of phosphorylated cofilin observed by Western blotting in the cerebellum. In the brain of EAE score-matched animals, 11C7 modified the expression of genes that can influence neurotransmission and cognitive functions, independently of the demyelination phenotype in the spinal cord. In conclusion, our data show the feasibility of olfactory mucosa-directed administration for the delivery of therapeutic antibodies targeting CNS antigens in EAE mice.

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“…Promising results have been reported in 1 study of anti-Nogo-A Ab treatment for acute SCI in humans, 56 and new advances have led to a noninvasive, intranasal delivery method for anti-Nogo-A Abs, which may greatly improve future clinical trials. 57 project was supported by the VA Polytrauma and Traumatic Brain Injury Rehabilitation Research Fellowship from the Department of Veterans Affairs, the Paul Kalmanovitz Central Nervous System Repair Research Program, NIH/NS115759, and the Department of Veterans Affairs.…”

Section: Discussionmentioning

confidence: 99%

“…Promising results have been reported in 1 study of anti-Nogo-A Ab treatment for acute SCI in humans, 56 and new advances have led to a non-invasive, intranasal delivery method for anti-Nogo-A Abs, which may greatly improve future clinical trials. 57…”

Section: Discussionmentioning

confidence: 99%

Anti-Nogo-A Antibody Therapy Improves Functional Outcome Following Traumatic Brain Injury

Powers,

Ton,

Farrer

et al. 2023

Neurorehabil Neural Repair

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Background Traumatic brain injury (TBI) can cause sensorimotor deficits, and recovery is slow and incomplete. There are no effective pharmacological treatments for recovery from TBI, but research indicates potential for anti-Nogo-A antibody (Ab) therapy. This Ab neutralizes Nogo-A, an endogenous transmembrane protein that inhibits neuronal plasticity and regeneration. Objective We hypothesized that anti-Nogo-A Ab treatment following TBI results in disinhibited axonal growth from the contralesional cortex, the establishment of new compensatory neuronal connections, and improved function. Methods We modeled TBI in rats using the controlled cortical impact method, resulting in focal brain damage and motor deficits like those observed in humans with a moderate cortical TBI. Rats were trained on the skilled forelimb reaching task and the horizontal ladder rung walking task. They were then given a TBI, targeting the caudal forelimb motor cortex, and randomly divided into 3 groups: TBI-only, TBI + Anti-Nogo-A Ab, and TBI + Control Ab. Testing resumed 3 days after TBI and continued for 8 weeks, when rats received an injection of the anterograde neuronal tracer, biotinylated dextran amine (BDA), into the corresponding area contralateral to the TBI. Results We observed significant improvement in rats that received anti-Nogo-A Ab treatment post-TBI compared to controls. Analysis of BDA-positive axons revealed that anti-Nogo-A Ab treatment resulted in cortico-rubral plasticity to the deafferented red nucleus. Conclusions. Anti-Nogo-A Ab treatment may improve functional recovery via neuronal plasticity to brain areas important for skilled movements, and this treatment shows promise to improve outcomes in humans who have suffered a TBI.

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Intranasal delivery of full-length anti-Nogo-A antibody: A potential alternative route for therapeutic antibodies to central nervous system targets

Cited by 16 publications

References 86 publications

Passive immunotherapy for Alzheimer’s disease: challenges & future directions

Passive immunotherapy for Alzheimer’s disease: challenges & future directions

Nogo-A antibody delivery through the olfactory mucosa mitigates experimental autoimmune encephalomyelitis in the mouse CNS

Anti-Nogo-A Antibody Therapy Improves Functional Outcome Following Traumatic Brain Injury

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