Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats

Marcek, John; Okerberg, Carlin V.; Liu, Chang‐Ning; Potter, David M.; Butler, Paul; Boucher, Magalie; Zorbas, Mark; Mouton, Peter R.; Nyengaard, Jens Randel; Somps, Chris

doi:10.1016/j.jchemneu.2016.05.007

Cited by 5 publications

(4 citation statements)

References 60 publications

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“…71–74 If sympathetic neurons have a prominent role in PDAC progression, a prediction is that anti-NGF would have a more robust effect than that seen in prior studies where only sensory neurons were depleted using neonatal capsaicin treatment 44,70 Our results show this does not occur, at least in the treatment paradigm employed (starting treatment at either 4 or 8 wk). Although not killing sensory or sympathetic neurons, 33 anti-NGF did decrease TH immunoreactivity in the SCG as well as reduced mRNAs encoding TrKA and p75, in DRG, which confirms anti-NGF bioactivity. Even so, this treatment was not sufficient for total denervation of the pancreas since TH and CGRP immunoreactivity were still present in nerve fibers within the pancreata of treated animals (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 56%

Systemic Depletion of Nerve Growth Factor Inhibits Disease Progression in a Genetically Engineered Model of Pancreatic Ductal Adenocarcinoma

Saloman

Singhi²,

Hartman

et al. 2018

Pancreas

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Section: Discussionsupporting

confidence: 56%

Systemic Depletion of Nerve Growth Factor Inhibits Disease Progression in a Genetically Engineered Model of Pancreatic Ductal Adenocarcinoma

Saloman

Singhi²,

Hartman

et al. 2018

Pancreas

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“…Thus, the degree of cell death may be overestimated” ( Ruit et al , 1990 ). We recently showed that using stereology techniques optimized to minimize process-related tissue shrinkage, treatment with an anti-NGF antibody was not associated with a reduction in the number of neurons in the SCG of rats, suggesting that process-related tissue shrinkage may be responsible, at least in part, for the undercounting of neurons in the current studies ( Marcek et al , 2016 )…”

Section: Discussionmentioning

confidence: 67%

From the Cover: Evaluation of the Effects of Tanezumab, a Monoclonal Antibody Against Nerve Growth Factor, on the Sympathetic Nervous System in Adult Cynomolgus Monkeys (Macaca fascicularis): A Stereologic, Histomorphologic, and Cardiofunctional Assessment

Bélanger

Butler

Butt

et al. 2017

Toxicological Sciences

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Tanezumab, a humanized monoclonal antibody against nerve growth factor is in development for treatment of chronic pain. Three nonclinical studies assessed effects of clinically relevant and supratherapeutic doses of tanezumab on the sympathetic nervous system (SNS) of adult nonhuman primates. Study 1 evaluated potential effects of subcutaneous (SC) tanezumab (1.2 mg/kg every 8 weeks [Q8W]) on SNS in cynomolgus monkeys for 3 or 6 months and reversibility or persistence of any effects through a nondosing/recovery period. Study 2 evaluated whether neuronal cell death occurs shortly after a single SC tanezumab injection (1.2 mg/kg). Assessments for these two studies included evaluations of superior cervical and cervicothoracic ganglia for neuronal cell death and morphology. Study 3 evaluated effects of SC tanezumab (1.2 mg/kg Q8W and 30 mg/kg/week) over 6 months on sympathetic control of cardiovascular function. Tanezumab exposure was associated with stereologic changes in sympathetic ganglia, including smaller ganglion volume, and smaller average neuron size/area beginning at 2 weeks and reaching maximal levels by 1 month with no further progression through 6 months. These changes were not associated with clinical signs, completely reversed upon tanezumab withdrawal, and were not considered adverse. Tanezumab had no adverse effects on sympathetic control of cardiovascular function. These data support the conclusion that tanezumab administration for up to 6 months has no adverse effects on SNS morphology or function and does not cause neuronal cell death in adult nonhuman primates.

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“…The difference in magnitude of apparent neuron loss when comparing the 2 assessment methods may reflect, in part, the different types of neurons being counted; in the case of the morphometric assessment, the counts were an estimate of TH-positive neurons, while in the case of the stereology assessments the neurons counted were an estimate of total number of neurons in the SCG. Given that catecholamine-containing neurons represent only about 80% of the total neurons present within the SCG 30 and that guanethidine affects only catecholamine (noradrenergic) neurons, 21,22 it makes sense that the effect would be somewhat larger when focused on just TH-positive neurons as done in the morphometric analysis. It is also important to keep in mind that our morphometric assessment quantifies changes in density (neurons per unit area), and differential shrinkage between control and injured SCG 31 could account in part for the difference in magnitude of apparent neuron loss when comparing the 2 assessment methods.…”

Section: Discussionmentioning

confidence: 99%

No Evidence of Neurogenesis in Adult Rat Sympathetic Ganglia Following Guanethidine-Induced Neuronal Loss

Walters

Boucher

et al. 2019

Toxicol Pathol

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The potential for neurogenesis in the cranial (superior) cervical ganglia (SCG) of the sympathetic nervous system was evaluated. Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered intraperitoneally to rats in order to destroy postganglionic sympathetic neurons in SCG. Following the last dose, animals were allowed to recover 1, 3, or 6 months. Right and left SCG from guanethidine-treated and age-matched, vehicle-treated control rats were harvested for histopathologic, morphometric, and stereologic evaluations. Both morphometric and stereologic evaluations confirmed neuron loss following guanethidine treatment. Morphometric analysis revealed a 50% to 60% lower number of tyrosine hydroxylase (TH)-positive neurons per unit area of SCG at both 3 and 6 months of recovery, compared to ganglia of age-matched controls, with no evidence of restoration of neuron density between 3 and 6 months. Reductions in TH-positive neurons following guanethidine treatment were corroborated by unbiased stereology of total hematoxylin and eosin-stained neuron numbers in SCG. Stereologic analyses revealed that total neuron counts were lower by 37% at 3 months of recovery when compared to age-matched vehicle controls, again with no obvious restoration between 3 and 6 months. Thus, no evidence was found that postganglionic neurons of the sympathetic nervous system in the adult rat have a neurogenic capacity.

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Anti-NGF monoclonal antibody muMab 911 does not deplete neurons in the superior cervical ganglia of young or old adult rats

Cited by 5 publications

References 60 publications

Systemic Depletion of Nerve Growth Factor Inhibits Disease Progression in a Genetically Engineered Model of Pancreatic Ductal Adenocarcinoma

Systemic Depletion of Nerve Growth Factor Inhibits Disease Progression in a Genetically Engineered Model of Pancreatic Ductal Adenocarcinoma

From the Cover: Evaluation of the Effects of Tanezumab, a Monoclonal Antibody Against Nerve Growth Factor, on the Sympathetic Nervous System in Adult Cynomolgus Monkeys (Macaca fascicularis): A Stereologic, Histomorphologic, and Cardiofunctional Assessment

No Evidence of Neurogenesis in Adult Rat Sympathetic Ganglia Following Guanethidine-Induced Neuronal Loss

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