title: Morphologic, stereologic, and morphometric evaluation of the nervous system in young cynomolgus monkeys (Macaca fascicularis) following maternal administration of tanezumab, a monoclonal antibody to nerve growth factor.
abstract: Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (∼GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of neurons in animals exposed to tanezumab 4 mg/kg (n = 9) and 30 mg/kg (n = 1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, active neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/sympathetic neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies.
authors.affiliation: *Tox Path Specialists, LLC, Frederick, Maryland 21701, Pfizer Inc., San Diego, California 92121, Pfizer Inc, Groton, Connecticut 06340, SNBL USA, Ltd., Everett, Washington 98203, and Pfizer Inc, South San Francisco, California 94080 mbutt@toxpath.net.
authors.forename: Mark
authors.initials: M
authors.lastname: Butt
authors.affiliation: *Tox Path Specialists, LLC, Frederick, Maryland 21701, Pfizer Inc., San Diego, California 92121, Pfizer Inc, Groton, Connecticut 06340, SNBL USA, Ltd., Everett, Washington 98203, and Pfizer Inc, South San Francisco, California 94080 mbutt@toxpath.net.
authors.forename: Mark
authors.initials: M
authors.lastname: Evans
authors.affiliation: *Tox Path Specialists, LLC, Frederick, Maryland 21701, Pfizer Inc., San Diego, California 92121, Pfizer Inc, Groton, Connecticut 06340, SNBL USA, Ltd., Everett, Washington 98203, and Pfizer Inc, South San Francisco, California 94080.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bowman
authors.affiliation: *Tox Path Specialists, LLC, Frederick, Maryland 21701, Pfizer Inc., San Diego, California 92121, Pfizer Inc, Groton, Connecticut 06340, SNBL USA, Ltd., Everett, Washington 98203, and Pfizer Inc, South San Francisco, California 94080.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cummings
authors.affiliation: *Tox Path Specialists, LLC, Frederick, Maryland 21701, Pfizer Inc., San Diego, California 92121, Pfizer Inc, Groton, Connecticut 06340, SNBL USA, Ltd., Everett, Washington 98203, and Pfizer Inc, South San Francisco, California 94080.
authors.forename: Satoru
authors.initials: S
authors.lastname: Oneda
authors.affiliation: *Tox Path Specialists, LLC, Frederick, Maryland 21701, Pfizer Inc., San Diego, California 92121, Pfizer Inc, Groton, Connecticut 06340, SNBL USA, Ltd., Everett, Washington 98203, and Pfizer Inc, South San Francisco, California 94080.
authors.forename: David
authors.initials: D
authors.lastname: Shelton
authors.affiliation: *Tox Path Specialists, LLC, Frederick, Maryland 21701, Pfizer Inc., San Diego, California 92121, Pfizer Inc, Groton, Connecticut 06340, SNBL USA, Ltd., Everett, Washington 98203, and Pfizer Inc, South San Francisco, California 94080.
authors.forename: Mark
authors.initials: M
authors.lastname: Zorbas
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000633:toxicity*; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D005260:Female; D008252:Macaca fascicularis; D018811:Maternal Exposure / Q000009:adverse effects*; D046529:Microscopy, Electron, Transmission; D009420:Nervous System / Q000187:drug effects / Q000196:embryology / Q000648:ultrastructure*; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020800:Receptor, Nerve Growth Factor; C549319:tanezumab
keywords: cholinergic neurons; nerve growth factor; sympathetic ganglia; tanezumab