title: SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.
abstract: Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit.
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Smith
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Jonason
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Reilly
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Janaki
authors.initials: J
authors.lastname: Veeraraghavan
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Terrence
authors.initials: T
authors.lastname: Fisher
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klimatcheva
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Mallow
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Cornelius
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Leonard
authors.affiliation: Cerebrovascular Research Center, Department of Molecular and Cellular Biology, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
authors.affiliation: Cerebrovascular Research Center, Department of Molecular and Cellular Biology, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA.
authors.forename: Damir
authors.initials: D
authors.lastname: Janigro
authors.affiliation: Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Azeb Tadesse
authors.initials: AT
authors.lastname: Argaw
authors.affiliation: Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Trinh
authors.initials: T
authors.lastname: Pham
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Seils
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Holm
authors.initials: H
authors.lastname: Bussler
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Sebold
authors.initials: S
authors.lastname: Torno
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Kirk
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Howell
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Evans
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Paris
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
authors.affiliation: Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Gareth
authors.initials: G
authors.lastname: John
authors.affiliation: Vaccinex, Inc., Rochester, NY 14620, USA. Electronic address: mzauderer@vaccinex.com.
authors.forename: Maurice
authors.initials: M
authors.lastname: Zauderer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D039961:Semaphorins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C103150:Sema4d protein, mouse; D039961:Semaphorins
keywords: Blood–brain barrier; Monoclonal antibody; Multiple sclerosis; Neuroinflammation; Oligodendrocytes; Remyelination; Semaphorin-4D