title: Novel antagonist antibody to TLR3 blocks poly(I:C)-induced inflammation in vivo and in vitro.
abstract: Toll-like receptor 3 (TLR3) binds and signals in response to dsRNA and poly(I:C), a synthetic double stranded RNA analog. Activation of TLR3 triggers innate responses that may play a protective or detrimental role in viral infections or in immune-mediated inflammatory diseases through amplification of inflammation. Two monoclonal antibodies, CNTO4685 (rat anti-mouse TLR3) and CNTO5429 (CDRs from CNTO4685 grafted onto a mouse IgG1 scaffold) were generated and characterized. These mAbs bind the extracellular domain of mouse TLR3, inhibit poly(I:C)-induced activation of HEK293T cells transfected with mTLR3, and reduce poly(I:C)-induced production of CCL2 and CXCL10 by primary mouse embryonic fibroblasts. CNTO5429 decreased serum IL-6 and TNFα levels post-intraperitoneal poly(I:C) administration, demonstrating in vivo activity. In summary, specific anti-mTLR3 mAbs have been generated to assess TLR3 antagonism in mouse models of inflammation.
authors.affiliation: Immunology Discovery Department, Centocor Research & Development, Inc., Radnor, PA, USA. Rbunting@its.jnj.com
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Bunting
authors.forename: Karen E
authors.initials: KE
authors.lastname: Duffy
authors.forename: Roberta J
authors.initials: RJ
authors.lastname: Lamb
authors.forename: Lani R
authors.initials: LR
authors.lastname: San Mateo
authors.forename: Karen
authors.initials: K
authors.lastname: Smalley
authors.forename: Holly
authors.initials: H
authors.lastname: Raymond
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Ted
authors.initials: T
authors.lastname: Petley
authors.forename: Jamie
authors.initials: J
authors.lastname: Fisher
authors.forename: Heena
authors.initials: H
authors.lastname: Beck
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Lena
authors.initials: L
authors.lastname: Alexopoulou
authors.forename: Christine K
authors.initials: CK
authors.lastname: Ward
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000276:immunology; D042541:Intracellular Space / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C