title: Dual specificity of anti-CXCL10-CXCL9 antibodies is governed by structural mimicry.
abstract: Dual-specific antibodies are characterized by an antigen-combining site mediating specific interactions with two different antigens. We have generated five dual-specific single chain variable fragments (scFv) that neutralize the activity of the two chemokines, CXCL9 and CXCL10, to bind to their receptor CXCR3. To better understand how these dual-specific scFvs bind these two chemokines that only share a 37% sequence identity, we mapped their epitopes on human CXCL9 and CXCL10 and identified serine 13 (Ser(13)) as a critical residue. It is conserved between the two chemokines but not in the third ligand for CXCR3, CXCL11. Furthermore, Ser(13) is exposed in the tetrameric structure of CXCL10, which is consistent with our finding that the scFvs are able to bind to CXCL9 and CXCL10 immobilized on glycosaminoglycans. Overall, the data indicate that these dual-specific scFvs bind to a conserved surface involved in CXCR3 receptor interaction for CXCL10 and CXCL9. Thus, structural mimicry between the two targets is likely to be responsible for the observed dual specificity of these antibody fragments.
authors: NovImmune SA, 1228 Plan Les Ouates, Switzerland.
authors: Séverine
authors: S
authors: Fagète
authors: François
authors: F
authors: Rousseau
authors: Giovanni
authors: G
authors: Magistrelli
authors: Franck
authors: F
authors: Gueneau
authors: Ulla
authors: U
authors: Ravn
authors: Marie H
authors: MH
authors: Kosco-Vilbois
authors: Nicolas
authors: N
authors: Fischer
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D054357:Chemokine CXCL10 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D054371:Chemokine CXCL11 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D054370:Chemokine CXCL9 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D008252:Macaca fascicularis; D008253:Macaca mulatta; D051379:Mice; D018716:Molecular Mimicry; D011817:Rabbits; D054367:Receptors, CXCR3 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D057127:Single-Chain Antibodies / Q000737:chemistry* / Q000235:genetics / Q000276:immunology
chemical_list: C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D057127:Single-Chain Antibodies