title: Neutralizing nanobodies targeting diverse chemokines effectively inhibit chemokine function.
abstract: Chemokine receptors and their ligands play a prominent role in immune regulation but many have also been implicated in inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, allograft rejection after transplantation, and also in cancer metastasis. Most approaches to therapeutically target the chemokine system involve targeting of chemokine receptors with low molecular weight antagonists. Here we describe the selection and characterization of an unprecedented large and diverse panel of neutralizing Nanobodies (single domain camelid antibodies fragment) directed against several chemokines. We show that the Nanobodies directed against CCL2 (MCP-1), CCL5 (RANTES), CXCL11 (I-TAC), and CXCL12 (SDF-1α) bind the chemokines with high affinity (at nanomolar concentration), thereby blocking receptor binding, inhibiting chemokine-induced receptor activation as well as chemotaxis. Together, we show that neutralizing Nanobodies can be selected efficiently for effective and specific therapeutic treatment against a wide range of immune and inflammatory diseases.
authors.affiliation: From the Departments of Cellular Biology and Biology, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanchetot
authors.affiliation: the Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, and.
authors.forename: Dennis
authors.initials: D
authors.lastname: Verzijl
authors.affiliation: the Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, and.
authors.forename: Azra
authors.initials: A
authors.lastname: Mujić-Delić
authors.affiliation: the Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, and.
authors.forename: Leontien
authors.initials: L
authors.lastname: Bosch
authors.affiliation: From the Departments of Cellular Biology and Biology, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
authors.forename: Louise
authors.initials: L
authors.lastname: Rem
authors.affiliation: the Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, and.
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.affiliation: From the Departments of Cellular Biology and Biology, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.
authors.forename: C Theo
authors.initials: CT
authors.lastname: Verrips
authors.affiliation: Ablynx N.V., Technologiepark 21, 9052 Ghent, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.affiliation: From the Departments of Cellular Biology and Biology, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands,; Ablynx N.V., Technologiepark 21, 9052 Ghent, Belgium. Electronic address: hdehaard@argen-x.com.
authors.forename: Hans
authors.initials: H
authors.lastname: de Haard
authors.affiliation: the Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, and. Electronic address: mj.smit@vu.nl.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D002161:Camelids, New World; D018925:Chemokines / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D041681:NIH 3T3 Cells; D061905:Single-Domain Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018925:Chemokines; D061905:Single-Domain Antibodies
keywords: Antibodies; Chemokines; Chemotaxis; G Protein-coupled Receptors (GPCR); Nanobodies; Radioreceptor Assays