Neutralizing Nanobodies Targeting Diverse Chemokines Effectively Inhibit Chemokine Function |
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| Authors: | Christophe Blanchetot Dennis Verzijl Azra Muji?-Deli? Leontien Bosch Louise Rem Rob Leurs C. Theo Verrips Michael Saunders Hans de Haard Martine J. Smit |
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| Affiliation: | From the ‡Departments of Cellular Biology and Biology, Utrecht University, Padualaan 8, 3584CH Utrecht, The Netherlands.;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 ;¶Ablynx N.V., Technologiepark 21, 9052 Ghent, Belgium |
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| 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. |
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| Keywords: | Antibodies Chemokines Chemotaxis G Protein-coupled Receptors (GPCR) Radioreceptor Assays Nanobodies |
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