Abstract
The CCR5 receptor plays a role in several key physiological and pathological processes and is an important therapeutic target. Inhibition of the CCR5 axis by passive or active immunisation offers one very selective strategy for intervention. In this study we define a new linear epitope within the extracellular domain of CCR5 recognised by two independently produced monoclonal antibodies. A short peptide encoding the linear epitope can induce antibodies which recognise the intact receptor when administered colinear with a tetanus toxoid helper T cell epitope. The monoclonal antibody RoAb 13 is shown to bind to both cells and peptide with moderate to high affinity (6x10^8 and 1.2x107 M-1 respectively), and binding to the peptide is enhanced by sulfation of tyrosines at positions 10 and 14. RoAb13, which has previously been shown to block HIV infection, also blocks migration of monocytes in response to CCR5 binding chemokines and to inflammatory macrophage conditioned medium. A Fab fragment of RoAb13 has been crystallised and a structure of the antibody is reported to 2.1 angstrom resolution.
Highlights
The chemokine receptor CCR5 and its ligands CCL3 (MIP1α), CCL4 (MIP1β) and CCL5 (RANTES) play an important role in orchestrating the inflammatory response [1]
In this study we have examined a number of available monoclonal antibodies raised against intact human CCR5, and identified two which recognise a synthetic peptide spanning the Nterminal domain of CCR5
R&D1801 and RoAb13 recognised the synthetic peptide, confirming that the antibodies were able to recognise a linear epitope in the first extracellular domain of CCR5
Summary
The chemokine receptor CCR5 and its ligands CCL3 (MIP1α), CCL4 (MIP1β) and CCL5 (RANTES) play an important role in orchestrating the inflammatory response [1]. CCR5 mediated inflammation may play an important role in promoting the growth of tumours[2] and in other diseases exhibiting chronic inflammatory pathologies [3]. An individual who received a stem cell transplant from a CCR5 negative donor (for treatment of acute myeloid leukemia) is believed to be the only patient to have been cured of HIV [6]. For all these reasons, there has been and continues to be great.
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