Structure activity relationships of monocyte chemoattractant proteins in complex with a blocking antibody.

Abstract

Monocyte chemoattractant proteins (MCPs) are cytokines that direct immune cells bearing appropriate receptors to sites of inflammation or injury and are therefore attractive therapeutic targets for inhibitory molecules. 11K2 is a blocking mouse monoclonal antibody active against several human and murine MCPs. A 2.5 A structure of the Fab fragment of this antibody in complex with human MCP-1 has been solved. The Fab blocks CCR2 receptor binding to MCP-1 through an adjacent but distinct binding site. The orientation of the Fab indicates that a single MCP-1 dimer will bind two 11K2 antibodies. Several key residues on the antibody and on human MCPs were predicted to be involved in antibody selectivity. Mutational analysis of these residues confirms their involvement in the antibody-chemokine interaction. In addition to mutations that decreased or disrupted binding, one antibody mutation resulted in a 70-fold increase in affinity for human MCP-2. A key residue missing in human MCP-3, a chemokine not recognized by the antibody, was identified and engineering the preferred residue into the chemokine conferred binding to the antibody.

• Authors: Carl Reid, Mia Rushe, Matthew Jarpe, Herman van Vlijmen, Brian Dolinski, Fang Qian, Teresa G Cachero, Hernan Cuervo, Milka Yanachkova, Chioma Nwankwo, Xin Wang, Natalie Etienne, Ellen Garber, Véronique Bailly, Antonin de Fougerolles, P Ann Boriack-Sjodin
• Journal: Protein engineering, design & selection : PEDS (Protein Eng Des Sel) Vol. 19 Issue 7 Pg. 317-24 (Jul 2006) ISSN: 1741-0126 [Print] England
• PMID: 16682434 (Publication Type: Journal Article)

Chemical References

• Antibodies, Blocking
• CCL2 protein, human
• CCL7 protein, human
• CCL8 protein, human
• CCR2 protein, human
• Ccl7 protein, mouse
• Ccl8 protein, mouse
• Ccr2 protein, mouse
• Chemokine CCL2
• Chemokine CCL7
• Chemokine CCL8
• Cytokines
• Immunoglobulin Fab Fragments
• Monocyte Chemoattractant Proteins
• Receptors, CCR2
• Receptors, Chemokine

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Blocking (immunology, pharmacology)
• Binding Sites
• Chemokine CCL2 (chemistry, pharmacology)
• Chemokine CCL7
• Chemokine CCL8
• Cytokines (metabolism, pharmacology)
• Humans
• Immunoglobulin Fab Fragments (immunology, pharmacology)
• Inflammation (drug therapy)
• Mice
• Models, Molecular
• Molecular Sequence Data
• Monocyte Chemoattractant Proteins (chemistry, pharmacology)
• Mutation
• Receptors, CCR2
• Receptors, Chemokine (antagonists & inhibitors, chemistry, drug effects)
• Structure-Activity Relationship
• Wounds and Injuries (drug therapy)