The high affinity binding of thearithrax protective antigen (PA) to one of its receptors, capillary morphogenesis protein 2 (CMG2), is essential for the intoxication process of anthrax toxin. To acquire novel research tools to Study the PA-CMG2 interaction, we generated several anti-CMG2 monoclonal antibodies (MAbs). We demonstrated that one of the MAbs, 4B5, Could inhibit PA-CMG2 binding and Could also protect the sensitive cells against an anthrax lethal toxin challenge. We identified the epitope recognized by 4B5 and confirmed that the key residues of the epitope were the residues (YI)-Y-119-LK125 of CMG2. Based on our results, we propose that 4B5 binds to the E122 pocket of CMG2 and interrupts the interaction between the pocket and the PA 2 beta 3-2 beta 4 loop. TO our knowledge, this is the first report to illustrate that an anti-CMG2 antibody Could inhibit the PA-CMG2 interaction and therefore interfere with the intoxication of anthrax toxin. (c) 2009 Elsevier Inc. All rights reserved.