Lessons from the Crystal Structure of the S. aureus Surface Protein Clumping Factor A in Complex With Tefibazumab, an Inhibiting Monoclonal Antibody.

Highlights

The crystal structure of the monoclonal antibody tefibazumab in complex with ClfA (Clumping factor A) of S. aureus

Biochemical studies reveal a second binding site for fibrinogen in ClfA partially overlapping the tefibazumab epitope.

An explanation for tefibazumab modest effect in a clinical trial compared to the monoclonal's efficacy in animal models


The S. aureus fibrinogen binding surface protein ClfA (Clumping factor A) is an important virulence factor and a target in several staphylococcal experimental vaccines and immunotherapeutic. One monoclonal antibody to ClfA called aurexis showed great promise in animal models for the treatment of staphylococcal infections. However, in a limited phase II clinical trial the efficacy was less impressive. We have solved the structure of the Fab fragment of tefibazumab (the humanized version of aurexis) in complex with the fibrinogen binding region of ClfA. The tefibazumab epitope partially overlaps with a previously unknown second fibrinogen binding site on ClfA. Biochemical analysis show that although tefibazumab binds to ClfA with high affinity the IC50 concentration for fibrinogen binding is modest. Furthermore, analysis of sequence variations in ClfA shows that some clinically important strains are poorly recognized by tefibazumab. These observations may partially explain the modest efficacy observed for tefibazumab in the clinical trial but provide a structural base for the design of more potent inhibitors.