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

Ganesh, Vannakambadi K.; Liang, Xiaowen; Geoghegan, Joan A.; Cohen, Ana Luisa V.; Venugopalan, Nagarajan; Foster, Timothy J.; Hook, Magnus

doi:10.1016/j.ebiom.2016.09.027

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

Journal Article · Tue Nov 01 00:00:00 EDT 2016 · EBioMedicine

DOI:https://doi.org/10.1016/j.ebiom.2016.09.027· OSTI ID:1623661

Ganesh, Vannakambadi K. ^[1]; Liang, Xiaowen ^[2]; Geoghegan, Joan A. ^[3]; Cohen, Ana Luisa V. ^[2]; Venugopalan, Nagarajan ^[4]; Foster, Timothy J. ^[5]; Hook, Magnus ^[2]

Texas A & M University Health Science Center, Houston, TX (United States). Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology; DOE/OSTI
Texas A & M University Health Science Center, Houston, TX (United States). Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology
Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland

The Staphylococcus aureus fibrinogen binding MSCRAMM (Microbial Surface Components Recognizing Adhesive Matrix Molecules), ClfA (clumping factor A) is an important virulence factor in staphylococcal infections and a component of several vaccines currently under clinical evaluation. The mouse monoclonal antibody aurexis (also called 12-9), and the humanized version tefibazumab are therapeutic monoclonal antibodies targeting ClfA that in combination with conventional antibiotics were effective in animal models but showed less impressive efficacy in a limited Phase II clinical trial. We here report the crystal structure and a biochemical characterization of the ClfA/tefibazumab (Fab) complex. The epitope for tefibazumab is located to the “top” of the N3 subdomain of ClfA and partially overlaps with a previously unidentified second binding site for fibrinogen. A high-affinity binding of ClfA to fibrinogen involves both an interaction at the N3 site and the previously identified docking of the C-terminal segment of the fibrinogen γ-chain in the N2N3 trench. Although tefibazumab binds ClfA with high affinity we observe a modest IC50 value for the inhibition of fibrinogen binding to the MSCRAMM. This observation, paired with a common natural occurring variant of ClfA that is not effectively recognized by the mAb, may partly explain the modest effect tefibazumab showed in the initial clinic trail. This information will provide guidance for the design of the next generation of therapeutic anti-staphylococcal mAbs targeting ClfA.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Lab (ANL), Lemont, IL (United States)

Sponsoring Organization:: Health Research Board of Ireland; NIH National Institute of General Medical Sciences (NIGMS); National Cancer Institute; National Institutes of Health (NIH); Science Foundation, Ireland; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1623661

Journal Information:: EBioMedicine, Journal Name: EBioMedicine Journal Issue: C Vol. 13; ISSN 2352-3964

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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