Molecular basis for the antagonistic activity of an anti-CXCR4 antibody

نویسندگان

  • Li Peng
  • Melissa M. Damschroder
  • Kimberly E. Cook
  • Herren Wu
  • William F. Dall'Acqua
چکیده

Antagonistic antibodies targeting the G-protein C-X-C chemokine receptor 4 (CXCR4) hold promising therapeutic potential in various diseases. We report for the first time the detailed mechanism of action at a molecular level of a potent anti-CXCR4 antagonistic antibody (MEDI3185). We characterized the MEDI3185 paratope using alanine scanning on all 6 complementary-determining regions (CDRs). We also mapped its epitope using CXCR4 mutagenesis to assess the relative importance of the CXCR4 N-terminal peptide, extracellular loops (ECL) and ligand-binding pocket. We show that the interaction between MEDI3185 and CXCR4 is mediated mostly by CDR3H in MEDI3185 and ECL2 in CXCR4. The MEDI3185 epitope comprises the entire ECL2 sequence, lacks any so-called 'hot-spot' and is remarkably resistant to mutations. The structure of MEDI3185 variable domains was modeled, and suggested a β-strand/β-strand interaction between MEDI3185 CDR3H and CXCR4 ECL2, resulting in direct steric hindrance with CXCR4 ligand SDF-1. These findings may have important implications for designing antibody therapies against CXCR4.

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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2016