To understand the molecular basis of human CEA recognition by MEDI-565 and the impact of amino acid polymorphisms and splice variants of CEA on the activity of MEDI-565, we sought to identify the CEA domain and the critical residues involved in MEDI-565 binding. The CEA-specific arm of MEDI-565 is a humanized version of the murine antibody A5B7 [40, 41] the binding epitope of which is unknown [40, 42] . We mapped its epitope using mutagenesis and computational modeling approaches. We further investigated what impact a CEA splice variant which lacks a large portion of the identified epitope could have on the binding and activity of MEDI-565.