ESK1 is a fully human T-cell receptor mimicking antibody targeting the Wilms Tumor 1 (WT1) derived peptide/HLA-A*02 complex. ESK1 was shown to be highly effective in leukemia mouse models via antibody-dependent cell-mediated cytotoxicity. The efficacy of ESK1 is a critical demonstration of the ability of therapeutic antibodies to target intracellular antigens. We present a 3.0 angstrom crystal structure of ESK1 Fab in complex with WT1 peptide/HLA-A*02:01. ESK1 binds WT1/HLA-A*02:01 with an orientation different from the canonical diagonal mode of T-cell receptors. Residues in the WT1 peptide act as an "electrostatic key" that provides the basis for ESK1 binding selectivity. Structural data also provided the basis for predicting ESK1 binding beyond the HLA-A*02:01 subtype to other common HLA-A*02 subtypes, which was then confirmed in direct binding studies. These data potentially greatly expand the range of patients treatable by ESK1.

Structural basis for high affinity antibody recognition of an intracellular target

250th National Meeting (2015)

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