Structure of a TCR-mimic antibody with target predicts pharmacogenetics

N Ataie, J Xiang, N Cheng, EJ Brea, W Lu… - Journal of molecular …, 2016 - Elsevier
N Ataie, J Xiang, N Cheng, EJ Brea, W Lu, DA Scheinberg, C Liu, HL Ng
Journal of molecular biology, 2016Elsevier
Antibody therapies currently target only extracellular antigens. A strategy to recognize
intracellular antigens is to target peptides presented by immune HLA receptors. ESK1 is a
human, T-cell receptor (TCR)-mimic antibody that binds with subnanomolar affinity to the
RMF peptide from the intracellular Wilms tumor oncoprotein WT1 in complex with HLA-A*
02: 01. ESK1 is therapeutically effective in mouse models of WT1+ human cancers. TCR-
based therapies have been presumed to be restricted to one HLA subtype. The mechanism …
Abstract
Antibody therapies currently target only extracellular antigens. A strategy to recognize intracellular antigens is to target peptides presented by immune HLA receptors. ESK1 is a human, T-cell receptor (TCR)-mimic antibody that binds with subnanomolar affinity to the RMF peptide from the intracellular Wilms tumor oncoprotein WT1 in complex with HLA-A*02:01. ESK1 is therapeutically effective in mouse models of WT1+ human cancers. TCR-based therapies have been presumed to be restricted to one HLA subtype. The mechanism for the specificity and high affinity of ESK1 is unknown. We show in a crystal structure that ESK1 Fab binds to RMF/HLA-A*02:01 in a mode different from that of TCRs. From the structure, we predict and then experimentally confirm high-affinity binding with multiple other HLA-A*02 subtypes, broadening the potential patient pool for ESK1 therapy. Using the crystal structure, we also predict potential off-target binding that we experimentally confirm. Our results demonstrate how protein structure information can contribute to personalized immunotherapy.
Elsevier