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J Mol Biol. 2016 Jan 16;428(1):194-205. doi: 10.1016/j.jmb.2015.12.002. Epub 2015 Dec 11.

Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics.

Author information

1
University of Hawaii at Manoa, Department of Chemistry, 2545 McCarthy Mall, Honolulu, HI 96822-2275, USA.
2
Eureka Therapeutics Inc., 5858 Horton Street, Emeryville, CA 94608, USA.
3
Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
4
Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA; Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA.
5
University of Hawaii at Manoa, Department of Chemistry, 2545 McCarthy Mall, Honolulu, HI 96822-2275, USA; University of Hawaii Cancer Center, 2545 McCarthy Mall, Honolulu, HI 96822-2275, USA. Electronic address: hng@hawaii.edu.

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.

KEYWORDS:

MHC; antibodies; cancer; immunotherapy

PMID:
26688548
PMCID:
PMC4738012
DOI:
10.1016/j.jmb.2015.12.002
[Indexed for MEDLINE]
Free PMC Article

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