Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics.
J Mol Biol
; 428(1): 194-205, 2016 Jan 16.
Article
in En
| MEDLINE
| ID: mdl-26688548
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*0201. 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*0201 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HLA-A2 Antigen
/
WT1 Proteins
/
Antibodies
/
Antineoplastic Agents
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Mol Biol
Year:
2016
Document type:
Article
Affiliation country:
Estados Unidos