title: Structure of a TCR-Mimic Antibody with Target Predicts Pharmacogenetics.
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.
authors.affiliation: University of Hawaii at Manoa, Department of Chemistry, 2545 McCarthy Mall, Honolulu, HI 96822-2275, USA.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Ataie
authors.affiliation: Eureka Therapeutics Inc., 5858 Horton Street, Emeryville, CA 94608, USA.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Eureka Therapeutics Inc., 5858 Horton Street, Emeryville, CA 94608, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Cheng
authors.affiliation: Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Brea
authors.affiliation: University of Hawaii at Manoa, Department of Chemistry, 2545 McCarthy Mall, Honolulu, HI 96822-2275, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Lu
authors.affiliation: Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA; Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.affiliation: Eureka Therapeutics Inc., 5858 Horton Street, Emeryville, CA 94608, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Ho Leung
authors.initials: HL
authors.lastname: Ng
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010597:Pharmacogenetics; D011485:Protein Binding; D011487:Protein Conformation; D025721:WT1 Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; D025721:WT1 Proteins; C583751:WT1 protein, human
keywords: MHC; antibodies; cancer; immunotherapy