{"display":true,"structure":{"allele":{"alpha":{"identifier":"ipd-imgt:HLA35266","locus":"hla-a","match_type":"histo:exact","name":"HLA-A*02:01","slug":"hla_a_02_01","species_stem":"hla"},"beta":{}},"assemblies":{"1":{"assembly_name":"7bbg_1","chains":["A","B","C","H","L"],"downloaded_at":"2022-11-09T14:38:34.721001"}},"assembly_count":null,"assigned_chains":{"ab_heavy":{"chains":["H"],"match_type":"sabdab","sabdab":"Hchain","sequence":"QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSIELWWGGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC"},"ab_light":{"chains":["L"],"match_type":"sabdab","sabdab":"Lchain","sequence":"DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTIGSLQPDDFATYYCQQYEDYTTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC"},"beta2m":{"chains":["B"],"match_type":"histo:assign_chains","score":0.99,"sequence":"MIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM"},"class_i_alpha":{"chains":["A"],"match_type":"histo:assign_chains","score":0.94,"sequence":"MGSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDSDAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWRFLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKETLQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVVVPSGQEQRYTCHVQHEGLPKPLTLRWEGGGGSGGGGSGSGLNDIFEAQKIEWHEHHHHHH"},"peptide":{"chains":["C"],"match_type":"histo:classify_peptide","sequence":"RMFPNAPYL"}},"chronology":{"deposition_date":"2020-12-17","deposition_year":2020,"release_date":"2021-10-27","release_year":2021,"revision_date":"2022-01-05","revision_year":2022},"class":"class_i","classical":true,"complex_type":"class_i_with_peptide_and_antibody","components":["class_i_alpha","beta2m","peptide","ab_heavy","ab_light"],"experimental_method":"X-ray diffraction","facets":{},"ligands":[],"locus":"hla-a","manually_edited":{},"missing_residues":[],"page_title":"7BBG | HLA-A*02:01 binding \"RMFPNAPYL\" with antibody","pdb_code":"7bbg","pdb_title":"Crystal structure of hla-a2-wt1-rmf and fab 11d06","peptide":{"C":{"actual_length":9,"actual_sequence":"RMFPNAPYL","chain_id":"C","features":["correct_sequence_and_length"],"full_length":9,"full_sequence":"RMFPNAPYL"}},"peptide_length":9,"peptide_length_name":"nonamer","peptide_neighbours":{"1":{"neighbours":[{"position":58,"residue":"GLU"},{"position":63,"residue":"GLU"},{"position":159,"residue":"TYR"},{"position":59,"residue":"TYR"},{"position":62,"residue":"GLY"},{"position":7,"residue":"TYR"},{"position":33,"residue":"PHE"},{"position":171,"residue":"TYR"},{"position":66,"residue":"LYS"},{"position":163,"residue":"THR"},{"position":167,"residue":"TRP"},{"position":5,"residue":"MET"}],"position":1,"residue":"ARG"},"2":{"neighbours":[{"position":45,"residue":"MET"},{"position":70,"residue":"HIS"},{"position":99,"residue":"TYR"},{"position":66,"residue":"LYS"},{"position":9,"residue":"PHE"},{"position":63,"residue":"GLU"},{"position":67,"residue":"VAL"},{"position":159,"residue":"TYR"},{"position":7,"residue":"TYR"}],"position":2,"residue":"MET"},"3":{"neighbours":[{"position":159,"residue":"TYR"},{"position":70,"residue":"HIS"},{"position":99,"residue":"TYR"},{"position":155,"residue":"GLN"},{"position":66,"residue":"LYS"},{"position":156,"residue":"LEU"},{"position":97,"residue":"ARG"}],"position":3,"residue":"PHE"},"4":{"neighbours":[{"position":70,"residue":"HIS"},{"position":66,"residue":"LYS"}],"position":4,"residue":"PRO"},"5":{"neighbours":[{"position":70,"residue":"HIS"},{"position":155,"residue":"GLN"},{"position":97,"residue":"ARG"}],"position":5,"residue":"ASN"},"6":{"neighbours":[{"position":70,"residue":"HIS"},{"position":97,"residue":"ARG"},{"position":73,"residue":"THR"},{"position":74,"residue":"HIS"},{"position":116,"residue":"TYR"}],"position":6,"residue":"ALA"},"7":{"neighbours":[{"position":73,"residue":"THR"},{"position":77,"residue":"ASP"},{"position":116,"residue":"TYR"},{"position":114,"residue":"HIS"},{"position":152,"residue":"VAL"},{"position":97,"residue":"ARG"},{"position":147,"residue":"TRP"}],"position":7,"residue":"PRO"},"8":{"neighbours":[{"position":143,"residue":"THR"},{"position":76,"residue":"VAL"},{"position":146,"residue":"LYS"},{"position":147,"residue":"TRP"},{"position":73,"residue":"THR"},{"position":77,"residue":"ASP"}],"position":8,"residue":"TYR"},"9":{"neighbours":[{"position":116,"residue":"TYR"},{"position":84,"residue":"TYR"},{"position":80,"residue":"THR"},{"position":95,"residue":"VAL"},{"position":147,"residue":"TRP"},{"position":143,"residue":"THR"},{"position":123,"residue":"TYR"},{"position":146,"residue":"LYS"},{"position":81,"residue":"LEU"},{"position":77,"residue":"ASP"}],"position":9,"residue":"LEU"}},"peptide_sequence":"RMFPNAPYL","pockets":{"a":{"a159":{"number":159,"one_letter":"A","three_letter":"ALA"},"a163":{"number":163,"one_letter":"G","three_letter":"GLY"},"a167":{"number":167,"one_letter":"E","three_letter":"GLU"},"a171":{"number":171,"one_letter":"R","three_letter":"ARG"},"a5":{"number":5,"one_letter":"S","three_letter":"SER"},"a59":{"number":59,"one_letter":"E","three_letter":"GLU"},"a63":{"number":63,"one_letter":"G","three_letter":"GLY"},"a66":{"number":66,"one_letter":"R","three_letter":"ARG"},"a7":{"number":7,"one_letter":"R","three_letter":"ARG"}},"b":{"a24":{"number":24,"one_letter":"I","three_letter":"ILE"},"a34":{"number":34,"one_letter":"F","three_letter":"PHE"},"a45":{"number":45,"one_letter":"R","three_letter":"ARG"},"a63":{"number":63,"one_letter":"G","three_letter":"GLY"},"a66":{"number":66,"one_letter":"R","three_letter":"ARG"},"a67":{"number":67,"one_letter":"K","three_letter":"LYS"},"a7":{"number":7,"one_letter":"R","three_letter":"ARG"},"a70":{"number":70,"one_letter":"A","three_letter":"ALA"},"a9":{"number":9,"one_letter":"F","three_letter":"PHE"},"a99":{"number":99,"one_letter":"M","three_letter":"MET"}},"c":{"a70":{"number":70,"one_letter":"A","three_letter":"ALA"},"a73":{"number":73,"one_letter":"Q","three_letter":"GLN"},"a74":{"number":74,"one_letter":"T","three_letter":"THR"},"a9":{"number":9,"one_letter":"F","three_letter":"PHE"},"a97":{"number":97,"one_letter":"Q","three_letter":"GLN"}},"d":{"a114":{"number":114,"one_letter":"Y","three_letter":"TYR"},"a155":{"number":155,"one_letter":"E","three_letter":"GLU"},"a156":{"number":156,"one_letter":"Q","three_letter":"GLN"},"a159":{"number":159,"one_letter":"A","three_letter":"ALA"},"a160":{"number":160,"one_letter":"Y","three_letter":"TYR"},"a99":{"number":99,"one_letter":"M","three_letter":"MET"}},"e":{"a114":{"number":114,"one_letter":"Y","three_letter":"TYR"},"a147":{"number":147,"one_letter":"K","three_letter":"LYS"},"a152":{"number":152,"one_letter":"H","three_letter":"HIS"},"a156":{"number":156,"one_letter":"Q","three_letter":"GLN"},"a97":{"number":97,"one_letter":"Q","three_letter":"GLN"}},"f":{"a116":{"number":116,"one_letter":"Q","three_letter":"GLN"},"a123":{"number":123,"one_letter":"D","three_letter":"ASP"},"a143":{"number":143,"one_letter":"T","three_letter":"THR"},"a146":{"number":146,"one_letter":"H","three_letter":"HIS"},"a147":{"number":147,"one_letter":"K","three_letter":"LYS"},"a77":{"number":77,"one_letter":"V","three_letter":"VAL"},"a80":{"number":80,"one_letter":"G","three_letter":"GLY"},"a81":{"number":81,"one_letter":"T","three_letter":"THR"},"a84":{"number":84,"one_letter":"G","three_letter":"GLY"},"a95":{"number":95,"one_letter":"T","three_letter":"THR"}}},"publication":{"abstract":"Antibody-based immunotherapy is a promising strategy for targeting chemoresistant leukemic cells. However, classical antibody-based approaches are restricted to targeting lineage-specific cell surface antigens. By targeting intracellular antigens, a large number of other leukemia-associated targets would become accessible. In this study, we evaluated a novel T-cell bispecific (TCB) antibody, generated by using CrossMAb and knob-into-holes technology, containing a bivalent T-cell receptor-like binding domain that recognizes the RMFPNAPYL peptide derived from the intracellular tumor antigen Wilms tumor protein (WT1) in the context of HLA-A*02. Binding to CD3\u03b5 recruits T cells irrespective of their T-cell receptor specificity. WT1-TCB elicited antibody-mediated T-cell cytotoxicity against AML cell lines in a WT1- and HLA-restricted manner. Specific lysis of primary acute myeloid leukemia (AML) cells was mediated in ex vivo long-term cocultures by using allogeneic (mean \u00b1 standard error of the mean [SEM] specific lysis, 67 \u00b1 6% after 13-14 days; n = 18) or autologous, patient-derived T cells (mean \u00b1 SEM specific lysis, 54 \u00b1 12% after 11-14 days; n\u00a0= 8). WT1-TCB-treated T cells exhibited higher cytotoxicity against primary AML cells than an HLA-A*02 RMF-specific T-cell clone. Combining WT1-TCB with the immunomodulatory drug lenalidomide further enhanced antibody-mediated T-cell cytotoxicity against primary AML cells (mean \u00b1 SEM specific lysis on days 3-4, 45.4 \u00b1 9.0% vs 70.8 \u00b1 8.3%; P = .015; n = 9-10). In vivo, WT1-TCB-treated humanized mice bearing SKM-1 tumors exhibited a significant and dose-dependent reduction in tumor growth. In summary, we show that WT1-TCB facilitates potent in vitro, ex vivo, and in vivo killing of AML cell lines and primary AML cells; these results led to the initiation of a phase 1 trial in patients with relapsed/refractory AML (#NCT04580121).","bibjson":{"author":[{"initials":"C","lastname":"Augsberger","name":"Augsberger C"},{"initials":"G","lastname":"H\u00e4nel","name":"H\u00e4nel G"},{"initials":"W","lastname":"Xu","name":"Xu W"},{"initials":"V","lastname":"Pulko","name":"Pulko V"},{"initials":"LJ","lastname":"Hanisch","name":"Hanisch LJ"},{"initials":"A","lastname":"Augustin","name":"Augustin A"},{"initials":"J","lastname":"Challier","name":"Challier J"},{"initials":"K","lastname":"Hunt","name":"Hunt K"},{"initials":"B","lastname":"Vick","name":"Vick B"},{"initials":"PE","lastname":"Rovatti","name":"Rovatti PE"},{"initials":"C","lastname":"Krupka","name":"Krupka C"},{"initials":"M","lastname":"Rothe","name":"Rothe M"},{"initials":"A","lastname":"Sch\u00f6nle","name":"Sch\u00f6nle A"},{"initials":"J","lastname":"Sam","name":"Sam J"},{"initials":"E","lastname":"Lezan","name":"Lezan E"},{"initials":"A","lastname":"Ducret","name":"Ducret A"},{"initials":"D","lastname":"Ortiz-Franyuti","name":"Ortiz-Franyuti D"},{"initials":"AC","lastname":"Walz","name":"Walz AC"},{"initials":"J","lastname":"Benz","name":"Benz J"},{"initials":"A","lastname":"Bujotzek","name":"Bujotzek A"},{"initials":"FS","lastname":"Lichtenegger","name":"Lichtenegger FS"},{"initials":"C","lastname":"Gassner","name":"Gassner C"},{"initials":"A","lastname":"Carpy","name":"Carpy A"},{"initials":"V","lastname":"Lyamichev","name":"Lyamichev V"},{"initials":"J","lastname":"Patel","name":"Patel J"},{"initials":"N","lastname":"Konstandin","name":"Konstandin N"},{"initials":"A","lastname":"Tunger","name":"Tunger A"},{"initials":"M","lastname":"Schmitz","name":"Schmitz M"},{"initials":"M","lastname":"von Bergwelt-Baildon","name":"von Bergwelt-Baildon M"},{"initials":"K","lastname":"Spiekermann","name":"Spiekermann K"},{"initials":"L","lastname":"Vago","name":"Vago L"},{"initials":"I","lastname":"Jeremias","name":"Jeremias I"},{"initials":"E","lastname":"Marrer-Berger","name":"Marrer-Berger E"},{"initials":"P","lastname":"Uma\u00f1a","name":"Uma\u00f1a P"},{"initials":"C","lastname":"Klein","name":"Klein C"},{"initials":"M","lastname":"Subklewe","name":"Subklewe M"}],"identifier":[{"id":"10.1182/blood.2020010477","type":"doi"},{"id":"34280257","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"Blood","name":""},"pages":[null],"title":"Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC specific T-cell bispecific antibody.","type":"article","url":"https://ashpublications.org/blood/article/138/25/2655/476420/Targeting-intracellular-WT1-in-AML-with-a-novel","volume":[null],"year":[2021]},"in_pmc":"N","in_pmce":"Y","open_access":"N"},"resolution":"2.64","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/7bbg"},"rcsb":{"url":"https://www.rcsb.org/structure/7bbg"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-A*02:01 binding \"RMFPNAPYL\" with antibody at 2.64Å resolution","unique_chain_count":5}}