PMID- 32770595
OWN - NLM
STAT- MEDLINE
DCOM- 20201215
LR  - 20210110
IS  - 1349-7006 (Electronic)
IS  - 1347-9032 (Print)
IS  - 1347-9032 (Linking)
VI  - 111
IP  - 10
DP  - 2020 Oct
TI  - Development of a T-cell receptor mimic antibody targeting a novel Wilms tumor 
      1-derived peptide and analysis of its specificity.
PG  - 3516-3526
LID - 10.1111/cas.14602 [doi]
AB  - Wilms tumor 1 (WT1) is an intracellular tumor-associated antigen that remains 
      inaccessible to antibodies. Recently, T-cell receptor (TCR) mimic antibodies 
      (TCRm-Abs), which recognize peptides loaded on human leukocyte antigen (HLA) with 
      higher specificity and affinity than TCR, have been developed as a new antibody 
      class that can target intracellular antigens. To expand the therapeutic targets 
      in tumors with WT1, we developed TCRm-Abs targeting a novel 
      HLA-A*02:01-restricted peptide, WT1C (ALLPAVPSL), and validated their specificity 
      using multiple techniques. Screening of these antibodies by ELISA with a panel of 
      peptide/HLA complexes and by glycine scanning of peptide-pulsed T2 cells 
      identified one specific clone, #25-8. Despite the low risk for eliciting broad 
      cross-reactivity of this TCRm-Ab, analysis of a panel of cell lines, in 
      conjunction with exogenous expression of either or both the HLA-A*02:01 and WT1 
      genes in HeLa cells, revealed that #25-8 reacts with WT1C but also with unknown 
      peptides in the context of HLA-A*02:01. This potentially dangerous 
      cross-reactivity was confirmed through analysis using chimeric antigen receptor 
      T-cells carrying the single-chain variable fragment of #25-8, which targets 
      WT1-negative HeLa/A02 cells. To determine the cross-reactive profiles of #25-8, 
      we applied the PresentER antigen presentation platform with the #25-8-recognition 
      motif, which enables the identification of potential off-target peptides 
      expressed in the human proteome. Our results demonstrate the potential of 
      TCRm-Abs to target a variety of peptides in the context of HLA but also depict 
      the need for systematic validation to identify the cross-reactive peptides for 
      the prediction of off-target toxicity in future clinical translation.
CI  - (c) 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd 
      on behalf of Japanese Cancer Association.
FAU - Kurosawa, Nobuyuki
AU  - Kurosawa N
AUID- ORCID: 0000-0002-1548-4541
AD  - Laboratory of Molecular and Cellular Biology, Faculty of Science and Engineering, 
      Graduate School, University of Toyama, Toyama, Japan.
FAU - Midorikawa, Aki
AU  - Midorikawa A
AD  - Graduate School of Science and Engineering for Education, University of Toyama, 
      Toyama, Japan.
FAU - Ida, Kenta
AU  - Ida K
AD  - Graduate School of Science and Engineering for Education, University of Toyama, 
      Toyama, Japan.
FAU - Fudaba, Yuka Wakata
AU  - Fudaba YW
AD  - Laboratory of Molecular and Cellular Biology, Faculty of Science and Engineering, 
      Graduate School, University of Toyama, Toyama, Japan.
FAU - Isobe, Masaharu
AU  - Isobe M
AD  - Laboratory of Molecular and Cellular Biology, Faculty of Science and Engineering, 
      Graduate School, University of Toyama, Toyama, Japan.
LA  - eng
GR  - H27HIAC122/Hokuriku Industrial Advancement Center (HIAC)/
GR  - 15657579/Japan Agency for Medical Research and Development/
GR  - 16768665/Japan Agency for Medical Research and Development/
PT  - Journal Article
DEP - 20200826
PL  - England
TA  - Cancer Sci
JT  - Cancer science
JID - 101168776
RN  - 0 (Antibodies)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (HLA-A Antigens)
RN  - 0 (Peptides)
RN  - 0 (Proteome)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Single-Chain Antibodies)
RN  - 0 (WT1 Proteins)
RN  - 0 (WT1 protein, human)
SB  - IM
MH  - Animals
MH  - Antibodies/*immunology
MH  - Antigen Presentation/immunology
MH  - Antigens, Neoplasm/immunology
MH  - Cell Line, Tumor
MH  - Cross Reactions/immunology
MH  - HLA-A Antigens/immunology
MH  - HeLa Cells
MH  - Humans
MH  - Mice
MH  - Peptides/*immunology
MH  - Proteome/immunology
MH  - Receptors, Antigen, T-Cell/*immunology
MH  - Sensitivity and Specificity
MH  - Single-Chain Antibodies/immunology
MH  - WT1 Proteins/*immunology
PMC - PMC7540971
OTO - NOTNLM
OT  - T-cell receptor mimic antibody
OT  - Wilms tumor 1
OT  - chimeric antigen receptor T-cells
OT  - off-target
OT  - tumor-associated antigen
COIS- The authors declare no competing interests for this article.
EDAT- 2020/08/10 06:00
MHDA- 2020/12/16 06:00
PMCR- 2020/10/01
CRDT- 2020/08/10 06:00
PHST- 2020/05/25 00:00 [received]
PHST- 2020/07/27 00:00 [revised]
PHST- 2020/07/28 00:00 [accepted]
PHST- 2020/08/10 06:00 [pubmed]
PHST- 2020/12/16 06:00 [medline]
PHST- 2020/08/10 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - CAS14602 [pii]
AID - 10.1111/cas.14602 [doi]
PST - ppublish
SO  - Cancer Sci. 2020 Oct;111(10):3516-3526. doi: 10.1111/cas.14602. Epub 2020 Aug 26.