PMID- 25774714
OWN - NLM
STAT- MEDLINE
DCOM- 20160321
LR  - 20181113
IS  - 1546-1696 (Electronic)
IS  - 1087-0156 (Linking)
VI  - 33
IP  - 4
DP  - 2015 Apr
TI  - Identification of human T-cell receptors with optimal affinity to cancer antigens 
      using antigen-negative humanized mice.
PG  - 402-7
LID - 10.1038/nbt.3147 [doi]
AB  - Identifying T-cell receptors (TCRs) that bind tumor-associated antigens (TAAs) 
      with optimal affinity is a key bottleneck in the development of adoptive T-cell 
      therapy of cancer. TAAs are unmutated self proteins, and T cells bearing 
      high-affinity TCRs specific for such antigens are commonly deleted in the thymus. 
      To identify optimal-affinity TCRs, we generated antigen-negative humanized mice 
      with a diverse human TCR repertoire restricted to the human leukocyte antigen 
      (HLA) A*02:01 (ref. 3). These mice were immunized with human TAAs, for which they 
      are not tolerant, allowing induction of CD8(+) T cells with optimal-affinity TCRs. 
      We isolate TCRs specific for the cancer/testis (CT) antigen MAGE-A1 (ref. 4) and 
      show that two of them have an anti-tumor effect in vivo. By comparison, 
      human-derived TCRs have lower affinity and do not mediate substantial therapeutic 
      effects. We also identify optimal-affinity TCRs specific for the CT antigen 
      NY-ESO. Our humanized mouse model provides a useful tool for the generation of 
      optimal-affinity TCRs for T-cell therapy.
FAU - Obenaus, Matthias
AU  - Obenaus M
AUID- ORCID: 0000000250909162
AD  - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
FAU - Leitao, Catarina
AU  - Leitao C
AUID- ORCID: 0000000198842983
AD  - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
FAU - Leisegang, Matthias
AU  - Leisegang M
AD  - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
FAU - Chen, Xiaojing
AU  - Chen X
AD  - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
FAU - Gavvovidis, Ioannis
AU  - Gavvovidis I
AD  - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
FAU - van der Bruggen, Pierre
AU  - van der Bruggen P
AD  - 1] Ludwig Institute for Cancer Research and WELBIO, Brussels, Belgium. [2] De 
      Duve Institute, Universite Catholique de Louvain, Brussels, Belgium.
FAU - Uckert, Wolfgang
AU  - Uckert W
AD  - 1] Max-Delbruck-Center for Molecular Medicine, Berlin, Germany. [2] Institute of 
      Biology, Humboldt University, Berlin, Germany.
FAU - Schendel, Dolores J
AU  - Schendel DJ
AD  - Medigene AG, Planegg/Martinsried, Germany.
FAU - Blankenstein, Thomas
AU  - Blankenstein T
AD  - 1] Max-Delbruck-Center for Molecular Medicine, Berlin, Germany. [2] Institute of 
      Immunology, Charite Campus Buch, Berlin, Germany.
LA  - eng
SI  - GENBANK/KM501069
SI  - GENBANK/KM501070
SI  - GENBANK/KM501071
SI  - GENBANK/KM501072
SI  - GENBANK/KM501073
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150316
PL  - United States
TA  - Nat Biotechnol
JT  - Nature biotechnology
JID - 9604648
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal, Humanized/*immunology
MH  - Antigens, Neoplasm/*immunology
MH  - Binding Sites
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Immunoassay/*methods
MH  - Immunotherapy, Adoptive/methods
MH  - Mice
MH  - Molecular Sequence Data
MH  - Neoplasms, Experimental/*immunology/*therapy
MH  - Protein Binding
MH  - Protein Interaction Mapping/instrumentation/methods
MH  - Receptors, Antigen, T-Cell/*immunology
MH  - Species Specificity
EDAT- 2015/03/17 06:00
MHDA- 2016/03/22 06:00
CRDT- 2015/03/17 06:00
PHST- 2014/08/28 00:00 [received]
PHST- 2015/01/12 00:00 [accepted]
PHST- 2015/03/17 06:00 [entrez]
PHST- 2015/03/17 06:00 [pubmed]
PHST- 2016/03/22 06:00 [medline]
AID - nbt.3147 [pii]
AID - 10.1038/nbt.3147 [doi]
PST - ppublish
SO  - Nat Biotechnol. 2015 Apr;33(4):402-7. doi: 10.1038/nbt.3147. Epub 2015 Mar 16.