Selective expansion of genetically modified T cells using an antibody/interleukin-2 receptor chimera.
Although adoptive transfer of tumor-specific T cells is a plausible approach for cancer immunotherapy, the therapeutic application was hampered due to severe side effects caused by administration of high-dose interleukin (IL)-2, which was used for long-lasting maintenance of tumor-specific T cells in vivo. To solve this problem, here we propose to use an antibody/IL-2 receptor chimera, which can transduce a growth signal in response to a cognate antigen. As a model system, V(H) or V(L) region of anti-hen egg lysozyme (HEL) antibody HyHEL-10 was tethered to extracellular D2 domain of erythropoietin receptor and transmembrane/cytoplasmic domains of IL-2 receptor beta or gamma chain. When the pairs of chimeric receptors (V(H)-IL-2Rbeta and V(L)-IL-2Rgamma, or V(H)-IL-2Rgamma and V(L)-IL-2Rbeta) were expressed in IL-3-dependent pro-B cell line Ba/F3 and IL-2-dependent T cell line CTLL-2, the cognate antigen HEL induced selective expansion of gene-modified cells in the absence of IL-3 and IL-2, respectively. Growth assay revealed that the combination of V(H)-IL-2Rbeta and V(L)-IL-2Rgamma transduced a more stringent HEL-dependent growth signal, indicating some conformational effects of the chimeras. Furthermore, STAT3, STAT5 and ERK1/2, which are hallmarks for IL-2R signaling, were all activated by the antibody/IL-2R chimeras. These results clearly demonstrate that the antibody/IL-2R chimeras could substantially mimic the wild-type IL-2R signaling, suggesting the potential application in expansion of gene-modified T cells.
Sogo
Takahiro
T
Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Kawahara
Masahiro
M
Tsumoto
Kouhei
K
Kumagai
Izumi
I
Ueda
Hiroshi
H
Nagamune
Teruyuki
T
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism*; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism*; D007377:Interleukin-3 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D009113:Muramidase / Q000276:immunology*; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D013997:Time Factors; D014162:Transfection
C508020:IL2RB protein, human; C507941:IL2RG protein, human; D007135:Immunoglobulin Variable Region; D053631:Interleukin Receptor Common gamma Subunit; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D007377:Interleukin-3; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; C421864:hen egg lysozyme; D009113:Muramidase