The bispecific immunoligand ULBP2-aCEA redirects natural killer cells to tumor cells and reveals potent anti-tumor activity against colon carcinoma.
NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.
Department I of Internal Medicine, Innate Immunity Group, University Hospital Cologne, Cologne, Germany.
Achim
A
Rothe
Ron D
RD
Jachimowicz
Sven
S
Borchmann
Marie
M
Madlener
Jörg
J
Keßler
Katrin S
KS
Reiners
Maike
M
Sauer
Hinrich P
HP
Hansen
Roland T
RT
Ullrich
Sampurna
S
Chatterjee
Peter
P
Borchmann
Paul
P
Yazaki
Thomas C
TC
Koslowsky
Andreas
A
Engert
Lukas C
LC
Heukamp
Michael
M
Hallek
Elke Pogge
EP
von Strandmann
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy*; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D016219:Immunotherapy, Adoptive; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation; D037181:Lectins, C-Type / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002272:Carcinoembryonic Antigen; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D000099192:CD69 Antigens; C527085:KLRK1 protein, human; C423230:ULBP2 protein, human; C516769:PTPRC protein, human
NK cells; NKG2D; colon carcinoma; immunotherapy