title: Targeting tumor-initiating cancer cells with dCD133KDEL shows impressive tumor reductions in a xenotransplant model of human head and neck cancer.
abstract: A novel anticancer agent was constructed by fusing a gene encoding the scFV that targets both glycosylated and unglycosylated forms of CD133 to a gene fragment encoding deimmunized PE38KDEL. The resulting fusion protein, dCD133KDEL, was studied to determine its ability to bind and kill tumor-initiating cells in vitro and in vivo. The anti-CD133 scFV selectively bound HEK293 cells transfected with the CD133 receptor gene. Time course viability studies showed that dCD133KDEL selectively inhibited NA-SCC and UMSCC-11B, 2 head and neck squamous cell carcinomas that contain a CD133 expressing subpopulation. Importantly, the drug did not inhibit the viability of hematopoietic lineages measured by long-term culture-initiating cell and colony-forming assays from sorted human CD34+ progenitor cells. In addition to in vitro studies, in vivo tumor initiation experiments confirmed that CD133-sorted cells implanted into the flanks of nude mice grew faster and larger than unsorted cells. In contrast, cells that were pretreated with dCD133KDEL before implantation showed the slowest and lowest incidence of tumors. Furthermore, UMSCC-11B-luc tumors treated with multiple intratumoral injections of dCD133KDEL showed marked growth inhibition, leading to complete degradation of the tumors that was not observed with an irrelevant control-targeted toxin. Experiments in immunocompetent mice showed that toxin deimmunization resulted in a 90% reduction in circulating antitoxin levels. These studies show that dCD133KDEL is a novel anticancer agent effective at inhibiting cell proliferation, tumor initiation, and eliminating established tumors by targeting the CD133 subpopulation. This agent shows significant promise for potential development as a clinically useful therapy.
authors.affiliation: Department of Pharmacology, Masonic Cancer Center, University of Minnesota, MMC: 367, Minneapolis, MN 55455, USA.
authors.forename: Nate N
authors.initials: NN
authors.lastname: Waldron
authors.forename: Dan S
authors.initials: DS
authors.lastname: Kaufman
authors.forename: Seunguk
authors.initials: S
authors.lastname: Oh
authors.forename: Zintis
authors.initials: Z
authors.lastname: Inde
authors.forename: Melinda K
authors.initials: MK
authors.lastname: Hexum
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
mesh_terms: D000071916:AC133 Antigen; D036002:ADP Ribose Transferases / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D001427:Bacterial Toxins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005098:Exotoxins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000494:pharmacology; D000922:Immunotoxins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D014162:Transfection; D037521:Virulence Factors / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D000071916:AC133 Antigen; D036002:ADP Ribose Transferases; D015703:Antigens, CD; D001427:Bacterial Toxins; D005098:Exotoxins; D006023:Glycoproteins; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse