title: Induction of in vitro and in vivo NK cell cytotoxicity using high-avidity immunoligands targeting prostate-specific membrane antigen in prostate carcinoma.
abstract: Cancer that might develop as host natural killer (NK) cells fail to detect ligands for their activating NK receptors. Immunoligands represent promising immunotherapeutic tools to overcome this deficit. These are fusion proteins containing a single-chain antibody fragment (scFv) to target an available tumor antigen and ULBP2 to activate host NK cells by targeting the activatory receptor NKG2D. Prostate-specific membrane antigen (PSMA) is an integral non-shed type 2 membrane protein that is highly and specifically expressed on prostate epithelial cells and strongly upregulated in prostate cancer. Here, we compare the impact of various anti-PSMA immunoligand formats on the therapeutic efficacy against prostate carcinoma cells by activating NK cells via NKG2D. Shortening of the linker separating the heavy and light chain antibody domain leads to the formation of dimers, trimers, and higher molecular mass oligomers. NK cells are most efficiently activated by multimeric immunoligands, thus showing an altered cytokine release pattern. The high avidity format is also superior in in vitro NK-mediated tumor cell targeting as shown in cytotoxicity assays. Finally, the efficacy of a multimeric immunoligand is shown in a prostate carcinoma mouse xenograft model showing a strong activity against advanced established tumors.
authors.affiliation: Department I of Internal Medicine, University Hospital Cologne, LFI, Ebene 4, Room 703, Kerpener Str. 62, 50927 Cologne, Germany.
authors.forename: Ron D
authors.initials: RD
authors.lastname: Jachimowicz
authors.forename: Giulio
authors.initials: G
authors.lastname: Fracasso
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yazaki
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Power
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Hinrich P
authors.initials: HP
authors.lastname: Hansen
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Reiners
authors.forename: Madlener
authors.initials: M
authors.lastname: Marie
authors.forename: Elke Pogge
authors.initials: EP
authors.lastname: von Strandmann
authors.forename: Achim
authors.initials: A
authors.lastname: Rothe
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000276:immunology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D055607:Receptors, Natural Killer Cell / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D057127:Single-Chain Antibodies / Q000276:immunology / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C423230:ULBP2 protein, human; D017430:Prostate-Specific Antigen