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Free keywords:
Animals
Antibody Affinity
Cell Line, Tumor
Cytotoxicity, Immunologic/immunology
GPI-Linked Proteins/immunology/metabolism
Humans
Intercellular Signaling Peptides and Proteins/immunology/metabolism
Killer Cells, Natural/*immunology/metabolism
Male
Mice
Mice, SCID
NK Cell Lectin-Like Receptor Subfamily K/immunology/metabolism
Prostate-Specific Antigen/*immunology/metabolism
Prostatic Neoplasms/*immunology/metabolism/*therapy
Receptors, Natural Killer Cell/immunology/metabolism
Recombinant Fusion Proteins/immunology/pharmacology
Single-Chain Antibodies/immunology/*pharmacology
Xenograft Model Antitumor Assays
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.
