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  Induction of in vitro and in vivo NK cell cytotoxicity using high-avidity immunoligands targeting prostate-specific membrane antigen in prostate carcinoma

Jachimowicz, R. D., Fracasso, G., Yazaki, P. J., Power, B. E., Borchmann, P., Engert, A., et al. (2011). Induction of in vitro and in vivo NK cell cytotoxicity using high-avidity immunoligands targeting prostate-specific membrane antigen in prostate carcinoma. Mol Cancer Ther, 10(6), 1036-45. doi:10.1158/1535-7163.MCT-10-1093.

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externe Referenz:
https://www.ncbi.nlm.nih.gov/pubmed/21525185 (beliebiger Volltext)
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 Urheber:
Jachimowicz, R. D.1, Autor           
Fracasso, G., Autor
Yazaki, P. J., Autor
Power, B. E., Autor
Borchmann, P., Autor
Engert, A., Autor
Hansen, H. P., Autor
Reiners, K. S., Autor
Marie, M., Autor
von Strandmann, E. P., Autor
Rothe, A., Autor
Affiliations:
1Jachimowicz – Mechanisms of DNA Repair, Max Planck Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_3394003              

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Schlagwörter: 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
 Zusammenfassung: 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.

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 Datum: 2011-062011-04-29
 Publikationsstatus: Erschienen
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 Identifikatoren: Anderer: 21525185
DOI: 10.1158/1535-7163.MCT-10-1093
ISSN: 1538-8514 (Electronic)1535-7163 (Linking)
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Titel: Mol Cancer Ther
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 10 (6) Artikelnummer: - Start- / Endseite: 1036 - 45 Identifikator: -