| Literature DB >> 29308327 |
Maria Carmen Ochoa1,2,3, Luna Minute1,2, Ascensión López4,5, Elisabeth Pérez-Ruiz1,2, Celia Gomar1,2, Marcos Vasquez1,2, Susana Inoges4,5, Iñaki Etxeberria1,2, Inmaculada Rodriguez1,2,3, Saray Garasa1,2, Jan-Peter Andreas Mayer6, Peter Wirtz6, Ignacio Melero1,2,4,3, Pedro Berraondo1,2,3.
Abstract
Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15Rα, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8+ T cells. On cell cultures, Sushi-IL15-Apo increases NK cell proliferation and survival as well as spontaneous and antibody-mediated cytotoxicity. Scavenger receptor class B type I (SR-B1) is the receptor for ApoA-I and is expressed on the surface of tumor cells. SR-B1 can adsorb the chimeric protein on tumor cells and can transpresent IL-15 to NK and CD8+ T cells. A transient NK-humanized murine model was developed to test the increase of ADCC attained by the chimeric protein in vivo. The EGFR+ human colon cancer cell line HT-29 was intraperitoneally inoculated in immune-deficient Rag2-/-γc-/- mice that were reconstituted with freshly isolated PBMCs and treated with the anti-EGFR mAb cetuximab. The combination of the Sushi-IL15-Apo protein and cetuximab reduced the number of remaining tumor cells in the peritoneal cavity and delayed tumor engraftment in the peritoneum. Furthermore, Sushi-IL15-Apo increased the anti-tumor effect of a murine anti-EGFR mAb in Rag1-/- mice bearing subcutaneous MC38 colon cancer transfected to express EGFR. Thus, Sushi-IL15-Apo is a potent tool to increase the number and the activation of NK cells to promote the ADCC activity of antibodies targeting tumor antigens.Entities:
Keywords: NK cell; antibody-dependent cellular cytotoxicity; apolipoprotein A-I; cetuximab; interleukin 15; scavenger receptor class B type I
Year: 2017 PMID： 29308327 PMCID： PMC5749662 DOI： 10.1080/2162402X.2017.1393597
Source DB: PubMed Journal: Oncoimmunology ISSN： 2162-4011 Impact factor: 8.110