التفاصيل البيبلوغرافية
| العنوان: |
Enhancement of antibody-dependent cellular cytotoxicity of cetuximab by a chimeric protein encompassing interleukin-15 |
| المؤلفون: |
Ochoa, M.C. (María Carmen), Minute, L. (Luna), Lopez, A. (Ascensión), Perez-Ruiz, E. (Elisabeth), Gomar, C. (Celia), Vasquez, M. (Marcos), Inoges, S. (Susana), Etxeberria, I. (Iñaki), Rodriguez, I. (Inmaculada), Garasa, S. (Saray), Mayer, J.P. (Jan Peter), Wirtz, P. (Peter), Melero, I. (Ignacio), Berraondo, P. (Pedro) |
| بيانات النشر: |
Taylor & Francis |
| سنة النشر: |
2018 |
| المجموعة: |
dadun - Depósito Académico Digital Universidad de Navarra |
| مصطلحات موضوعية: |
Interleukin 15, Apolipoprotein A-I, Scavenger receptor class B type I, Antibody-dependent cellular cytotoxicity, NK cell, Cetuximab |
| الوصف: |
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. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| Relation: |
https://hdl.handle.net/10171/64487 |
| الاتاحة: |
https://hdl.handle.net/10171/64487 |
| Rights: |
info:eu-repo/semantics/openAccess |
| رقم الانضمام: |
edsbas.8B9408CF |
| قاعدة البيانات: |
BASE |