Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy
| Autor: | Nora Hornig, Anastasiia Bondarieva, Vanessa Kermer, Roland E. Kontermann, Markus Harder, Dafne Müller |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
medicine.medical_treatment Recombinant Fusion Proteins Lymphocyte Activation Receptors Tumor Necrosis Factor Mice Cancer immunotherapy Cell Line Tumor Neoplasms medicine Animals Humans Receptor Cell Proliferation Interleukin-15 biology Immunotherapy Fusion protein Trifunctional antibody Molecular biology 4-1BB Ligand Oncology Interleukin 15 biology.protein Cancer research Antibody Cytokine receptor Single-Chain Antibodies T-Lymphocytes Cytotoxic |
| Zdroj: | Molecular cancer therapeutics. 13(1) |
| ISSN: | 1538-8514 |
| Popis: | Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common γ-chain (γc) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Rα chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-γ release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy. Mol Cancer Ther; 13(1); 112–21. ©2013 AACR. |
| Databáze: | OpenAIRE |
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