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Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy.
. 2014 Jan; 13(1):112-21.

Abstract

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.

Authors+Show Affiliations

Corresponding Author: Dafne Müller, Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, Stuttgart 70569, Germany. dafne.mueller@izi.uni-stuttgart.de.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24198185

Citation

Kermer, Vanessa, et al. "Combining Antibody-directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy." Molecular Cancer Therapeutics, vol. 13, no. 1, 2014, pp. 112-21.
Kermer V, Hornig N, Harder M, et al. Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy. Mol Cancer Ther. 2014;13(1):112-21.
Kermer, V., Hornig, N., Harder, M., Bondarieva, A., Kontermann, R. E., & Müller, D. (2014). Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy. Molecular Cancer Therapeutics, 13(1), 112-21. https://doi.org/10.1158/1535-7163.MCT-13-0282
Kermer V, et al. Combining Antibody-directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy. Mol Cancer Ther. 2014;13(1):112-21. PubMed PMID: 24198185.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy. AU - Kermer,Vanessa, AU - Hornig,Nora, AU - Harder,Markus, AU - Bondarieva,Anastasiia, AU - Kontermann,Roland E, AU - Müller,Dafne, Y1 - 2013/11/06/ PY - 2013/11/8/entrez PY - 2013/11/8/pubmed PY - 2014/9/30/medline SP - 112 EP - 21 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 13 IS - 1 N2 - 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. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/24198185/Combining_antibody_directed_presentation_of_IL_15_and_4_1BBL_in_a_trifunctional_fusion_protein_for_cancer_immunotherapy_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=24198185 DB - PRIME DP - Unbound Medicine ER -