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Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy.
J Immunother. 2012 Jun; 35(5):418-29.JI

Abstract

Initiation of a tumor-directed immune response and appropriate modulation of its progress are key issues in cancer immunotherapy. Combinatorial strategies addressing both aspects might therefore be especially suitable. Here, we report a targeted approach combining a bispecific antibody with 2 costimulatory antibody-ligand fusion proteins. According to the concept, the bispecific antibody (scDbFAP×CD3) retargets T cells in a MHC-independent manner to tumor cells, providing an artificial first signal that allows the costimulatory antibody-ligand fusion proteins (B7.2-Db and scFv-4-1BBL) likewise targeted to the tumor cells to modulate the T-cell response. In our model system, the target cells coexpress the fibroblast activation protein (FAP) and endoglin as antigens. ScDbFAPCD3 and B7.2-Db are targeted to FAP although by different antibody moieties, whereas scFv-4-1BBL is directed against endoglin. ScDbFAPCD3-induced T-cell stimulation could be enhanced by the addition of either B7.2-Db or scFv-4-1BBL and even further by the combination of both as shown in terms of cytokine release (interleukin-2/interferon γ), proliferation and activation marker expression (CD25). By combined costimulation, overall T-cell population strongly increased in activation-experienced memory phenotype accompanied by a decrease in naive phenotype. ScFv-4-1BBL-mediated costimulation of naive CD8+ T cells promoted the expansion and development of cytotoxic T cells with strong effector potential. Thus, combining a bispecific antibody with antibody-ligand fusion protein-mediated CD28 and 4-1BB costimulation in a targeted approach shows great potential to generate and shape an immune response at the tumor site. Therefore, the adaptation of this approach to other immune modulatory ligands and tumor-relevant targets seems to be promising.

Authors+Show Affiliations

Institut für Zellbiologie und Immunologie, Universität Stuttgart, Stuttgart, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22576347

Citation

Hornig, Nora, et al. "Combination of a Bispecific Antibody and Costimulatory Antibody-ligand Fusion Proteins for Targeted Cancer Immunotherapy." Journal of Immunotherapy (Hagerstown, Md. : 1997), vol. 35, no. 5, 2012, pp. 418-29.
Hornig N, Kermer V, Frey K, et al. Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. J Immunother. 2012;35(5):418-29.
Hornig, N., Kermer, V., Frey, K., Diebolder, P., Kontermann, R. E., & Müller, D. (2012). Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. Journal of Immunotherapy (Hagerstown, Md. : 1997), 35(5), 418-29. https://doi.org/10.1097/CJI.0b013e3182594387
Hornig N, et al. Combination of a Bispecific Antibody and Costimulatory Antibody-ligand Fusion Proteins for Targeted Cancer Immunotherapy. J Immunother. 2012;35(5):418-29. PubMed PMID: 22576347.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy. AU - Hornig,Nora, AU - Kermer,Vanessa, AU - Frey,Katharina, AU - Diebolder,Philipp, AU - Kontermann,Roland E, AU - Müller,Dafne, PY - 2012/5/12/entrez PY - 2012/5/12/pubmed PY - 2013/5/17/medline SP - 418 EP - 29 JF - Journal of immunotherapy (Hagerstown, Md. : 1997) JO - J. Immunother. VL - 35 IS - 5 N2 - Initiation of a tumor-directed immune response and appropriate modulation of its progress are key issues in cancer immunotherapy. Combinatorial strategies addressing both aspects might therefore be especially suitable. Here, we report a targeted approach combining a bispecific antibody with 2 costimulatory antibody-ligand fusion proteins. According to the concept, the bispecific antibody (scDbFAP×CD3) retargets T cells in a MHC-independent manner to tumor cells, providing an artificial first signal that allows the costimulatory antibody-ligand fusion proteins (B7.2-Db and scFv-4-1BBL) likewise targeted to the tumor cells to modulate the T-cell response. In our model system, the target cells coexpress the fibroblast activation protein (FAP) and endoglin as antigens. ScDbFAPCD3 and B7.2-Db are targeted to FAP although by different antibody moieties, whereas scFv-4-1BBL is directed against endoglin. ScDbFAPCD3-induced T-cell stimulation could be enhanced by the addition of either B7.2-Db or scFv-4-1BBL and even further by the combination of both as shown in terms of cytokine release (interleukin-2/interferon γ), proliferation and activation marker expression (CD25). By combined costimulation, overall T-cell population strongly increased in activation-experienced memory phenotype accompanied by a decrease in naive phenotype. ScFv-4-1BBL-mediated costimulation of naive CD8+ T cells promoted the expansion and development of cytotoxic T cells with strong effector potential. Thus, combining a bispecific antibody with antibody-ligand fusion protein-mediated CD28 and 4-1BB costimulation in a targeted approach shows great potential to generate and shape an immune response at the tumor site. Therefore, the adaptation of this approach to other immune modulatory ligands and tumor-relevant targets seems to be promising. SN - 1537-4513 UR - https://www.unboundmedicine.com/medline/citation/22576347/Combination_of_a_bispecific_antibody_and_costimulatory_antibody_ligand_fusion_proteins_for_targeted_cancer_immunotherapy_ L2 - http://dx.doi.org/10.1097/CJI.0b013e3182594387 DB - PRIME DP - Unbound Medicine ER -