Tags

Type your tag names separated by a space and hit enter

A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy.
J Immunother. 2008 Oct; 31(8):714-22.JI

Abstract

Costimulation is an essential step in T-cell activation and hence, represents an important aspect in cancer immunotherapy. 4-1BB, a member of the tumor necrosis factor receptor family, has gained particular interest as a costimulatory molecule. Here, we investigated the potential of a targeted activation of 4-1BB-mediated costimulation at the tumor site by generating a recombinant antibody-cytokine fusion protein composed of a single-chain antibody fragment (scFv36) specific for the tumor stromal antigen fibroblast activation protein (FAP) and the extracellular domain of the 4-1BB ligand (4-1BBL). The scFv36-4-1BBL fusion protein is a homotrimeric molecule that binds specifically to FAP and the receptor 4-1BB. T-cell costimulation was demonstrated by interferon-gamma release of peripheral blood mononuclear cells cocultured with FAP-expressing HT1080 cells upon T-cell receptor triggering by monoclonal anti-CD3 antibody. Costimulatory activity of the scFv36-4-1BBL fusion protein was concentration dependent, ligand-specific, and substantially constrained to FAP-expressing target cell binding. Furthermore, scFv36-4-1BBL enhanced T-cell activation when the bispecific antibody scDb33CD3 (specific for FAP and CD3) was used as primary stimulus. Thus, target cell-dependent costimulation with scFv36-4-1BBL constitutes a new option to enhance T-cell activation by bispecific antibodies or antigen-dependent T-cell receptor triggering and should be useful to improve T cell-mediated antitumor responses.

Authors+Show Affiliations

Institut für Zellbiologie und Immunologie, Universität Stuttgart, Stuttgart, Germany. dafne.mueller@izi.uni-stuttgart.deNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

18779748

Citation

Müller, Dafne, et al. "A Novel antibody-4-1BBL Fusion Protein for Targeted Costimulation in Cancer Immunotherapy." Journal of Immunotherapy (Hagerstown, Md. : 1997), vol. 31, no. 8, 2008, pp. 714-22.
Müller D, Frey K, Kontermann RE. A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. J Immunother. 2008;31(8):714-22.
Müller, D., Frey, K., & Kontermann, R. E. (2008). A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. Journal of Immunotherapy (Hagerstown, Md. : 1997), 31(8), 714-22. https://doi.org/10.1097/CJI.0b013e31818353e9
Müller D, Frey K, Kontermann RE. A Novel antibody-4-1BBL Fusion Protein for Targeted Costimulation in Cancer Immunotherapy. J Immunother. 2008;31(8):714-22. PubMed PMID: 18779748.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy. AU - Müller,Dafne, AU - Frey,Katharina, AU - Kontermann,Roland E, PY - 2008/9/10/pubmed PY - 2009/2/13/medline PY - 2008/9/10/entrez SP - 714 EP - 22 JF - Journal of immunotherapy (Hagerstown, Md. : 1997) JO - J. Immunother. VL - 31 IS - 8 N2 - Costimulation is an essential step in T-cell activation and hence, represents an important aspect in cancer immunotherapy. 4-1BB, a member of the tumor necrosis factor receptor family, has gained particular interest as a costimulatory molecule. Here, we investigated the potential of a targeted activation of 4-1BB-mediated costimulation at the tumor site by generating a recombinant antibody-cytokine fusion protein composed of a single-chain antibody fragment (scFv36) specific for the tumor stromal antigen fibroblast activation protein (FAP) and the extracellular domain of the 4-1BB ligand (4-1BBL). The scFv36-4-1BBL fusion protein is a homotrimeric molecule that binds specifically to FAP and the receptor 4-1BB. T-cell costimulation was demonstrated by interferon-gamma release of peripheral blood mononuclear cells cocultured with FAP-expressing HT1080 cells upon T-cell receptor triggering by monoclonal anti-CD3 antibody. Costimulatory activity of the scFv36-4-1BBL fusion protein was concentration dependent, ligand-specific, and substantially constrained to FAP-expressing target cell binding. Furthermore, scFv36-4-1BBL enhanced T-cell activation when the bispecific antibody scDb33CD3 (specific for FAP and CD3) was used as primary stimulus. Thus, target cell-dependent costimulation with scFv36-4-1BBL constitutes a new option to enhance T-cell activation by bispecific antibodies or antigen-dependent T-cell receptor triggering and should be useful to improve T cell-mediated antitumor responses. SN - 1537-4513 UR - https://www.unboundmedicine.com/medline/citation/18779748/A_novel_antibody_4_1BBL_fusion_protein_for_targeted_costimulation_in_cancer_immunotherapy_ L2 - http://dx.doi.org/10.1097/CJI.0b013e31818353e9 DB - PRIME DP - Unbound Medicine ER -