A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy.

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: Dafne Müller, Katharina Frey, Roland E Kontermann
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 31 Issue 8 Pg. 714-22 (Oct 2008) ISSN: 1537-4513 [Electronic] United States
• PMID: 18779748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-1BB Ligand
• Antigens, Neoplasm
• Biomarkers, Tumor
• Immunoglobulin Variable Region
• Membrane Proteins
• Recombinant Fusion Proteins
• Tumor Necrosis Factor Receptor Superfamily, Member 9
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases

Topics

• 4-1BB Ligand (genetics, immunology, therapeutic use)
• Antigens, Neoplasm (immunology)
• Biomarkers, Tumor (immunology)
• Cell Line, Tumor
• Endopeptidases
• Gelatinases
• Humans
• Immunoglobulin Variable Region (genetics, immunology, therapeutic use)
• Immunotherapy
• Lymphocyte Activation
• Membrane Proteins
• Neoplasms (therapy)
• Recombinant Fusion Proteins (genetics, immunology, therapeutic use)
• Serine Endopeptidases (immunology)
• Transfection
• Tumor Necrosis Factor Receptor Superfamily, Member 9 (immunology)