Characterization of a novel single-chain bispecific antibody for retargeting of T cells to tumor cells via the TCR co-receptor CD8.

Abstract

There is currently growing interest in retargeting of effector T cells to tumor cells via bispecific antibodies (bsAbs). Usually, bsAbs are directed on the one hand to the CD3 complex of T cells and on the other hand to a molecule expressed on the surface of the target cell. A bsAb-mediated cross-linkage via CD3 leads to an activation of CD8+ T cells and consequently to killing of the target cells. In parallel, CD4+ T cells including TH1, TH2, TH17 cells and even regulatory T cells (Tregs) will be activated as well. Cytokines produced by CD4+ T cells can contribute to severe side effects e. g. life-threatening cytokine storms and, thinking of the immunosupressive function of Tregs, can even be counterproductive. Therefore, we asked whether or not it is feasible to limit retargeting to CD8+ T cells e. g. via targeting of the co-receptor CD8 instead of CD3. In order to test for proof of concept, a novel bsAb with specificity for CD8 and a tumor-associated surface antigen was constructed. Interestingly, we found that pre-activated (but not freshly isolated) CD8+ T cells can be retargeted via CD8-engaging bsAbs leading to an efficient lysis of target cells.

• Authors: Irene Michalk, Anja Feldmann, Stefanie Koristka, Claudia Arndt, Marc Cartellieri, Armin Ehninger, Gerhard Ehninger, Michael P Bachmann
• Journal: PloS one (PLoS One) Vol. 9 Issue 4 Pg. e95517 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24751697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• CD3 Complex
• CD8 Antigens
• Cross-Linking Reagents
• Cytokines
• Receptors, Antigen, T-Cell
• Single-Chain Antibodies

Topics

• Animals
• Antibodies, Bispecific (immunology, isolation & purification)
• CD3 Complex (metabolism)
• CD8 Antigens (metabolism)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line
• Cell Separation
• Cross-Linking Reagents (metabolism)
• Cytokines (metabolism)
• Cytotoxicity, Immunologic (immunology)
• Humans
• Lymphocyte Activation (immunology)
• Mice
• Neoplasms (immunology, pathology)
• Protein Binding
• Receptors, Antigen, T-Cell (metabolism)
• Single-Chain Antibodies (immunology)