DNA vaccination with T-cell epitopes encoded within Ab molecules induces high-avidity anti-tumor CD8 T cells (2009)

Victoria A. Pudney, Rachael L. Metheringham, Barbara Gunn, Ian Spendlove, Judith M. Ramage and Lindy G. Durrant

ABSTRACT: Stimulation of high-avidity CTL responses is essential for effective anti-tumor and antiviral vaccines. In this study we have demonstrated that a DNA vaccine incorporating CTL epitopes within an Ab molecule results in high-avidity T-cell responses to both foreign and self epitopes. The avidity and frequency was superior to peptide, peptide-pulsed DC vaccines or a DNA vaccine incorporating the epitope within the native Ag. The DNA Ab vaccine was superior to an identical proteinvaccine that can only cross-present, indicating a role for direct presentation by the DNA vaccine. However, the avidity of CTL responses was significantly reduced in Fc receptor γ knockout mice or if the Fc region was removed suggesting that cross presentation of Ag via Fc receptor was also important in the induction of high-avidity CTL. These results suggest that generation of high-avidity CTL responses by the DNA vaccine is related to its ability to both directly present and crosspresent the epitope. High-avidity responses were capable of efficient anti-tumor activity in vitro and in vivo. This study demonstrates a vaccine strategy to generate high-avidity CTL responses that can be used in anti-tumor and anti-viral vaccine settings

Antibodies designed as effective cancer vaccines (2009)

R.L. Metheringham, V.A. Pudney, B. Gunn, M. Towey, I. Spendlove and L.G. Durrant

ABSTRACT: Antigen/antibody complexes can efficiently target antigen presenting cells to allow stimulation of the cellular immune response. Due to the difficulty of manufacture and their inherent instability complexes have proved inefficient cancer vaccines. However, anti-idiotypic antibodies mimicking antigens have been shown to stimulate both antibody and T cell responses. The latter are due to T cell mimotopes expressed within the complementarity-determining regions (CDRs) of antibodies that are efficiently presented to dendritic cells in vivo. Based on this observation we have designed a DNA vaccine platform called ImmunoBody^TM, where cytotoxic T lymphocyte (CTL) and helper T cell epitopes replace CDR regions within the framework of a human IgG1 antibody. The ImmunoBody^TM expression system has a number of design features which allow for rapid production of a wide range of vaccines. The CDR regions of the heavy and light chain have been engineered to contain unique restriction endonuclease sites, which can be easily opened, and oligonucleotides encoding the T cell epitopes inserted. The variable and constant regions of the ImmunoBody^TM are also flanked by restriction sites, which permit easy exchange of other IgG subtypes. Here we show a range of T cell epitopes can be inserted into the ImmunoBody^TM vector and upon immunization these T cell epitopes are efficiently processed and presented to stimulate high frequency helper and CTL responses capable of anti-tumor activity