A tetanus-way of improving synthetic long peptide tumor vaccination

We have previously identified a natural B cell epitope derived from tetanus toxin named Minimal Tetanus Toxin Epitope (MTTE)[1]. Most healthy individuals have IgG1 antibodies to this peptide sequence but no IgM antibodies. We have assessed the possibility to apply this MTTE sequence in drug development with the intention to create immune complexes and use them as vehicles to carry antigen-material into dendritic cells. Thru a conjugation method three MTTE sequences and a longer synthetic peptide stretch harboring T cell epitopes are linked together. As immune complexes are efficient carriers of antigen material and can promote cross-presentation the aim is to use these conjugates for therapeutic purposes in diseases where a strong cellular immune response should be induced. To further evaluate the MTTE peptide conjugates in drug development we have investigated how a diphtheria, tetanus, pertussis (DTP) vaccination induces antibody titers against the linear tetanus sequence. Herein we have studied the MTTE location in the tertiary structure of the protein, how cancer patients respond with antibody titers against MTTE along with a subsequent T cell response and in vivo anti-tumor responses (mice). In addition we have studied safety in terms of cytokine release assessment pre and post a DTP vaccination. We found that the MTTE sequence is part of an alpha-helix that is externally oriented and thereby accessible for peptide binding. We found that not helper epitope is part of the MTTE sequence and that healthy individuals as well as cancer patients can mount IgG titers against the epitope, this also result in more efficient induction of recall responses post a DTP booster than pre boost. Mice seropositive to the MTTE sequence can mount anti-tumor responses, while this is not seen in seronegative animals. In addition, a cytokine release assessment using a modified chandler loop model with intact complement does not display a broad immediate cytokine release pre or post a DTP booster. We conclude that it is efficacious and safe to make use of a peptide conjugate in a drug development project with the aim to use it as a vaccine strategy. [1] Mangsbo et al. In press. Molecular Immunology 2017 Citation Format: Jan Wouter Drijfhout, Erika Fletcher, Justyna Leja-Jarblad, Iliana Kerzeli, Robert Cordfunke, Gunilla Tornqvist, Frida Lindqvist, Greta Hultqvist, Rob Valentijn, Sam Ladjervardi, Michael Haggman, Gustav Ullenhag, Sara Mangsbo. A tetanus-way of improving synthetic long peptide tumor vaccination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5638.