Preclinical development and clinical safety assessment of a synthetic peptide conjugate enabling endogenous antibody binding to promote innate receptor engagement
Peptide-based vaccines can be used to deliver tumor-specific antigens to dendritic cells (DCs), leading to tumor-directed T cell responses. We previously developed a peptide-peptide conjugate technology enabling <i>in vivo</i> cross-linking of pre-existing tetanus toxin-directed antibodies, facilitating antigen delivery to, and activation of DCs. To achieve this, multiple identical tetanus toxin-derived B cell epitopes (MTTEs) are conjugated to synthetically produce target antigens of choice. Herein, we describe the generation of a prostate cancer vaccine candidate (TENDU) based on this technology. It includes long synthetic peptides harboring epitopes (CD4 and CD8) from prostate-specific antigen (PAP) and prostate-specific membrane antigen (PSMA). The preclinical efficacy of TENDU was assessed in experimental systems, and safety was evaluated in a rabbit toxicity study and a human whole blood loop assay. We also report the first clinical safety assessment of TENDU. Experimental studies showed that prostate cancer patients mounted anti-MTTE antibodies in response to tetanus vaccination with recall T cell responses detected in two patients. Transgenic humanized HLA-DR4 mice displayed T cell responses and increased anti-MTTE IgG levels after vaccination with a peptide construct including an HLA-DR4 epitope. The vaccine candidate was found safe, and a positive correlation between T cell responses and anti-MTTE antibodies was noted in the first-in-human study.
Authors
- Maria Lampinen (ORCID: https://orcid.org/0000-0002-0396-2147)
- Kees L. M. C. Franken (ORCID: https://orcid.org/0000-0002-4747-6060)
- Sara M. Mangsbo (ORCID: https://orcid.org/0000-0002-1355-2678)
- Jan W. Drijfhout (ORCID: https://orcid.org/0000-0003-4808-5296)
- Wenche Rasch
- Marita Westhrin (ORCID: https://orcid.org/0000-0001-6932-2102)
- Gustav Ullenhag (ORCID: https://orcid.org/0000-0003-4949-3267)
- Gunilla Törnqvist
- Anna Bergqvist
- Michael Häggman (ORCID: https://orcid.org/0000-0001-7234-2534)
- Silvia Johansson (ORCID: https://orcid.org/0000-0002-4446-796X)
- Erika Fletcher
- Ferry Ossendorp (ORCID: https://orcid.org/0000-0001-9730-7954)
- Frida Lindqvist
- Wolfgang Lilleby (ORCID: https://orcid.org/0000-0002-8390-9353)
- Murrium Ahmad (ORCID: https://orcid.org/0000-0002-6074-2001)
- Jacques Neefjes (ORCID: https://orcid.org/0000-0001-6763-2211)
- Martin Lord (ORCID: https://orcid.org/0000-0002-3238-3187)
- Inken Dillmann (ORCID: https://orcid.org/0000-0003-3773-3446)
- Stéphanie McArdle (ORCID: https://orcid.org/0000-0001-6929-9782)
- Aikaterini Nasi (ORCID: https://orcid.org/0000-0002-9935-1008)
- Robert A. Cordfunke (ORCID: https://orcid.org/0000-0002-7200-7434)
- Sam Ladjevardi
- Rob Valentijn
- Neanke Bouwman
- Justyna Leja-Jarblad
Institutions
- Uppsala University (SE)
- Oslo University Hospital (NO)
- Uppsala University Hospital (SE)
- Leiden University Medical Center (NL)
- Science for Life Laboratory (SE)
- Ultimovacs (Norway) (NO)
- Nottingham Trent University (GB)
Publication Details
- Journal
- Molecular Therapy Oncology
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1016/j.omton.2025.200954
- Citations
- 1
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 1.36
Funders
- Cancerfonden
- Svenska Sällskapet för Medicinsk Forskning
- Stichting voor de Technische Wetenschappen