Preclinical development and clinical safety assessment of a synthetic peptide conjugate enabling endogenous antibody binding to promote innate receptor engagement

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 in vivo cross-linking of pre-existing tetanus toxin-directed antibodies, facilitating an...

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Main Authors: Erika A.K. Fletcher, Robert A. Cordfunke, Aikaterini Nasi, Gunilla Törnqvist, Rob R.P.M. Valentijn, Anna Bergqvist, Marita Westhrin, Wenche Rasch, Frida Lindqvist, Inken Dillmann, Martin Lord, Neanke Bouwman, Jacques J. Neefjes, Kees L.M.C. Franken, Stephanie McArdle, Murrium Ahmad, Silvia Johansson, Ferry Ossendorp, Michael Haggman, Maria Lampinen, Gustav Ullenhag, Sam Ladjevardi, Justyna Leja-Jarblad, Wolfgang Lilleby, Jan Wouter Drijfhout, Sara M. Mangsbo
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:Molecular Therapy: Oncology
Subjects:
MT: Regular Issue
prostate cancer
peptide-conjugate vaccine
tetanus toxoid
immunotherapy
dendritic cells
Online Access:http://www.sciencedirect.com/science/article/pii/S2950329925000232
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Summary: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 in vivo 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.
ISSN:2950-3299

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