title: A plant-expressed conjugate vaccine breaks CD4(+) tolerance and induces potent immunity against metastatic Her2(+) breast cancer.
abstract: Passive antibody therapy for cancer is an effective but costly treatment modality. Induction of therapeutically potent anticancer antibodies by active vaccination is an attractive alternative but has proven challenging in cancer due to tolerogenic pressure in patients. Here, we used the clinically relevant cancer target Her2, known to be susceptible to targeting by antibody therapy, to demonstrate how potent antibody can be induced by vaccination. A novel 44kD Her2 protein fragment was generated and found to be highly effective at inducing anti-Her2 antibody including trastuzumab-like reactivities. In the tolerant and spontaneous BALB-neuT mouse model of metastatic breast cancer this Her2-targeting vaccine was only effective if the fragment was conjugated to a foreign immunogenic carrier; Fragment C of tetanus toxin. Only the conjugate vaccine induced high affinity anti-Her2 antibody of multiple isotypes and suppressed tumor development. The magnitude of CD4(+) T-cell help and breadth of cytokines secreted by the CD4(+) T helper (Th) cells induced to the foreign antigen was critical. We used a highly efficient plant-based bio-manufacturing process for protein antigens, magnICON, for vaccine expression, to underpin feasibility of future clinical testing. Hence, our novel Her2-targeting conjugate vaccine combines preclinical efficacy with clinical deliverability, thus setting the scene for therapeutic testing.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton , Southampton, UK.
authors.forename: Warayut
authors.initials: W
authors.lastname: Chotprakaikiat
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton , Southampton, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Allen
authors.affiliation: Icon Genetics , Halle, Germany.
authors.forename: Duc
authors.initials: D
authors.lastname: Bui-Minh
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton , Southampton, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Harden
authors.affiliation: Oral Biology Department, Naresuan University , Phitsanulok, Thailand.
authors.forename: Jantipa
authors.initials: J
authors.lastname: Jobsri
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin , Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
authors.affiliation: Icon Genetics , Halle, Germany.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Gleba
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton , Southampton, UK.
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton , Southampton, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Ottensmeier
authors.affiliation: Icon Genetics , Halle, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Klimyuk
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton , Southampton, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Savelyeva
keywords: Antibody; CD4+ T helper cells; breast cancer; plant-based bio-manufacturing; vaccines