Highly Specific Auto-Antibodies against Claudin-18 Isoform 2 Induced by a Chimeric HBcAg Virus-Like Particle Vaccine Kill Tumor Cells and Inhibit the Growth of Lung Metastases

Abstract

Strategies for antibody-mediated cancer immunotherapy, such as active immunization with virus-like particle (VLP)-based vaccines, are gaining increasing attention. We developed chimeric hepatitis B virus core antigen (HBcAg)-VLPs that display a surface epitope of the highly selective tumor-associated cell lineage marker claudin-18 isoform 2 (CLDN18.2) flanked by a mobility-increasing linker. Auto-antibodies elicited by immunization with these chimeric HBcAg-VLPs in 2 relevant species (mouse and rabbit) bind with high precision to native CLDN18.2 at physiologic densities on the surface of living cells but not to the corresponding epitope of the CLDN18.1 splice variant that differs by merely one amino acid. The induced auto-antibodies are capable of efficiently killing CLDN18.2 expressing cells in vitro by complement-dependent and antibody-dependent cellmediated cytotoxicity. Moreover, they provide partial protective immunity against the challenge of mice with syngeneic tumor cells stably expressing CLDN18.2. Our study provides a first proof-of-concept that immunization combining VLPs as antigen carriers with specific conformational epitopes of a highly selective differentiation antigen may elicit auto-antibodies with high cytocidal and tumoricidal potential. Cancer Res; 71(2); 516-27. Ó2011 AACR.

SplitCore Technology Allows Efficient Production of Virus-Like Particles Presenting a Receptor-Contacting Epitope of Human IgE

“…It is generally assumed that the flexible linkers facilitate correct folding of the fusion proteins. In case of complex inserts, sufficiently long flexible linkers were needed to preserve the ability of the carrier to form VLPs [35]. The second variant (HBcAg-IgE/Cys) has contiguous sequence in which the insert is additionally flanked with adjacent Cys residues.…”

Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation

“…When attached to a hepatitis virus core antigen, mice with claudin 18.2-expressing tumours developed immunity resulting in destruction of 18.2-expressing tumour cells 46. Such strategies might present new treatment opportunities for patients with this dismal and aggressive disease.…”

Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals

“…This antibody has been shown to execute potent antitumoral activity in vitro and in animal models (manuscript in preparation) and is currently in clinical development. The other uses virus-like particles decorated with the extra-cellular loop of CLDN18.2 as vaccine to induce immune responses recognizing CLDN18.2 expressing cancer cells (Klamp et al, 2011) and is currently evaluated for the pre-clinical proof of efficacy.…”