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A Virus-Like Particle-Based Vaccine Selectively Targeting Soluble TNF- Protects from Arthritis without Inducing Reactivation of Latent Tuberculosis

Gunther Spohn^1,*, Reto Guler^2,, Pål Johansen, Iris Keller^*, Muazzam Jacobs, Markus Beck^*, Franziska Rohner^*, Monika Bauer^*, Klaus Dietmeier^*, Thomas M. Kündig, Gary T. Jennings^*, Frank Brombacher and Martin F. Bachmann^*

^* Cytos Biotechnology AG, Zurich-Schlieren, Switzerland; Institute of Infectious Disease and Molecular Medicine, Department of Immunology, Health Science Faculty, University of Cape Town, Cape Town, South Africa; and Unit for Experimental Immunotherapy, Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland

Neutralization of the proinflammatory cytokine TNF- by mAbs or soluble receptors represents an effective treatment for chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, or Crohn’s disease. In this study, we describe a novel active immunization approach against TNF-, which results in the induction of high titers of therapeutically active autoantibodies. Immunization of mice with virus-like particles of the bacteriophage Q covalently linked to either the entire soluble TNF- protein (Q-C-TNF_1–156) or a 20-aa peptide derived from its N terminus (Q-C-TNF_4–23) yielded specific Abs, which protected from clinical signs of inflammation in a murine model of rheumatoid arthritis. Whereas mice immunized with Q-C-TNF_1–156 showed increased susceptibility to Listeria monocytogenes infection and enhanced reactivation of latent Mycobacterium tuberculosis, mice immunized with Q-C-TNF_4–23 were not immunocompromised with respect to infection with these pathogens. This difference was attributed to recognition of both transmembrane and soluble TNF- by Abs elicited by Q-C-TNF_1–156, and a selective recognition of only soluble TNF- by Abs raised by Q-C-TNF_4–23. Thus, by specifically targeting soluble TNF-, Q-C-TNF_4–23 immunization has the potential to become an effective and safe therapy against inflammatory disorders, which might overcome the risk of opportunistic infections associated with the currently available TNF- antagonists.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Gunther Spohn, Cytos Biotechnology AG, Wagistrasse 25, Zurich-Schlieren, Switzerland. E-mail address: gunther.spohn{at}cytos.com

² R.G. was supported by grants from the Swiss National Foundation and the Swiss Foundation for Fellowships in Biology and Medicine.

³ Abbreviations used in this paper: VLP, virus-like particle; RANKL, receptor activator of NF-B ligand; AG, aminoguanidine; BHK, baby hamster kidney; iNOS, inducible nitric-oxide synthase.