Intrabody strategies for the treatment of human papillomavirus-associated disease

Abstract

Human papillomaviruses (HPVs) are associated with a variety of epithelial lesions, including benign genital warts and cervical intraepithelial neoplasia. Both cause significant morbidity in the general population, with cervical intraepithelial neoplasia progressing to cervical cancer in a subset of women who cannot resolve their infection. At present, there are no antiviral agents for the treatment of genital HPV infections, with many lesions requiring surgical intervention. Although other approaches are available for the treatment of genital warts, HPV infection cannot usually be cured and lesion recurrence is often a problem. A growing understanding of the molecular biology of HPV infection has identified several viral protein functions that may serve as drug targets. Among these are the HPV E1 and E2 proteins, which are necessary for viral genome replication and partitioning, and the E6 and E7 proteins, which are necessary for cell proliferation and apoptotic inhibition. With the exception of E1, these proteins lack enzymatic activity and achieve their effects by interacting with cellular proteins. Protein–protein interactions are in general quite difficult to inhibit using conventional small molecule drugs, but are amenable to inhibition using intracellular antibodies or intrabodies, which bind the viral proteins and sterically inhibit their association with cellular partners. The lack of homology between viral and cellular proteins, and the fact that HPV infections can be treated topically, makes them particularly well suited to the intrabody approach. This review covers the various strategies that are being considered for the treatment of HPV infections and the different intrabody formats that have been used to inhibit HPV function in model systems. The clinical utility of the approach is considered alongside the general difficulties of using protein molecules as intracellular therapeutics.

Keywords::

• antibodies
• cervical cancer
• HPV
• intrabodies
• papillomaviruses

Acknowledgements

Thanks to J Stoye (Division of Virology, National Institute for Medical Research) for supporting the use of antibody engineering approaches at the National Institute for Medical Research, and to G Winter (Protein and Nucleic Acid Chemistry division of the MRC Laboratory of Molecular Biology, Cambridge) for encouraging the various HPV antibody engineering projects and for helping in the development of the Griffin Library from which the E6 intrabodies were isolated. The work was funded by the UK Medical Research Council.

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