Tumor growth inhibition by interferon-alpha using PEGylated protein or adenovirus gene transfer with constitutive or regulated expression

Abstract

Inducible synthesis and secretion of therapeutic proteins following gene transfer could be a viable strategy to deliver biopharmaceuticals that currently require parenteral administration. Evaluating the protein pharmacokinetics and biological responses generated by different delivery modalities will provide a better understanding of the advantages and disadvantages of each strategy. The interferon-alpha (IFN-alpha) family of proteins, used clinically for infectious and malignant diseases, has a short half-life, and IFN-alpha therapy requires frequent administration of the drug by injection. Subcutaneous xenograft tumors were inhibited by weekly administration of polyethylene glycol modified (PEGylated) IFN-alpha protein or by a single administration of an adenovirus constitutively expressing IFN-alpha (IACB). Both treatment modalities inhibited tumor growth in a dose-dependent manner, suggesting that increasing exposure to IFN-alpha could result in effective tumor control. A single adenovirus that encodes the components necessary for tetracycline induction (IADR) expressed IFN-alpha in a ligand-dependent manner. Adding doxycycline to the drinking water of mice treated intravenously with the inducible adenovirus IADR inhibited tumor growth by 85% compared with mice that were not given doxycycline. The correlation between serum IFN-alpha concentration and the degree of tumor growth inhibition did not depend on the delivery technology used. It is likely that it will be feasible to control expression of IFN-alpha by oral administration of small molecule drugs after gene delivery to induce therapeutic concentrations of proteins.