The presence of humoral immunity (circulating antibodies) to adenovirus capsid proteins is a barrier to the use of adenovirus vectors for gene therapy. The prototype adenovirus vectors that have been developed for gene therapy are based on subgroup C adenoviruses such as that of serotype 5. The prevalence of neutralizing antibodies against subgroup C adenoviruses is generally high in human populations as a result of frequent exposure to these pathogens. This fact is likely to greatly limit the effectiveness of gene therapy vectors based on serotypes such as Ad5.
Analysis of the nature of the protective antibodies against adenoviruses has indicated that the most important target is the major capsid protein, hexon [Wolfhart (1988) J. Virol 62, 2321; Gall et al. (1996) J. Virol. 70, 2116]. Several efforts have been made to engineer the hexon so as to evade the anti-hexon antibodies by making chimeric adenoviruses harboring hexons from other serotypes [Roy et al. (1998) J. Virol. 72, 6875; U.S. Pat. No. 5,922,315; Gall et al. (1998) J. Virol. 72, 10260; Youil et al. (2002) Hum. Gene Ther. 13, 311; Wu et al. (2002) J. Virol. 76, 12775]. However, this has been largely unsuccessful when exchanges among distant serotypes are attempted.
Alternatively, investigators have proposed using adenovirus vectors that rarely cause human infections or using adenoviruses from non-human sources. However, the lack of a practical manner in which to produce large numbers of such vectors has proved to be a hindrance to developing such vectors.