Current strategies and future directions for eluding adenoviral vector immunity

Abstract

Adenoviral (Ad) vectors can efficiently transduce a broad range of cell types and have been used extensively in preclinical and clinical studies for gene delivery applications. The presence of preexisting Ad immunity in the majority of human population and a rapid development of immune response against the Ad vector backbone following the first inoculation with the vector have impeded clinical use of these vectors. In addition, a number of animal inoculation studies have demonstrated that high systemic doses of Ad vectors invariably lead to initiation of acute inflammatory responses. This is mainly due to activation of innate immunity by vector particles. In general, vector and innate immune responses drastically limit the vector transduction efficiency and the duration of transgene expression. In order to have a predictable response with Ad vectors for gene therapy applications, the above limitations must be overcome. Strategies that are being examined to circumvent these drawbacks of Ad vectors include immunosuppression, immunomodulation, serotype switching, use of targeted Ad vectors, microencapsulation of Ad vectors, use of helper-dependent (HD) Ad vectors, and development of nonhuman Ad vectors. Here we review the current understanding of immune responses to Ad vectors, and recent advances in the strategies for immune evasion to improve the vector transduction efficiency and the duration of transgene expression. Development of novel strategies for targeting specific cell types would further boost the utility of Ad vectors by enhancing the safety, efficacy and duration of transgene expression.

Fig. (1)

Preexisting immunity as a barrier to adenoviral (Ad) gene therapy. The presence of preexisting immunity in the majority of human population interferes with initial transduction with HAd vectors. In case of individuals with no preexisting immunity, the first inoculation with an HAd vector may be successful but subsequent development of strong cellular and humoral immunity renders repeat administration of the same vector less effective. Ad, adenoviral vector; HAd, human Ad vector

Fig. (2)

Development of adenoviral (Ad) vector immunity. The first use of an Ad vector leads to a strong innate as well as adaptive immune responses resulting in development of neutralizing antibodies and elimination of transduced cells. In response to high amount of vector administration, a strong innate immune is initiated, which is characterized by production of a variety of proinflammatory cytokines and chemokines leading to an acute toxic response and hepatotoxicity.

Fig. (3)

Some of the strategies for designing targeted adenoviral (Ad) vectors. A) Binding of adenovirus to cells via the knob domain of the fiber to CAR. B) Adenovirus complexed with an anti-knob antibody fails to bind to CAR. C) Conjugation of a specific ligand to the anti-knob antibody would allow virus binding to the targeted receptor on the cell surface. D) Conjugation of anti-receptor antibody to anti-knob antibody would target the Ad vector to the specific receptor on the cell surface.