Coagulation factor X shields adenovirus vectors from natural antibodies and complement: impact on liver transduction

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	FDA/CBER	VIROL/MICRO-24

* FARE Award Winner

Authors

• Z Xu
• J Tian
• Q Qiu
• AP Byrnes

Abstract

Adenovirus vector type 5 (Ad) is the most widely-used vector in clinical gene therapy trials, due to its advantages of high capacity for therapeutic genes, high transduction efficiency and ease of manufacture. However wider clinical success is hampered by Ad vector’s one major shortcoming: most systemically-administered Ad virions are sequestered into the liver, limiting their ability to reach other therapeutic targets such as metastatic tumors. The mechanisms underlying this have not been clear. Recently multiple groups have shown that the major adenovirus capsid protein (hexon) has a high-affinity binding site for coagulation Factor X (FX) and that FX plays a central role in the ability of Ad vectors to transduce the liver. Ad becomes unable to transduce mouse liver when FX is blocked, or when hexon is mutated at the FX-binding site. However, it is unclear exactly how FX facilitates liver transduction. We have found that FX acts as a defense for Ad virions against plasma opsonins, shielding the virions from attack by natural antibodies and complement. In contrast to wild-type mice, where FX is required for liver transduction by Ad vectors, FX is completely unnecessary for liver transduction in mice that lack natural antibodies or complement.

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