Humoral Anti-Vector Immunity and the Complement System

Fisher et al. (2001) first demonstrated that a modification of Ad vectors with pHPMA polymers allowed to evade from neutralizing antibodies. In addition to evasion from high titer nAb, the authors demonstrated efficient retargeting of the coated particles to the FGF receptor.

Several groups showed that PEGylated Ad vectors induced lower levels of adaptive immune responses to the vector. Even more, readministration of the vector in the presence of anti-vector humoral immunity was feasible to lung and liver (Croyle et al. 2001, 2002). Wortmann et al. (2008) demonstrated that PEGylated, fully detargeted Ad vectors (PEGylated with a dense shield of 20 kDa PEG molecules) were still able to induce cellular and humoral immune responses against their transgene product in the presence of neutralizing anti-Ad antibodies in a setting of genetic vaccination (Wortmann et al. 2008).

These results indicate that a polymer shield helps to protect Ad vectors from the neutralizing antibodies in vitro and in vivo. However, it has to be noted that all of the studies used different assays to determine the titers of anti-Ad antibodies. Furthermore, human anti-Ad antibodies generated upon a productive infection with the virus may very well differ from mouse anti-Ad antibodies which are generated after exposition to a replication defective Ad-derived vector. Unfortunately, this makes it very difficult to draw conclusions on the ability of polymer-modified vectors to evade from neutralizing antibodies. Side-by-side comparisons, ideally using human material (e.g., in the form of intravenous immunoglobulins, IVIG) and standardized assays are required here.

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