FUT-175, a Synthetic Inhibitor of the Complement Pathway, Protects Against the Inactivation of Infectious Retroviruses by Human Serum

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Abstract
Serum-induced inactivation of retroviruses is the most critical limitation for in vivo gene transfer therapy. To solve this problem, we searched for reagents that protect retroviruses from inactivation. The effects of the protease inhibitors FOY-007 and FOY-305 and of an inhibitor of the complement pathway FUT-175, all of which have been used clinically, were investigated. All of these agents protected against the inactivation of retroviruses by human serum, with 1 μM FUT-175 providing the most effective protection. Thus, the co-administration of FUT-175 with retroviruses may make retrovirus-mediated in vivo gene transfer feasible for the treatment of patients. FUT-175 dose-dependently inhibited the classical pathway of complement in a hemolysis protection assay of sensitized sheep erythrocytes with guinea pig serum or by cell-lysis assay of mouse fibroblasts with human serum. However, increasing the FUT-175 concentration by 10-fold (10 μM) did not produce further protection against retroviral inactivation in most human sera. There was also no correlation between the serum-induced inactivation of retroviruses and either the amount of anti-α-galactosyl (anti-α-Gal) antibody or the complement activity in human serum. These results suggest that retroviruses are not inactivated by utilizing the same pathway leading to cell lysis by the classical complement system. Among the agents tested at concentrations of clinical dose, FUT-175 showed the most effective protection against human serum-induced inactivation of retroviruses. Co-administration of FUT-175 may make retrovirus-mediated in vivo gene transfer feasible for the treatment of patients. Although FUT-175 dose-dependently inhibited the complement pathway, a 10-fold higher concentration did not produce further protection against retroviral inactivation in most human sera. There was no correlation between the serum-induced inactivation of retroviruses and either the amount of anti-α-galactosyl (anti-α-Gal) antibody or the complement activity in human serum, suggesting that retroviruses are not inactivated solely by the classical complement system.