A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b

Abstract

Abstract: GL-2045 is a recombinant human immunoglobulin G1 (IgG1)–based Fc multimer designed to recapitulate the anti-inflammatory activities of intravenous immunoglobulin (IVIG) on the innate and adaptive immune responses. We used functional in vitro studies to determine if GL-2045 could mimic the modulatory activity of IVIG on complement activation. GL-2045, at log-order lower concentrations than heat-aggregated IgG (HAGG) and IVIG, protected antibody-opsonized cells from complement-dependent cytotoxicity. These protective effects were completely mediated by the higher order multimer fractions of GL-2045 and were partially dependent upon sequestration of C1q. Exposure of serum to GL-2045 and, to a lesser extent, IVIG, resulted in high levels of C4a, limited levels of C3a, and no C5a. In contrast, HAGG induced high levels of C4a, C3a, and C5a. The means by which GL-2045 governed complement activation was dependent on its ability to augment the function of factor H, alone and in combination with factor I, to indirectly limit the alternative form of C3 convertase, with resultant increases in the anti-inflammatory molecule, the “inactive” form of C3b, called iC3b. Although IVIG, like GL-2045, potentiated factor H function, it also directly inhibited the alternative form of C3 convertase. Our findings help elucidate how IVIG, GL-2045, and HAGG regulate complement function. Furthermore, the capacity of GL-2045 to sequester C1q and augment factor H activity, in combination with its ability to generate activation-induced immunomodulatory complement split products, such as iC3b, make it a viable drug candidate for the treatment of diverse complement-mediated diseases.