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

Abstract

Key Points• GL-2045, a recombinant human IgG1-based Fc multimer, binds C1q and inhibits complementdependent cytotoxicity.• GL-2045 induces selflimited complement activation that is governed by both factors H and I and results in the generation of iC3b.

rIgG1 Fc Hexamer Inhibits Antibody-Mediated Autoimmune Disease via Effects on Complement and FcγRs

“…Studies with Hexa-Fc (21) bound to a solid phase indicated full complement activation; therefore, the inhibitory activity of Fc-mTP-L309C in solution was unexpected. A similar complement inhibitory activity was most recently reported by Zhou et al (40), demonstrating that GL-2045 bound C1q, leading to generation of C4a, but limited levels of C3a and no C5a. In a second publication, the same group reported novel versions of the Stradomer with reduced binding to FcgRs but intact capability of inhibiting full complement activation (41).…”

A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity

“…Based on these findings, we developed a human analogue of M-045, called GL-2045, in preparation for anticipated first in human (FIH) studies and recently reported that GL-2045 inhibits complement activation in vitro (29). Here, we show that GL-2045 binds with high avidity to the low-affinity human FcγRs and interferes with the interactions of immune complexes (IC) with FcγRs.…”

The evolving role of immuno‐oncology for the treatment of head and neck cancer

“…Similarly, using a series of FcγR ‐/‐ mice, we showed that the anti‐tumor activity of mAbs targeting the costimulatory molecule, CD137, are dependent on defined Fc:FcR interactions . Such observations become even more important when taken in the context of studies from others and us showing that engagement of FcRs through multimeric Fc fusion proteins—somewhat analogous to mAb opsonization of a tumor target—have the potential to induce tolerance . Collectively, these initial insights set the stage for future investigations to determine how the interplay between Fc:FcR interactions and ligation of the target molecule influence functions.…”

“…84 Such observations become even more important when taken in the context of studies from others and us showing that engagement of FcRs through multimeric Fc fusion proteins-somewhat analogous to mAb opsonization of a tumor target-have the potential to induce tolerance. [85][86][87][88][89][90] Collectively, these initial insights set the stage for future investigations to determine how the interplay between Fc:FcR interactions and ligation of the target molecule influence functions. Furthermore, they serve as a cautionary note for researchers performing rodent studies using immunocompetent mAbs to manipulate co-signaling pathways, as these studies may have limited relevance to clinically available mAbs.…”