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

Abstract

Activation of Fc receptors and complement by immune complexes is a common important pathogenic trigger in many autoimmune diseases and so blockade of these innate immune pathways may be an attractive target for treatment of immune complex-mediated pathomechanisms. High-dose IVIG is used to treat autoimmune and inflammatory diseases, and several studies demonstrate that the therapeutic effects of IVIG can be recapitulated with the Fc portion. Further, recent data indicate that recombinant multimerized Fc molecules exhibit potent anti-inflammatory properties. In this study, we investigated the biochemical and biological properties of an rFc hexamer (termed Fc-μTP-L309C) generated by fusion of the IgM μ-tailpiece to the C terminus of human IgG1 Fc. Fc-μTP-L309C bound FcγRs with high avidity and inhibited FcγR-mediated effector functions (Ab-dependent cell-mediated cytotoxicity, phagocytosis, respiratory burst) in vitro. In addition, Fc-μTP-L309C prevented full activation of the classical complement pathway by blocking C2 cleavage, avoiding generation of inflammatory downstream products (C5a or sC5b-9). In vivo, Fc-μTP-L309C suppressed inflammatory arthritis in mice when given therapeutically at approximately a 10-fold lower dose than IVIG, which was associated with reduced inflammatory cytokine production and complement activation. Likewise, administration of Fc-μTP-L309C restored platelet counts in a mouse model of immune thrombocytopenia. Our data demonstrate a potent anti-inflammatory effect of Fc-μTP-L309C in vitro and in vivo, likely mediated by blockade of FcγRs and its unique inhibition of complement activation.

Multimerized IgG1 Fc molecule as an anti-inflammatory agent

“…Altogether, the results reported by Spirig et al 1 could reinforce and propel the development of Fc-based therapeutics for autoimmune and inflammatory diseases. Although the Fc hexamers showed therapeutic effects in acute models of autoimmune diseases, the short half-life of this multimer and its limited mechanism of action (compared with IVIG) are major drawbacks.…”

“…In a model of chronic arthritis, although Fc-μTP-L309C improved the clinical signs of CIA its effect waned over time and additional doses were required; by contrast, such additional therapy was not required for IVIG-treated mice 1 . Two main factors could explain these observations.…”

“…Fc-μTP-L309C, but not the Fc monomer, avidly bound to low-affinity FcγRs such as CD16a, CD32a and CD32b/c as well as to the high-affinity receptor CD64 (REF. 1 ). In addition, Fc-μTP-L309C had greater avidity than IVIG for neonatal FcR (FcRn), a receptor implicated in prolonging the half-life of antibodies (Fig.…”

“…Having established that Fc-μTP-L309C could inhibit FcγR-mediated functions in vitro, Spirig et al 1 next evaluated the efficacy of the hexamer in vivo in an antibody-mediated model of acute arthritis. Treatment with a single dose of Fc-μTP-L309C (200 mg/kg; a dose 10-fold lower than that of IVIG) markedly decreased the formation of complement proteins C3 and C5a in the knee joints and also ameliorated bone degradation, restricted inflammatory cell infiltration and inhibited an array of pro-inflammatory cytokines and chemokines.…”

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.…”