Pathways Responsible for Human Autoantibody and Therapeutic Intravenous IgG Activity in Humanized Mice

Abstract

Immunoglobulin G (IgG) antibodies are major drivers of autoimmune pathology, but they are also used in the form of intravenous IgG (IVIg) therapy to suppress autoantibody activity. To identify the pathways underlying human autoantibody and IVIg activity, we established a humanized mouse model of an autoantibody-dependent autoimmune disease responding to treatment with IVIg preparations. We show that the human IgG subclass strongly impacts autoantibody activity and that the Fc-receptor genotype of the human donor immune system further modulates autoantibody activity. Human mononuclear phagocytes were responsible for autoantibody activity, and IVIg therapy was able to suppress disease pathology in an Fc-fragment-dependent manner. While highly sialylated IgG glycovariants were essential for IVIg activity, it was independent of the Fc-receptor genotype and did not result in a general block of activating or the neonatal Fc-receptor. These findings may help in the development of strategies to block autoantibody and enhance therapeutic IVIg activity in humans.

Therapeutic Activity of Agonistic, Human Anti-CD40 Monoclonal Antibodies Requires Selective FcγR Engagement

“…These conclusions were made possible through the use of a representative in vivo model that faithfully recapitulates the diversity and cell type specificity of the human FcγR system. Such in vivo models have recently been demonstrated to be essential to evaluating the FcγR-mediated activities of human IgGs in other applications (DiLillo and Ravetch, 2015; Schwab et al, 2015; Stylianos et al, 2014). …”

IgG subclass and vaccination stimulus determine changes in antigen specific antibody glycosylation in mice

“…Making use of this enhanced activity second generation therapeutic antibody preparations engineered to lack fucose residues to ensure optimal antibody dependent cellular cytotoxicity have entered the clinic. On the other hand, antibody glycovariants with terminal sialic acid residues may have an active anti-inflammatory activity as demonstrated in some [27][28][29][30][31][32][33][34][35] but not all [36][37][38] preclinical in vivo mouse model systems. Apart from sialylation, mouse IgG1 immune complex glycovariants with high levels of terminal galactose residues were demonstrated to interfere with complement-dependent inflammatory processes, providing another example for how individual IgG glycovariants can modulate IgG-dependent effector functions [39].…”

Immunomodulation of immunothrombocytopenia

“…The general validity of such an approach was demonstrated in humans thirty years ago by showing that a monoclonal antibody blocking the interaction of immune complexes with FcRIIIa and FcRIIIb was able to restore platelet counts in ITP patients [8]. Further confirming the important role of FcRIIIa in this process, experimental ITP could be blocked with FcRIII-specific antibodies in mice transgenic for human FcRIIIa or with a cocktail of FcR-specific antibodies in humanized mice [6,9]. Apart from using blocking antibodies, the induction of small immune complexes by injection of anti-D-specific antibodies in rhesus factor D-positive ITP patients or the use of multimeric IgG Fc-portions may achieve the same effect and compete for immune complex binding to FcRs [10][11][12].…”

“…Indeed, the inhibition of the spleen tyrosin kinase (SYK) was able to ameliorate ITP in mice and a human ITP patient cohort [13]. Apart from inhibiting activating FcR-dependent signaling pathways, a depletion or inactivation of the monocyte and macrophage subsets responsible for platelet removal was another very efficient strategy to block autoantibody-dependent platelet depletion at least in preclinical model systems [5,6].…”

“…Of note, several factors, such as the autoantibody IgG subclass or autoantibody glycosylation may directly impact the severity of the disease. Thus, platelet-specific antibodies of the mouse IgG2c/IgG2b or the human IgG1/IgG3 subclasses, which interact well with activating FcRs, have a much greater capacity to trigger platelet depletion than the same antibody with a mouse IgG3 or a human IgG2/IgG4 constant region [4,6]. Moreover, the affinity of the individual IgG subclass to bind to the inhibitory FcRIIb, which is coexpressed with activating FcRs on mononuclear phagocytes, is another important parameter determining autoantibody activity ( Fig.…”