Monoclonal antibodies capable of discriminating the human inhibitory Fcγ‐receptor IIB (CD32B) from the activating Fcγ‐receptor IIA (CD32A): biochemical, biological and functional characterization

Binding of immune complexes to cellular FcγRs can promote cell activation and inflammation. In previous studies, a recombinant human (rh) soluble FcγR, rh-FcγRIA (CD64A), was shown to block inflammation in passive transfer models of immune complex-mediated disease. To assess whether rh-FcγRIA could block inflammation in a T cell- and B cell-dependent model of immune complex-mediated disease, the efficacy of rh-FcγRIA in collagen-induced arthritis was evaluated. Mice with established arthritis were treated with a single s.c. injection of rh-FcγRIA (0.2–2.0 mg/dose) given every other day for 11 days. Relative to mice injected with vehicle alone, mice treated with rh-FcγRIA exhibited lower serum concentrations of IL-6, anti-type II collagen Abs, and total IgG2a. These changes were correlated with lower levels of paw swelling and joint damage in the rh-FcγRIA-treated mice and occurred in the presence of a significant murine Ab response to rh-FcγRIA. Comparison of the serum rh-FcγRIA concentration vs time profiles for rh-FcγRIA administered at two dose levels by i.v. and s.c. injection revealed that the bioavailabilty of s.c. administered rh-FcγRIA was 27–37%. Taken together, these data show that rh-FcγRIA is an effective inhibitor of inflammation in a model of established arthritis in mice.

Section: In Vitro Activities Of Rh-fc␥riasupporting

confidence: 80%

Recombinant Soluble Human FcγR1A (CD64A) Reduces Inflammation in Murine Collagen-Induced Arthritis

Ellsworth¹,

Hamacher²,

Harder³

et al. 2009

“…However, the most abundantly expressed Fc␥R isoform on PMN, Fc␥RIIIb (CD16b), is a GPI-linked receptor, which does not trigger ADCC (6). Furthermore, PMN were reported to express the inhibitory Fc␥RIIb isoform (32), although this issue is controversial (33). In our a In order to demonstrate that IgA-mediated killing by PMN was triggered by CD89, Fc␣RI was blocked by antibody My43 (10 g/ml).…”

Section: Discussionmentioning

confidence: 99%

Effector Mechanisms of Recombinant IgA Antibodies against Epidermal Growth Factor Receptor

Dechant

Beyer

Schneider-Merck

et al. 2007

109

IgA is the most abundantly produced Ab isotype in humans, but its potential as immunotherapeutic reagent has hardly been explored. In this study, we describe anti-tumor mechanisms of mouse/human chimeric IgA Abs against the epidermal growth factor receptor (EGF-R). EGF-R Abs of IgG isotype are currently approved for the treatment of colon or head and neck cancers. As expected, the human IgG1, IgA1, and IgA2 variants of the 225 Ab demonstrated similar binding to EGF-R. Furthermore, IgA Abs were as effective as IgG in mediating direct effector mechanisms such as blockade of EGF binding, inhibition of EGF-R phosphorylation, and induction of growth inhibition. None of the three variants induced complement-mediated lysis. Human IgG1 effectively recruited MNC for ADCC, but activated PMN only weakly, whereas both IgA isoforms proved to be effective in triggering neutrophils. Interestingly, the IgA2 isoform was significantly superior to its IgA1 counterpart in recruiting PMN as effector cells. Because neutrophils constitute the most abundant effector cell population in human blood, this enhanced neutrophil recruitment lead to increased killing of EGF-R expressing tumor cells in whole blood assays. This killing was further enhanced when blood from G-CSF-primed donors was compared with healthy donor blood. Together, these data suggest EGF-R Abs of human IgA isotype to bear promise for therapeutic use in cancer.

“…FLIPr bound preferentially to the high-affinity isoform FcgRIIa-H131, whereas binding to the low-affinity R131 isoform was almost negligible. The highly homologous inhibitory receptor FcgRIIb, whose ectodomain differs at 10 positions from FcgRIIa (11 for the FcgRIIa-H131 variant) (27), including two (or three for FcgRIIa-H131) amino acids involved in IgG binding, was bound equally well by FLIPr and FLIPr-like (Fig. 2D).…”

Section: Identification Of a Putative Staphylococcal Fcgriia Inhibitormentioning

confidence: 98%

Staphylococcus aureus Formyl Peptide Receptor–like 1 Inhibitor (FLIPr) and Its Homologue FLIPr-like Are Potent FcγR Antagonists That Inhibit IgG-Mediated Effector Functions

Stemerding

Köhl

Pandey

et al. 2013

To evade opsonophagocytosis, Staphylococcus aureus secretes various immunomodulatory molecules that interfere with effective opsonization by complement and/or IgG. Immune-evasion molecules targeting the phagocyte receptors for these opsonins have not been described. In this study, we demonstrate that S. aureus escapes from FcγR-mediated immunity by secreting a potent FcγR antagonist, FLIPr, or its homolog FLIPr-like. Both proteins were previously reported to function as formyl peptide receptor inhibitors. Binding of FLIPr was mainly restricted to FcγRII receptors, whereas FLIPr-like bound to different FcγR subclasses, and both competitively blocked IgG-ligand binding. They fully inhibited FcγR-mediated effector functions, including opsonophagocytosis and subsequent intracellular killing of S. aureus by neutrophils and Ab-dependent cellular cytotoxicity of tumor cells by both neutrophils and NK cells. In vivo, treatment of mice with FLIPr-like prevented the development of an immune complex–mediated FcγR-dependent Arthus reaction. This study reveals a novel immune-escape function for S. aureus–secreted proteins that may lead to the development of new therapeutic agents in FcγR-mediated diseases.