The Dual Targeting of FcRn and FcγRs via Monomeric Fc Fragments Results in Strong Inhibition of IgG-Dependent Autoimmune Pathologies.

Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that target FcRn are currently in clinical development and hold promise for reducing the levels of circulating IgG. Additionally, engineered structures containing multimeric Fc regions allow the dual targeting of FcRn and FcγRs; however, their tolerance needs to first be validated in phase I clinical studies. Here, for the first time, we have developed a modified monomeric recombinant Fc optimized for binding to all FcRns and FcγRs without the drawback of possible tolerance associated with FcγR cross-linking. A rational approach using Fc engineering allowed the selection of LFBD192, an Fc with a combination of six mutations that exhibits improved binding to human FcRn and FcγR as well as mouse FcRn and FcγRIV. The potency of LFBD192 was compared with that of intravenous immunoglobulin (IVIg), an FcRn blocker (Fc-MST-HN), and a trimeric Fc that blocks FcRn and/or immune complex-mediated cell activation through FcγR without triggering an immune reaction in several in vitro tests and validated in three mouse models of autoimmune disease.

A human anti-D monoclonal antibody selected for enhanced FcgammaRIII engagement clears RhD+ autologous red cells in human volunteers as efficiently as polyclonal anti-D antibodies.

A human anti-RhD immunoglobulin G1 monoclonal antibody (mAb), R297, was tested in a phase I study to assess its ability to induce the clearance of antibody-coated autologous RhD+ red blood cells (RBCs) in healthy male volunteers. The clearance potency of R297 was compared with that of a marketed human polyclonal anti-D product (Rhophylac). This mAb has been selected for its ability to strongly engage Fc-gamma receptor IIIA and to mediate a potent antibody-dependent cell cytotoxicity (ADCC) against RhD+ RBCs. Autologous RhD+ RBCs were sensitized with either Rhophylac or R297 at three different coating percentages (25, 12.5 and 6.25%), before re-infusion. This phase I study showed that the human R297 mAb promoted rapid and complete clearance of RBCs, and showed activity that was at least as potent as the human polyclonal anti-D antibody preparation. Clearance of RBCs could still be observed when the percentage of R297 used to coat the RBCs was reduced to 6.25%. Finally, none of the adverse events was severe or considered to be related to R297. Thus, R297 is a promising candidate for the prevention of allo-immunization and represents a new generation of Fc-modified monoclonal antibodies with increased FcgammaRIII binding and increased ADCC.

Polyreactive autoantibodies purified from human intravenous immunoglobulins prevent the development of experimental autoimmune diseases.

Intravenous immunoglobulins (IVIg) are therapeutic preparations of normal human polyclonal Ig G (IgG) that exert immunomodulatory effects in patients with autoimmune or systemic inflammatory diseases. Two different IgG subfractions were evaluated for their respective immunomodulatory effects in the treatment of experimental autoimmune diseases: a fraction enriched in antibodies that recognize the F(ab')(2) portion of IVIg and a fraction of natural polyreactive autoantibodies purified on a dinitrophenyl (DNP)-Affiprep immunoadsorbent. A very small fraction of IgG interacting with DNP but not with F(ab')(2) fragments expressed an increased ability to bind to self-antigens. The anti-DNP fraction, but not the anti-idiotype fraction, protected against inflammation observed in collagen-induced arthritis and experimental autoimmune encephalomyelitis in rats. Furthermore, it was able to reduce the occurrence of spontaneous diabetes mellitus in nonobese diabetic mice at lower concentrations than unfractionated IVIg. The therapeutic benefit of the anti-DNP fraction was associated with the inhibition of secretion of proinflammatory cytokines and stimulation of secretion of IL-1 receptor antagonist. Our results provide evidence that polyreactive autoantibodies play a role in the protective effect of IVIg in experimental models of autoimmune diseases in which inflammatory reactions are part of the disease process.