Fabian Käsermann, Switzerland
CSL Behring Research, CBRCPresenter of 1 Presentation
NEXT-GENERATION FC RECEPTOR–TARGETING BIOLOGICS FOR AUTOIMMUNE DISEASES [TOPIC: IVIG]
Abstract
Background and Aims
High-dose plasma-derived immunoglobulin (IVIG/SCIG) is a mainstay therapeutic of various autoimmune diseases. Some of the most important effector mechanisms relevant in therapy of autoimmunity are based on the Fc portion of IgG. This includes scavenging of complement and blockade of Fcgamma receptors (FcγR) or neonatal Fc-receptor.
Methods
Recent data indicate that multivalent arrangements of Fc fragments exhibit potent efficacy at substantially lower doses than IVIG. Such approaches include the use of multimerisation domains to link the Fc portions, or by fusing Fc domains to form multivalent molecules. Based on promising preclinical data several molecules of this novel class of biotherapeutics are now being studied in clinical trials.
Results
We investigated the properties of recombinant Fc-hexamers (IgG1-Fc fused to IgM-μ-tailpiece). In vitro, the Fc-hexamers showed high avidity binding to FcγR and C1q. Consequently, they suppressed FcγR -mediated cellular functions and inhibited full activation of the complement system. In vivo, therapeutic treatment of mice with rFc-multimers suppressed inflammatory arthritis and experimental ITP. In a rat model of acute neuromyelitis optica, administration of rFc-multimers reduced brain tissue damage and deposition of C5b-9.
Conclusions
Our data demonstrate potent anti-inflammatory effects of rFc-multimers in models of autoimmunity, supporting their potential as drug candidates for autoantibody mediated diseases