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Currently approved B-cell-targeted therapies either cause depletion of B cells, thus limiting their applicability due to the potential for infections, or exhibit a delayed onset of action and limited efficacy across patient populations. To address these limitations, we are developing MGD010, a humanized Dual-Affinity Re-Targeting, or DART®, molecule, which is designed to simultaneously target the B-cell surface proteins, CD32B and CD79B, and is being developed for the treatment of autoimmune disorders. CD32B is a checkpoint molecule expressed on B lymphocytes that, when co-ligated with CD79B, a component of the B-cell antigen receptor complex, delivers a co-inhibitory signal that dampens B-cell activation. The intended mechanism of MGD010 is to modulate the function of human B cells while avoiding their depletion.
In June 2016, MacroGenics presented clinical data from its Phase 1 study of MGD010 at the Annual European Congress of Rheumatology (EULAR 2016) in an oral presentation titled “Safety, Tolerability, and Functional Activity of MGD010, a DART® Molecule Targeting CD32B and CD79B, Following a Single Dose Administration in Healthy Volunteers.” (Learn More – EULAR 2016 Presentation)
The objectives of the study were to assess the safety, tolerability, pharmacokinetic and pharmacodynamic activity of MGD010 in healthy volunteers. The Phase 1 study of MGD010 was a first-in-human, double-blind, placebo-controlled study in which a single dose of MGD010 was intravenously (IV) administered to 49 healthy subjects. Data from the study showed that MGD010 was well tolerated at all dose levels and no serious adverse effects were reported. None of the subjects participating in the study had premature discontinuations or infusion reactions, systemic hypersensitivity reactions or injection site reactions.
In addition, MGD010 demonstrated linear pharmacokinetics and dose-dependent selective binding to B lymphocytes without persistent B-cell depletion. The data also showed: (1) a dose-dependent downregulation of B-cell receptor-induced signaling together with down-modulation of B-cell receptor expression among circulating memory and naïve B cells, (2) a decrease in expression of the costimulatory CD40 molecule and (3) a decrease in circulating immunoglobulin M levels, each consistent with the targeted action of MGD010. These data support the continued research and development of MGD010 in patients with autoimmune and inflammatory disorders. MacroGenics anticipates that the study will be completed in 2016
In pre-clinical studies, MGD010 was shown to modulate the function of human B cells without B-cell depletion. In normal conditions, B cells utilize CD32B, or Fc-gamma receptor IIb, as one of the key negative regulators to ensure that tolerance to self is maintained and autoimmune disease does not occur. MGD010 exploits this mechanism and triggers this inhibitory “immune checkpoint” loop for the inhibition of B-cell function, an approach that may be useful for the treatment of patients with autoimmune disorders. MacroGenics believes this molecule preferentially blocks those B cells that are activated to produce the pathogenic antibodies that promote the autoimmune process. MGD010 was shown to inhibit B lymphocytes from SLE (Systemic Lupus Erythematosus) patients in vitro; furthermore, MGD010 inhibits the onset of autoimmunity in humanized mouse models. In a non-human primate study, MGD010 has demonstrated a favorable safety profile and pharmacodynamic effect on targeted B cells in the absence of B-cell depletion.
In a poster presentation at IMMUNOLOGY 2014, the American Association of Immunologists’ Annual Meeting, the following findings were observed:
MacroGenics retains full worldwide rights to MGD010.