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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.
In June 2017, MacroGenics presented updated clinical data from its Phase 1 study of MGD010 at EULAR 2017 in a poster presentation titled “Immunomodulatory Effects of MGD010, a DART® Molecule Targeting Human B-cell CD32B and CD79B.” In this poster, the Company highlighted the immunomodulatory impact of MGD010 on the response to hepatitis A vaccination (HAV), a model antigen challenge, in normal healthy subjects. These data demonstrate that by pharmacologically exploiting the activity of the checkpoint molecule CD32B in combination with the B-cell receptor (BCR) CD79B component, a single dose adminisation of MGD010 at either 3 or 10 mg/kg delivers an immunomodulatory effect that counters B-cell function.
MacroGenics retains full worldwide rights to MGD010.