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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 that simultaneously targets CD32B and CD79B, to modulate the function of human B cells while avoiding their depletion.
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:
In March 2015, MacroGenics initiated a Phase 1 clinical study of MGD010. This first-in-human, double-blind, placebo-controlled, single ascending dose study is being conducted to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of MGD010 in healthy subjects. MacroGenics anticipates that the study will be completed in 2016.
Under the terms of a collaboration, Takeda has the option to obtain an exclusive worldwide license for MGD010 following the completion of the Phase 1 study. If Takeda exercises its option, it will assume responsibility for future development. If commercialized, MacroGenics would receive royalties on any global net sales and has the option to co-promote MGD010 with Takeda in the United States. MacroGenics may elect to fund a portion of Phase 3 clinical development in exchange for a North American profit share. (Learn More: Takeda MGD010 Collaboration)