Blocking human Fcγ receptor 1 in transfusion medicine

One of the major mechanisms of how intravenous immunoglobulin (IVIg) is considered to
improve immune thrombocytopenia (ITP) and other IgG-mediated diseases is by a mechanism
which results in Fcγ receptor (FcγR) blockade. Of the three major classes of FcγRs, we have
demonstrated that only FcγRI & III play a role in both platelet and red cell clearance
mechanisms and we have successfully developed a FcγRIII blocking entity which can
ameliorate ITP in FcγR-humanized mice. We have also recently developed an FcγRI blocking
entity that can block both platelet and red cell phagocytosis in vitro as part of our current CBS
intramural grant (ending October 2024). Together, blocking FcγRI and/or FcγRIII could
therefore potentially provide an effective alternative to donor derived IVIg.
In addition to the potential for reducing IVIg usage by employing FcγR blockade, there are a
number of unmet needs in transfusion medicine where we have demonstrated a strong positive
effect for employing FcγR blockade as a potential treatment. These include the treatment of
immune platelet-transfusion induced refractoriness (iPTR), fetal and neonatal alloimmune
thrombocytopenia (FNAIT) and patients with clinically significant transfusion-related
erythrocyte alloantibodies.
In each of these disease scenarios, we have demonstrated that FcγR blockade can be effective
and that both FcγRI and FcγRIII can contribute to IgG-dependent platelet or red cell
destruction mechanisms. This grant will therefore build on our work demonstrating the
effectiveness of FcγR blockade and in particular complete this project by testing the
effectiveness and potential synergy of FcγRI and FcγRIIII blockade both in vitro and in vivo.
This work will therefore bring us one step closer to a recombinant alternative to IVIg.

LAZARUS, Alan

Unity Health Toronto

Intramural Research Grant Program

Ontario

$400,000