Small molecule phagocytosis inhibitors for immune cytopenias.
Immune cytopenias are conditions characterized by low blood cell counts, such as platelets in immune thrombocytopenia (ITP) and red blood cells in autoimmune hemolytic anemia (AIHA). Chronic ITP affects approximately 4 in 100,000 adults annually while AIHA is much less common. Extravascular phagocytosis and massive destruction of autoantibody-opsonized blood cells by macrophages in the spleen and liver are the hallmark of these conditions. Current treatment modalities for ITP and AIHA include the first-line use of corticosteroids; whereas, IVIg shows efficacy in ITP but not AIHA. One main mechanism of action by which IVIg treatment leads to the reduction in platelet destruction rates in ITP is thought to involve Fcγ receptor (FcγR) blockade, ultimately leading to the inhibition of extravascular platelet phagocytosis. IVIg, which is manufactured from the human plasma of thousands of donors, is a limited resource, and alternative treatments, particularly those based on bioavailable small molecules, are needed. In this review, we overview the pathophysiology of ITP, the role of Fcγ receptors, and the mechanisms of action of IVIg in treating ITP, and outline the efforts and progress towards developing novel, first-in-class inhibitors of phagocytosis as synthetic, small molecule substitutes for IVIg in ITP and other conditions where the pathobiology of the disease involves phagocytosis.
Centre for Innovation, Canadian Blood Services, Toronto, ON, Canada.
Anton
A
Neschadim
Center for Molecular Design and Preformulations, University Health Network, Toronto, ON, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada; McLaughlin Center for Molecular Medicine, University of Toronto, Toronto, ON, Canada; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
Lakshmi P
LP
Kotra
Centre for Innovation, Canadian Blood Services, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Advanced Diagnostics, Infection and Immunity Group, Toronto General Hospital Research Institute, Toronto, ON, Canada. Electronic address: don.branch@utoronto.ca.
Donald R
DR
Branch
D000744:Anemia, Hemolytic, Autoimmune / Q000188:drug therapy* / Q000473:pathology; D001792:Blood Platelets / Q000473:pathology; D002908:Chronic Disease / Q000188:drug therapy; D004912:Erythrocytes / Q000473:pathology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D008264:Macrophages / Q000473:pathology; D010587:Phagocytosis; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy* / Q000473:pathology; D011720:Pyrazoles / Q000627:therapeutic use
D016756:Immunoglobulins, Intravenous; D011720:Pyrazoles
ITP; Immune cytopenias; Inhibitor; Phagocytosis; Small molecule drugs; Thrombocytopenia