Mechanism of increased efficacy of recombinant Fc-μTP-L309C compared to IVIg to ameliorate mouse immune thrombocytopenia

Bonnie J B Lewis; Beth Binnington; Megan Blacquiere; Rolf Spirig; Fabian Käsermann; Donald R Branch

doi:10.1002/jha2.304

Mechanism of increased efficacy of recombinant Fc-μTP-L309C compared to IVIg to ameliorate mouse immune thrombocytopenia

EJHaem. 2021 Sep 29;2(4):789-793. doi: 10.1002/jha2.304. eCollection 2021 Nov.

Authors

Bonnie J B Lewis^{1

2}, Beth Binnington¹, Megan Blacquiere¹, Rolf Spirig³, Fabian Käsermann³, Donald R Branch^{1

4}

Affiliations

¹ Donald R. Branch, BS, MT(ASCP)SBB, PhD Donald R. Branch, BS, MT(ASCP)SBB, PhD 30 Bond Street, Keenan Research Centre Toronto M5B 1W8 Canada.
² Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Canada.
³ Research, CSL Biologics Research Center CSL Behring AG Wankdorfstrasse 10 Bern 3010 Switzerland.
⁴ Department of Medicine University of Toronto Toronto Canada.

Abstract

Recombinant Fc-μTP-L309C is more efficacious than intravenous immunoglobulin (IVIg) at ameliorating antibody-mediated autoimmune diseases through its effects on Fcγ receptors (FcγRs). Fc-μTP-L309C inhibited in-vitro FcγR-mediated phagocytosis 10⁴/10⁵-fold better than IVIg. Fc-μTP-L309C, given subcutaneously, recovered platelet counts in an immune thrombocytopenia (ITP) mouse model to a higher degree than IVIg at a 10-fold lower dose. We show, using confocal microscopy, that Fc-μTP-L309C binds to monocyte-macrophages and is rapidly internalized, whereas, IVIg remains on the cell surface. Western blotting showed that internalized FcγRIII is degraded through a lysosomal pathway, and this reduction of cell surface FcγRIII is likely responsible for the increased efficacy to ameliorate ITP.

Keywords: ITP; ITP intravenous immunoglobulin; IVIG; IVIg; immune thrombocytopenia; immunotherapy; recombinant Fc hexamer.