Mechanism of Increased Efficacy of Recombinant Fc-μTP-L309C compared to IVIg to Ameliorate Mouse Immune Thrombocytopenia

Overview

Journal EJHaem

Specialty Hematology

Date 2022 Jul 18

PMID 35845218

Authors

Bonnie J B Lewis

Beth Binnington

Megan Blacquiere

Rolf Spirig

Fabian Kasermann

Donald R Branch

Affiliations

Soon will be listed here.

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 10/10-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.

Citing Articles

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

Lewis B, Binnington B, Blacquiere M, Spirig R, Kasermann F, Branch D EJHaem. 2022; 2(4):789-793.

PMID: 35845218 PMC: 9175896. DOI: 10.1002/jha2.304.

References

Zhou H, Olsen H, So E, Merigeon E, Rybin D, Owens J . A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b. Blood Adv. 2018; 1(8):504-515. PMC: 5728453. DOI: 10.1182/bloodadvances.2016001917. View

Spirig R, Campbell I, Koernig S, Chen C, Lewis B, Butcher R . rIgG1 Fc Hexamer Inhibits Antibody-Mediated Autoimmune Disease via Effects on Complement and FcγRs. J Immunol. 2018; 200(8):2542-2553. PMC: 5890536. DOI: 10.4049/jimmunol.1701171. View

Qureshi O, Rowley T, Junker F, Peters S, Crilly S, Compson J . Multivalent Fcγ-receptor engagement by a hexameric Fc-fusion protein triggers Fcγ-receptor internalisation and modulation of Fcγ-receptor functions. Sci Rep. 2017; 7(1):17049. PMC: 5719016. DOI: 10.1038/s41598-017-17255-8. View

Katsman Y, Foo A, Leontyev D, Branch D . Improved mouse models for the study of treatment modalities for immune-mediated platelet destruction. Transfusion. 2010; 50(6):1285-94. DOI: 10.1111/j.1537-2995.2009.02558.x. View

Lewis B, Ville J, Blacquiere M, Cen S, Spirig R, Zuercher A . Using the K/BxN mouse model of endogenous, chronic, rheumatoid arthritis for the evaluation of potential immunoglobulin-based therapeutic agents, including IVIg and Fc-μTP-L309C, a recombinant IgG1 Fc hexamer. BMC Immunol. 2019; 20(1):44. PMC: 6894239. DOI: 10.1186/s12865-019-0328-6. View

Nguyen A, Repesse Y, Ebbo M, Allenbach Y, Benveniste O, Vallat J . IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans. Clin Exp Immunol. 2021; 204(2):258-266. PMC: 8062997. DOI: 10.1111/cei.13580. View

Jain A, Olsen H, Vyzasatya R, Burch E, Sakoda Y, Merigeon E . Fully recombinant IgG2a Fc multimers (stradomers) effectively treat collagen-induced arthritis and prevent idiopathic thrombocytopenic purpura in mice. Arthritis Res Ther. 2012; 14(4):R192. PMC: 3580588. DOI: 10.1186/ar4024. View

Smith R, Coloma M, Morrison S . Addition of a mu-tailpiece to IgG results in polymeric antibodies with enhanced effector functions including complement-mediated cytolysis by IgG4. J Immunol. 1995; 154(5):2226-36. View

Ortiz D, Lansing J, Rutitzky L, Kurtagic E, Prodhomme T, Choudhury A . Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors. Sci Transl Med. 2016; 8(365):365ra158. DOI: 10.1126/scitranslmed.aaf9418. View

10.

Lewis B, Binnington B, Blacquiere M, Spirig R, Kasermann F, Branch D . Mechanism of increased efficacy of recombinant Fc-μTP-L309C compared to IVIg to ameliorate mouse immune thrombocytopenia. EJHaem. 2022; 2(4):789-793. PMC: 9175896. DOI: 10.1002/jha2.304. View

11.

Tong T, Burke-Murphy E, Sakac D, Pendergrast J, Cserti-Gazdewich C, Laroche V . Optimal conditions for the performance of a monocyte monolayer assay. Transfusion. 2016; 56(11):2680-2690. DOI: 10.1111/trf.13766. View

12.

Danieli M, Gelardi C, Pedini V, Moretti R, Gabrielli A, Logullo F . Subcutaneous IgG in immune-mediate diseases: proposed mechanisms of action and literature review. Autoimmun Rev. 2014; 13(12):1182-8. DOI: 10.1016/j.autrev.2014.08.018. View

13.

Jolles S, Chapel H, Litzman J . When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach. Clin Exp Immunol. 2016; 188(3):333-341. PMC: 5422851. DOI: 10.1111/cei.12915. View

14.

Washburn N, Schwab I, Ortiz D, Bhatnagar N, Lansing J, Medeiros A . Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity. Proc Natl Acad Sci U S A. 2015; 112(11):E1297-306. PMC: 4371931. DOI: 10.1073/pnas.1422481112. View