title: Polymeric human Fc-fusion proteins with modified effector functions.
abstract: The success of Fc-fusion bio-therapeutics has spurred the development of other Fc-fusion products for treating and/or vaccinating against a range of diseases. We describe a method to modulate their function by converting them into well-defined stable polymers. This strategy resulted in cylindrical hexameric structures revealed by tapping mode atomic force microscopy (AFM). Polymeric Fc-fusions were significantly less immunogenic than their dimeric or monomeric counterparts, a result partly owing to their reduced ability to interact with critical Fc-receptors. However, in the absence of the fusion partner, polymeric IgG1-Fc molecules were capable of binding selectively to FcγRs, with significantly increased affinity owing to their increased valency, suggesting that these reagents may prove of immediate utility in the development of well-defined replacements for intravenous immunoglobulin (IVIG) therapy. Overall, these findings establish an effective IgG Fc-fusion based polymeric platform with which the therapeutic and vaccination applications of Fc-fusion immune-complexes can now be explored.
authors.affiliation: Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
authors.forename: David N A
authors.initials: DN
authors.lastname: Mekhaiel
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Czajkowsky
authors.forename: Jan Terje
authors.initials: JT
authors.lastname: Andersen
authors.forename: Jianguo
authors.initials: J
authors.lastname: Shi
authors.forename: Marwa
authors.initials: M
authors.lastname: El-Faham
authors.forename: Michael
authors.initials: M
authors.lastname: Doenhoff
authors.forename: Richard S
authors.initials: RS
authors.lastname: McIntosh
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Jianfeng
authors.initials: J
authors.lastname: He
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Shao
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Pleass
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D001691:Biological Therapy; D003165:Complement System Proteins / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007114:Immunization; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008288:Malaria / Q000276:immunology / Q000469:parasitology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010962:Plasmodium berghei; D011485:Protein Binding; D055503:Protein Multimerization; D011961:Receptors, Fc / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D003165:Complement System Proteins; C100688:Fc receptor, neonatal