Targeting the neonatal fc receptor for antigen delivery using engineered fc fragments.
The development of approaches for Ag delivery to the appropriate subcellular compartments of APCs and the optimization of Ag persistence are both of central relevance for the induction of protective immunity or tolerance. The expression of the neonatal Fc receptor, FcRn, in APCs and its localization to the endosomal system suggest that it might serve as a target for Ag delivery using engineered Fc fragment-epitope fusions. The impact of FcRn binding characteristics of an Fc fragment on in vivo persistence allows this property to also be modulated. We have therefore generated recombinant Fc (mouse IgG1-derived) fusions containing the N-terminal epitope of myelin basic protein that is associated with experimental autoimmune encephalomyelitis in H-2(u) mice. The Fc fragments have distinct binding properties for FcRn that result in differences in intracellular trafficking and in vivo half-lives, allowing the impact of these characteristics on CD4(+) T cell responses to be evaluated. To dissect the relative roles of FcRn and the "classical" FcgammaRs in Ag delivery, analogous aglycosylated Fc-MBP fusions have been generated. We show that engineered Fc fragments with increased affinities for FcRn at pH 6.0-7.4 are more effective in delivering Ag to FcRn-expressing APCs in vitro relative to their lower affinity counterparts. However, higher affinity of the FcRn-Fc interaction at near neutral pH results in decreased in vivo persistence. The trade-off between improved FcRn targeting efficiency and lower half-life becomes apparent during analyses of T cell proliferative responses in mice, particularly when Fc-MBP fusions with both FcRn and FcgammaR binding activity are used.
Mi
Wentao
W
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093, USA.
Wanjie
Sylvia
S
Lo
Su-Tang
ST
Gan
Zhuo
Z
Pickl-Herk
Beatrix
B
Ober
Raimund J
RJ
Ward
E Sally
ES
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000941:Antigens / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006863:Hydrogen-Ion Concentration; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
D000941:Antigens; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D004676:Myelin Basic Protein; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C100688:Fc receptor, neonatal