Article ; Online: The Dual Targeting of FcRn and FcγRs
2021 Volume 12, Page(s) 728322
Abstract: Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that ... ...
| Abstract | Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that target FcRn are currently in clinical development and hold promise for reducing the levels of circulating IgG. Additionally, engineered structures containing multimeric Fc regions allow the dual targeting of FcRn and FcγRs; however, their tolerance needs to first be validated in phase I clinical studies. Here, for the first time, we have developed a modified monomeric recombinant Fc optimized for binding to all FcRns and FcγRs without the drawback of possible tolerance associated with FcγR cross-linking. A rational approach using Fc engineering allowed the selection of LFBD192, an Fc with a combination of six mutations that exhibits improved binding to human FcRn and FcγR as well as mouse FcRn and FcγRIV. The potency of LFBD192 was compared with that of intravenous immunoglobulin (IVIg), an FcRn blocker (Fc-MST-HN), and a trimeric Fc that blocks FcRn and/or immune complex-mediated cell activation through FcγR without triggering an immune reaction in several |
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| MeSH term(s) | Animals ; Antirheumatic Agents/metabolism ; Antirheumatic Agents/pharmacology ; Arthritis, Experimental/genetics ; Arthritis, Experimental/immunology ; Arthritis, Experimental/metabolism ; Arthritis, Experimental/prevention & control ; Autoimmunity/drug effects ; Binding, Competitive ; Complement C5a/metabolism ; Female ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Immunoglobulin Fc Fragments/genetics ; Immunoglobulin Fc Fragments/immunology ; Immunoglobulin Fc Fragments/metabolism ; Immunoglobulin Fc Fragments/pharmacology ; Interleukin-2/metabolism ; Jurkat Cells ; Kinetics ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Phagocytosis/drug effects ; Platelet Aggregation/drug effects ; Protein Binding ; Protein Engineering ; Receptors, Fc/antagonists & inhibitors ; Receptors, Fc/genetics ; Receptors, Fc/immunology ; Receptors, Fc/metabolism ; Receptors, IgG/antagonists & inhibitors ; Receptors, IgG/genetics ; Receptors, IgG/immunology ; Receptors, IgG/metabolism ; Secretory Pathway ; Signal Transduction ; THP-1 Cells ; Mice |
| Chemical Substances | Antirheumatic Agents ; Histocompatibility Antigens Class I ; IL2 protein, human ; Immunoglobulin Fc Fragments ; Interleukin-2 ; Receptors, Fc ; Receptors, IgG ; Complement C5a (80295-54-1) ; Fc receptor, neonatal (TW3XAW0RCY) |
| Language | English |
| Publishing date | 2021-08-26 |
| Publishing country | Switzerland |
| Document type | Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2606827-8 |
| ISSN | 1664-3224 ; 1664-3224 |
| ISSN (online) | 1664-3224 |
| ISSN | 1664-3224 |
| DOI | 10.3389/fimmu.2021.728322 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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