Developing the IVIG biomimetic, hexa-Fc, for drug and vaccine applications.
The remarkable clinical success of Fc-fusion proteins has driven intense investigation for even more potent replacements. Using quality-by-design (QbD) approaches, we generated hexameric-Fc (hexa-Fc), a ~20 nm oligomeric Fc-based scaffold that we here show binds low-affinity inhibitory receptors (FcRL5, FcγRIIb, and DC-SIGN) with high avidity and specificity, whilst eliminating significant clinical limitations of monomeric Fc-fusions for vaccine and/or cancer therapies, in particular their poor ability to activate complement. Mass spectroscopy of hexa-Fc reveals high-mannose, low-sialic acid content, suggesting that interactions with these receptors are influenced by the mannose-containing Fc. Molecular dynamics (MD) simulations provides insight into the mechanisms of hexa-Fc interaction with these receptors and reveals an unexpected orientation of high-mannose glycans on the human Fc that provides greater accessibility to potential binding partners. Finally, we show that this biosynthetic nanoparticle can be engineered to enhance interactions with the human neonatal Fc receptor (FcRn) without loss of the oligomeric structure, a crucial modification for these molecules in therapy and/or vaccine strategies where a long plasma half-life is critical.
Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240 P. R. China.
Daniel M
DM
Czajkowsky
Centre for Immune Regulation (CIR) and Department of Immunology, Oslo University Hospital Rikshospitalet, P.O. Box 4956, Oslo N-0424, Norway.
Jan Terje
JT
Andersen
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Anja
A
Fuchs
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Timothy J
TJ
Wilson
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
David
D
Mekhaiel
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Marco
M
Colonna
Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240 P. R. China.
Jianfeng
J
He
Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240 P. R. China.
Zhifeng
Z
Shao
Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, Coventry CV2 2DX, UK.
Daniel A
DA
Mitchell
Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7.
Gang
G
Wu
Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7.
Anne
A
Dell
Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7.
Stuart
S
Haslam
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
Katy A
KA
Lloyd
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
Shona C
SC
Moore
1] Centre for Immune Regulation (CIR) and Department of Immunology, Oslo University Hospital Rikshospitalet, P.O. Box 4956, Oslo N-0424, Norway [2] CIR and Department of Biosciences, University of Oslo, N-0316 Oslo, Norway.
Inger
I
Sandlie
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
Patricia A
PA
Blundell
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.
Richard J
RJ
Pleass
D032701:Biomimetics / Q000379:methods; D002352:Carrier Proteins / Q000276:immunology; D002478:Cells, Cultured; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D016756:Immunoglobulins, Intravenous / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology; D014612:Vaccines / Q000276:immunology*
D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D011961:Receptors, Fc; D014612:Vaccines; C100688:Fc receptor, neonatal