Fc fusion as a platform technology: Potential for modulating immunogenicity

Trends in Biotechnology

Volumn 33, Issue 1, 2015, Pages 27-34

  Levin, Ditza ^a   Golding, Basil ^a   Strome, Scott E ^b   Sauna, Zuben E ^a  

^a CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

^b UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

Drug development; Fc receptors; Fc fusion technology; Immunogenicity; Neutralizing antidrug antibodies; Therapeutic proteins

Indexed keywords

IMMUNE SYSTEM; PRODUCT DESIGN;

DRUG DEVELOPMENT; FC-RECEPTORS; FUSION TECHNOLOGY; IMMUNOGENICITY; THERAPEUTIC PROTEIN;

ANTIBODIES;

FC RECEPTOR; FRAGMENT CRYSTALLIZABLE FUSION PROTEIN; HYBRID PROTEIN; POLYMER; UNCLASSIFIED DRUG; IMMUNOGLOBULIN FC FRAGMENT; MONOCLONAL ANTIBODY;

BIOTECHNOLOGY; HUMAN; IMMUNE RESPONSE; IMMUNOCOMPETENT CELL; IMMUNOGENICITY; IMMUNOMODULATION; INNATE IMMUNE CELL; NONHUMAN; PLASMA HALF LIFE; PROTEIN PROTEIN INTERACTION; REVIEW; AUTOIMMUNE DISEASES; BIOLOGICAL MODEL; CHEMISTRY; DRUG DELIVERY SYSTEM; DRUG EFFECTS; PROCEDURES; PROTEIN ENGINEERING;

ANTIBODIES, MONOCLONAL; AUTOIMMUNE DISEASES; DRUG DELIVERY SYSTEMS; HUMANS; IMMUNOGLOBULIN FC FRAGMENTS; IMMUNOMODULATION; MODELS, IMMUNOLOGICAL; PROTEIN ENGINEERING; RECOMBINANT FUSION PROTEINS;

EID: 84918774655     PISSN: 01677799     EISSN: 18793096     Source Type: Journal    
DOI: 10.1016/j.tibtech.2014.11.001     Document Type: Review

References (88)

1. Kariolis M.S., et al. Beyond antibodies: using biological principles to guide the development of next-generation protein therapeutics. Curr. Opin. Biotechnol. 2013, 24:1072-1077.
2. Sauna Z.E., et al. Plasma derivatives: new products and new approaches. Biologicals 2012, 40:191-195.
3. Roopenian D.C., Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 2007, 7:715-725.
4. Huang C. Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology. Curr. Opin. Biotechnol. 2009, 20:692-699.
5. Beck A., Reichert J.M. Therapeutic Fc-fusion proteins and peptides as successful alternatives to antibodies. MAbs 2011, 3:415-416.
6. Rath T., et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit. Rev. Biotechnol. 2013, doi:10.3109/07388551.2013.834293.
7. Shankar G., et al. Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol. 2006, 24:274-280.
8. Hogarth P.M., Pietersz G.A. Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nat. Rev. Drug Discov. 2012, 11:311-331.
9. Liang Y., et al. Immunity against a therapeutic xenoprotein/Fc construct delivered by gene transfer is reduced through binding to the inhibitory receptor FcγRIIb. J. Gene Med. 2011, 13:470-477.
10. Buschor P., et al. Improved FcγRIIb targeting functionally translates into enhanced inhibition of basophil activation. Int. Arch. Allergy Immunol. 2014, 163:206-214.
11. Saxon A., et al. Accentuate the negative, eliminate the positive": engineering allergy therapeutics to block allergic reactivity through negative signaling. J. Allergy Clin. Immunol. 2008, 121:320-325.
12. Van Scott M.R., et al. Systemic administration of an Fcγ-Fce{open}-fusion protein in house dust mite sensitive nonhuman primates. Clin. Immunol. 2008, 128:340-348.
13. Jain A., et al. Fully recombinant IgG2a Fc multimers (Stradomers) effectively treat collagen-induced arthritis and prevent idiopathic thrombocytopenic purpura in mice. Arthritis Res. Ther. 2012, 14:R192.
14. Mekhaiel D.N., et al. Polymeric human Fc-fusion proteins with modified effector functions. Sci. Rep. 2011, 1:124.
15. Pincetic A., et al. Type I and type II Fc receptors regulate innate and adaptive immunity. Nat. Immunol. 2014, 15:707-716.
16. Karsten C.M., et al. Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcγRIIB and Dectin-1. Nat. Med. 2012, 18:1401-1406.
17. Lux A., et al. Impact of immune complex size and glycosylation on IgG binding to human FcγRs. J. Immunol. 2013, 190:4315-4323.
18. Nimmerjahn F., Ravetch J.V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 2008, 8:34-47.
19. Schwab I., Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system?. Nat. Rev. Immunol. 2013, 13:176-189.
20. Eck M.J., Sprang S.R. The structure of tumor necrosis factor-α at 2.6Å resolution. Implications for receptor binding. J. Biol. Chem. 1989, 264:17595-17605.
21. Liang S., et al. Structural basis for treating tumor necrosis factor alpha (TNFα)-associated diseases with the therapeutic antibody infliximab. J. Biol. Chem. 2013, 288:13799-13807.
22. Kaymakcalan Z., et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin. Immunol. 2009, 131:308-316.
23. Moreland L., et al. Abatacept. Nat. Rev. Drug Discov. 2006, 5:185-186.
24. Smith K.G., Clatworthy M.R. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat. Rev. Immunol. 2010, 10:328-343.
25. Pricop L., et al. Differential modulation of stimulatory and inhibitory Fc gamma receptors on human monocytes by Th1 and Th2 cytokines. J. Immunol. 2001, 166:531-537.
26. Bezbradica J.S., et al. A role for the ITAM signaling module in specifying cytokine-receptor functions. Nat. Immunol. 2014, 15:333-342.
27. Cassard L., et al. Fcγ receptors inhibit mouse and human basophil activation. J. Immunol. 2012, 189:2995-3006.
28. van der Poel C.E., et al. Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG. Blood 2010, 116:5327-5333.
29. Bruhns P. Properties of mouse and human IgG receptors and their contribution to disease models. Blood 2012, 119:5640-5649.
30. Beck A., et al. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr. Pharm. Biotechnol. 2008, 9:482-501.
31. Strome S.E., et al. A mechanistic perspective of monoclonal antibodies in cancer therapy beyond target-related effects. Oncologist 2007, 12:1084-1095.
32. Gillis C., et al. Contribution of human FcγRs to disease with evidence from human polymorphisms and transgenic animal studies. Front. Immunol. 2014, 5:254.
33. Eckhardt C.L., et al. The Fc gamma receptor IIa R131H polymorphism is associated with inhibitor development in severe hemophilia A. J. Thromb. Haemost. 2014, 12:1294-1301.
34. Unkeless J.C., Eisen H.N. Binding of monomeric immunoglobulins to Fc receptors of mouse macrophages. J. Exp. Med. 1975, 142:1520-1533.
35. Ioan-Facsinay A., et al. FcγRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses, and protection from bacterial infection. Immunity 2002, 16:391-402.
36. Suzuki T., et al. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J. Immunol. 2010, 184:1968-1976.
37. Guilliams M., et al. The function of Fcγ receptors in dendritic cells and macrophages. Nat. Rev. Immunol. 2014, 14:94-108.
38. Swanson J.A., Hoppe A.D. The coordination of signaling during Fc receptor-mediated phagocytosis. J. Leukoc. Biol. 2004, 76:1093-1103.
39. Rath T., et al. The immunologic functions of the neonatal Fc receptor for IgG. J. Clin. Immunol. 2013, 33(Suppl. 1):S9-S17.
40. Bolland S., Ravetch J.V. Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis. Immunity 2000, 13:277-285.
41. Boruchov A.M., et al. Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. J. Clin. Invest. 2005, 115:2914-2923.
42. Dhodapkar K.M., et al. Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells. Proc. Natl. Acad. Sci. U.S.A. 2005, 102:2910-2915.
43. van Montfoort N., et al. Fcγ receptor IIb strongly regulates Fcγ receptor-facilitated T cell activation by dendritic cells. J. Immunol. 2012, 189:92-101.
44. Pearse R.N., et al. SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis. Immunity 1999, 10:753-760.
45. Xiang Z., et al. FcγRIIb controls bone marrow plasma cell persistence and apoptosis. Nat. Immunol. 2007, 8:419-429.
46. Pfirsch-Maisonnas S., et al. Inhibitory ITAM signaling traps activating receptors with the phosphatase SHP-1 to form polarized "inhibisome" clusters. Sci. Signal. 2011, 4:ra24.
47. Bergtold A., et al. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 2005, 23:503-514.
48. White A.L., et al. FcγRIIB controls the potency of agonistic anti-TNFR mAbs. Cancer Immunol. Immunother. 2013, 62:941-948.
49. Blank U., et al. Inhibitory ITAMs as novel regulators of immunity. Immunol. Rev. 2009, 232:59-71.
50. Aloulou M., et al. IgG1 and IVIg induce inhibitory ITAM signaling through FcγRIII controlling inflammatory responses. Blood 2012, 119:3084-3096.
51. Ben M.S., et al. Role of FcγRIIIA (CD16) in IVIg-mediated anti-inflammatory function. J. Clin. Immunol. 2014, 34(Suppl. 1):S46-S50.
52. Siragam V., et al. Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat. Med. 2006, 12:688-692.
53. Hansel T.T., et al. The safety and side effects of monoclonal antibodies. Nat. Rev. Drug Discov. 2010, 9:325-338.
54. Imbach P., et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981, 1:1228-1231.
55. Bazin R., et al. Reversal of immune thrombocytopenia in mice by cross-linking human immunoglobulin G with a high-affinity monoclonal antibody. Br. J. Haematol. 2006, 135:97-100.
56. Bussel J.B., et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood 1991, 77:1884-1893.
57. De Groot A.S., et al. Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood 2008, 112:3303-3311.
58. De Groot A.S., et al. Tregitope peptides: the active pharmaceutical ingredient of IVIG?. Clin. Dev. Immunol. 2013, 2013:493138.
59. Su Y., et al. Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se. J. Leukoc. Biol. 2013, 94:377-383.
60. Anthony R.M., et al. Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 2011, 475:110-113.
61. Tjon A.S., et al. Intravenous immunoglobulin treatment in humans suppresses dendritic cell function via stimulation of IL-4 and IL-13 production. J. Immunol. 2014, 192:5625-5634.
62. Aukrust P., et al. Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo. Blood 1994, 84:2136-2143.
63. Wypych J., et al. Human IgG2 antibodies display disulfide-mediated structural isoforms. J. Biol. Chem. 2008, 283:16194-16205.
64. Yoo E.M., et al. Human IgG2 can form covalent dimers. J. Immunol. 2003, 170:3134-3138.
65. Niknami M., et al. Beneficial effect of a multimerized immunoglobulin Fc in an animal model of inflammatory neuropathy (experimental autoimmune neuritis). J. Peripher. Nerv. Syst. 2013, 18:141-152.
66. Thiruppathi M., et al. Recombinant IgG2a Fc (M045) multimers effectively suppress experimental autoimmune myasthenia gravis. J. Autoimmun. 2014, 52:64-73.
67. Bendtzen K. Anti-TNF-α biotherapies: perspectives for evidence-based personalized medicine. Immunotherapy 2012, 4:1167-1179.
68. Schiff M.H., et al. Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a Phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase. Ann. Rheum. Dis. 2014, 73:2174-2177.
69. Puxeddu I., et al. Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann. Allergy Asthma Immunol. 2012, 108:123-124.
70. Krieckaert C.L., et al. Comparison of long-term clinical outcome with etanercept treatment and adalimumab treatment of rheumatoid arthritis with respect to immunogenicity. Arthritis Rheum. 2012, 64:3850-3855.
71. Czajkowsky D.M., et al. Fc-fusion proteins: new developments and future perspectives. EMBO Mol. Med. 2012, 4:1015-1028.
72. Larsen C.P., et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am. J. Transplant. 2005, 5:443-453.
73. Bernett M.J., et al. Immune suppression in cynomolgus monkeys by XPro9523: an improved CTLA4-Ig fusion with enhanced binding to CD80, CD86 and neonatal Fc receptor FcRn. MAbs 2013, 5:384-396.
74. Smith P., et al. Mouse model recapitulating human Fcγ receptor structural and functional diversity. Proc. Natl. Acad. Sci. U.S.A. 2012, 109:6181-6186.
75. Roopenian D.C., et al. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J. Immunol. 2003, 170:3528-3533.
76. McEwan W.A., et al. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat. Immunol. 2013, 14:327-336.
77. Muller J., Nitschke L. The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. Nat. Rev. Rheumatol. 2014, 10:422-428.
78. Franco A., et al. Human Fc receptor-like 5 binds intact IgG via mechanisms distinct from those of Fc receptors. J. Immunol. 2013, 190:5739-5746.
79. Meulenbroek L.A., et al. IgG antibodies in food allergy influence allergen-antibody complex formation and binding to B cells: a role for complement receptors. J. Immunol. 2013, 191:3526-3533.
80. Schwab I., et al. Broad requirement for terminal sialic acid residues and FcγRIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo. Eur. J. Immunol. 2014, 44:1444-1453.
81. Sondermann P., et al. General mechanism for modulating immunoglobulin effector function. Proc. Natl. Acad. Sci. U.S.A. 2013, 110:9868-9872.
82. Campbell I.K., et al. Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils. J. Immunol. 2014, 192:5031-5038.
83. Crow A.R., et al. A role for IL-1 receptor antagonist or other cytokines in the acute therapeutic effects of IVIg?. Blood 2007, 109:155-158.
84. Bruhns P., et al. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 2009, 113:3716-3725.
85. Grubb J.H., et al. Infused Fc-tagged β-glucuronidase crosses the placenta and produces clearance of storage in utero in mucopolysaccharidosis VII mice. Proc. Natl. Acad. Sci. U.S.A. 2008, 105:8375-8380.
86. Carvalheiras G., et al. Fetal outcome in autoimmune diseases. Autoimmun. Rev. 2012, 11:A520-A530.
87. Low S.C., et al. Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis. Hum. Reprod. 2005, 20:1805-1813.
88. Ko S.Y., et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature 2014, 514:642-645.