Engineered IgG1-Fc - one fragment to bind them all

Immunological Reviews

Volumn 270, Issue 1, 2016, Pages 113-131

  Lobner, Elisabeth ^a   Traxlmayr, Michael W ^a,b   Obinger, Christian ^a   Hasenhindl, Christoph ^a,c  

^a UNIVERSITY OF NATURAL RESOURCES AND LIFE SCIENCES   (Austria)

^b Massachusetts Institute of Technology Cambridge   (United States)

^c Austrianni GmbH   (Austria)

Author keywords

Antibody engineering; Fcab; IgG1 Fc; Library design

Indexed keywords

HYBRID PROTEIN; IMMUNOGLOBULIN FC FRAGMENT; IMMUNOGLOBULIN G1; IMMUNOGLOBULIN G1 FC FRAGMENT FUSION PROTEIN; UNCLASSIFIED DRUG; IMMUNOGLOBULIN G; LIGAND; MONOCLONAL ANTIBODY; PROTEIN BINDING;

AMINO ACID SEQUENCE; ANTIBODY ENGINEERING; ANTIGEN BINDING; DRUG DESIGN; DRUG STRUCTURE; HUMAN; MOLECULAR LIBRARY; PRIORITY JOURNAL; PROTEIN ENGINEERING; REVIEW; ANIMAL; CHEMISTRY; GENE LIBRARY; GENETIC ENGINEERING; GENETICS; IMMUNOLOGY; METABOLISM; PROTEIN DOMAIN;

ANIMALS; ANTIBODIES, MONOCLONAL; GENE LIBRARY; GENETIC ENGINEERING; HUMANS; IMMUNOGLOBULIN FC FRAGMENTS; IMMUNOGLOBULIN G; LIGANDS; PROTEIN BINDING; PROTEIN ENGINEERING; PROTEIN INTERACTION DOMAINS AND MOTIFS;

EID: 84957708807     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12385     Document Type: Review

References (122)

1. Melmed GY, Targan SR, Yasothan U, Hanicq D, Kirkpatrick P. Certolizumab pegol. Nat Rev Drug Discov 2008;7:641-642.
2. Pieramici DJ, Avery RL. Ranibizumab: treatment in patients with neovascular age-related macular degeneration. Expert Opin Biol Ther 2006;6:1237-1245.
3. Genetta TB, Mauro VF. ABCIXIMAB: a new antiaggregant used in angioplasty. Ann Pharmacother 1996;30:251-257.
4. Bird RE, et al. Single-chain antigen-binding proteins. Science 1988;242:423-426.
5. Worn A, Pluckthun A. Stability engineering of antibody single-chain Fv fragments. J Mol Biol 2001;305:989-1010.
6. Raag R, Whitlow M. Single-chain Fvs. FASEB J 1995;9:73-80.
7. Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res 2009;69:4941-4944.
8. Holliger P, Prospero T, Winter G. Diabodies - small bivalent and bispecific antibody fragments. Proc Natl Acad Sci USA 1993;90:6444-6448.
9. Johnson S, et al. Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol 2010;399:436-449.
10. Xiao X, Feng Y, Vu BK, Ishima R, Dimitrov DS. A large library based on a novel (CH2) scaffold: identification of HIV-1 inhibitors. Biochem Biophys Res Commun 2009;387:387-392.
11. De Meyer T, Muyldermans S, Depicker A. Nanobody-based products as research and diagnostic tools. Trends Biotechnol 2014;32:263-270.
12. Harmsen MM, De Haard HJ. Properties, production, and applications of camelid single-domain antibody fragments. Appl Microbiol Biotechnol 2007;77:13-22.
13. Stumpp MT, Binz HK, Amstutz P. DARPins: a new generation of protein therapeutics. Drug Discovery Today 2008;13:695-701.
14. Koide A, Bailey CW, Huang X, Koide S. The fibronectin type III domain as a scaffold for novel binding proteins. J Mol Biol 1998;284:1141-1151.
15. Rüker F, Wozniak-Knopp G. Engineering of non-CDR loops in immunoglobulin domains. In: Little M ed. Recombinant Antibodies for Immunotherapy. New York: Cambridge University Press, 2009:231-242.
16. Halaby DM, Poupon A, Mornon J. The immunoglobulin fold family: sequence analysis and 3D structure comparisons. Protein Eng 1999;12:563-571.
17. Ying T, Gong R, Ju TW, Prabakaran P, Dimitrov DS. Engineered Fc based antibody domains and fragments as novel scaffolds. Biochim Biophys Acta 2014;1844:1977-1982.
18. Huber R, Deisenhofer J, Colman PM, Matsushima M, Palm W. Crystallographic structure studies of an IgG molecule and an Fc fragment. Nature 1976;264:415-420.
19. Hogarth PM, Pietersz GA. Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nat Rev Drug Discov 2012;11:311-331.
20. Kabat EA, Wu TT, Perry HM, Gottesman KS, Foeller C. Sequences of Proteins of Immunological Interest. 5th edn. Bethesda, MD: National Institutes of Health, 1991:688-696.
21. Jefferis R, Lund J. Interaction sites on human IgG-Fc for FcgammaR: current models. Immunol Lett 2002;82:57-65.
22. Burton DR, Woof JM. Human antibody effector function. Adv Immunol 1992;51:1-84.
23. Deisenhofer J. Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution. Biochemistry 1981;20:2361-2370.
24. Padlan EA. Anatomy of the antibody molecule. Mol Immunol 1994;31:169-217.
25. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006;313:670-673.
26. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008;8:34-47.
27. Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol 2007;25:21-50.
28. Lai B, Hasenhindl C, Obinger C, Oostenbrink C. Molecular dynamics simulation of the crystallizable fragment of IgG1-insights for the design of Fcabs. Int J Mol Sci 2014;15:438-455.
29. Mimura Y, et al. The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms. Mol Immunol 2000;37:697-706.
30. Ghirlando R, Lund J, Goodall M, Jefferis R. Glycosylation of human IgG-Fc: influences on structure revealed by differential scanning micro-calorimetry. Immunol Lett 1999;68:47-52.
31. Vermeer AW, Norde W. The thermal stability of immunoglobulin: unfolding and aggregation of a multi-domain protein. Biophys J 2000;78:394-404.
32. Traxlmayr MW, Obinger C. Directed evolution of proteins for increased stability and expression using yeast display. Arch Biochem Biophys 2012;526:174-180.
33. Shusta EV, Holler PD, Kieke MC, Kranz DM, Wittrup KD. Directed evolution of a stable scaffold for T-cell receptor engineering. Nat Biotechnol 2000;18:754-759.
34. Boder ET, Wittrup KD. Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol 1997;15:553-557.
35. Hulett MD, Hogarth PM. Molecular basis of Fc receptor function. Adv Immunol 1994;57:1-127.
36. Fridman WH. Fc receptors and immunoglobulin binding factors. FASEB J 1991;5:2684-2690.
37. Wines BD, Powell MS, Parren PW, Barnes N, Hogarth PM. The IgG Fc contains distinct Fc receptor (FcR) binding sites: the leukocyte receptors Fc gamma RI and Fc gamma RIIa bind to a region in the Fc distinct from that recognized by neonatal FcR and protein A. J Immunol 2000;164:5313-5318.
38. Feige MJ, Nath S, Catharino SR, Weinfurtner D, Steinbacher S, Buchner J. Structure of the murine unglycosylated IgG1 Fc fragment. J Mol Biol 2009;391:599-608.
39. Sazinsky SL, Ott RG, Silver NW, Tidor B, Ravetch JV, Wittrup KD. Aglycosylated immunoglobulin G1 variants productively engage activating Fc receptors. Proc Natl Acad Sci USA 2008;105:20167-20172.
40. Lund J, Takahashi N, Pound JD, Goodall M, Jefferis R. Multiple interactions of IgG with its core oligosaccharide can modulate recognition by complement and human Fc gamma receptor I and influence the synthesis of its oligosaccharide chains. J Immunol 1996;157:4963-4969.
41. Jefferis R, Lund J, Pound J. Molecular definition of interaction sites on human IgG for Fc receptors (huFc gamma R). Mol Immunol 1990;27:1237-1240.
42. Shields RL, et al. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 2001;276:6591-6604.
43. Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol 2001;19:275-290.
44. Anthony RM, Wermeling F, Ravetch JV. Novel roles for the IgG Fc glycan. Ann N Y Acad Sci 2012;1253:170-180.
45. Gornik I, Maravic G, Dumic J, Flogel M, Lauc G. Fucosylation of IgG heavy chains is increased in rheumatoid arthritis. Clin Biochem 1999;32:605-608.
46. Duncan AR, Winter G. The binding site for C1q on IgG. Nature 1988;332:738-740.
47. Gaboriaud C, et al. The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties. J Biol Chem 2003;278:46974-46982.
48. Diebolder CA, et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 2014;343:1260-1263.
49. Ghetie V, Ward ES. Multiple roles for the major histocompatibility complex class I- related receptor FcRn. Annu Rev Immunol 2000;18:739-766.
50. Martin WL, West AP Jr, Gan L, Bjorkman PJ. Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell 2001;7:867-877.
51. Mallery DL, McEwan WA, Bidgood SR, Towers GJ, Johnson CM, James LC. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc Natl Acad Sci USA 2010;107:19985-19990.
52. Randow F, MacMicking JD, James LC. Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 2013;340:701-706.
53. Wozniak-Knopp G, et al. Introducing antigen-binding sites in structural loops of immunoglobulin constant domains: Fc fragments with engineered HER2/neu-binding sites and antibody properties. Protein Eng Des Sel 2010;23:289-297.
54. Chernajovsky Y, et al. Herceptin. Therapeutic Antibodies. Berlin, Heidelberg: Springer, 2008:183-219.
55. Kainer M, et al. Correlation between CD16a binding and immuno effector functionality of an antigen specific immunoglobulin Fc fragment (Fcab). Arch Biochem Biophys 2012;526:154-158.
56. Woisetschläger M, et al. In vivo and in vitro activity of an immunoglobulin Fc fragment (Fcab) with engineered Her-2/neu binding sites. Biotechnol J 2014;9:844-851.
57. Jez J, et al. Significant impact of single N-glycan residues on the biological activity of Fc-based antibody-like fragments. J Biol Chem 2012;287:24313-24319.
58. Leung KM, et al. A HER2-specific modified Fc fragment (Fcab) induces antitumor effects through degradation of HER2 and apoptosis. Mol Ther 2015; in press.
59. Chaparro-Riggers J, et al. Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. J Biol Chem 2012;287:11090-11097.
60. Igawa T, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol 2010;28:1203-1207.
61. Traxlmayr MW, et al. Construction of pH-sensitive Her2-binding IgG1-Fc by directed evolution. Biotechnol J 2014;9:1013-1022.
62. Bonvin P, et al. De novo isolation of antibodies with pH-dependent binding properties. MAbs 2015;7:294-302.
63. Lazar GA, et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 2006;103:4005-4010.
64. Heiss MM, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int J Cancer 2010;127:2209-2221.
65. Kienast Y, et al. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res 2013;19:6730-6740.
66. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today 2015;20:838-847.
67. Lewis SM, et al. Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat Biotechnol 2014;32:191-198.
68. Weidle UH, Kontermann RE, Brinkmann U. Tumor-antigen-binding bispecific antibodies for cancer treatment. Semin Oncol 2014;41:653-660.
69. Schaefer W, et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci USA 2011;108:11187-11192.
70. Ridgway JB, Presta LG, Carter P. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng 1996;9:617-621.
71. Atwell S, Ridgway JB, Wells JA, Carter P. Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J Mol Biol 1997;270:26-35.
72. Merchant AM, et al. An efficient route to human bispecific IgG. Nat Biotechnol 1998;16:677-681.
73. Davis JH, et al. SEEDbodies: fusion proteins based on strand-exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies. Protein Eng Des Sel 2010;23:195-202.
74. Gunasekaran K, et al. Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG. J Biol Chem 2010;285:19637-19646.
75. Strop P, et al. Generating bispecific human IgG1 and IgG2 antibodies from any antibody pair. J Mol Biol 2012;420:204-219.
76. Moore GL, et al. A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens. MAbs 2011;3:546-557.
77. Von Kreudenstein TS, et al. Improving biophysical properties of a bispecific antibody scaffold to aid developability: quality by molecular design. MAbs 2013;5:646-654.
78. Choi HJ, Kim YJ, Lee S, Kim YS. A heterodimeric Fc-based bispecific antibody simultaneously targeting VEGFR-2 and Met exhibits potent antitumor activity. Mol Cancer Ther 2013;12:2748-2759.
79. Choi HJ, Seok SH, Kim YJ, Seo MD, Kim YS. Crystal structures of immunoglobulin Fc heterodimers reveal the molecular basis for heterodimer formation. Mol Immunol 2015;65:377-383.
80. Traxlmayr MW, Wozniak-Knopp G, Antes B, Stadlmayr G, Ruker F, Obinger C. Integrin binding human antibody constant domains-probing the C-terminal structural loops for grafting the RGD motif. J Biotechnol 2011;155:193-202.
81. Willuda J, et al. High thermal stability is essential for tumor targeting of antibody fragments: engineering of a humanized anti-epithelial glycoprotein-2 (epithelial cell adhesion molecule) single-chain Fv fragment. Cancer Res 1999;59:5758-5767.
82. Shi L, et al. De novo selection of high-affinity antibodies from synthetic fab libraries displayed on phage as pIX fusion proteins. J Mol Biol 2010;397:385-396.
83. Kehoe JW, et al. Isolation and optimization for affinity and biophysical characteristics of anti-CCL17 antibodies from the VH1-69 germline gene. Protein Eng Des Sel 2014;27:199-206.
84. Buchanan A, et al. Engineering a therapeutic IgG molecule to address cysteinylation, aggregation and enhance thermal stability and expression. MAbs 2013;5:255-262.
85. Traxlmayr MW, et al. Directed evolution of stabilized IgG1-Fc scaffolds by application of strong heat shock to libraries displayed on yeast. Biochim Biophys Acta 2012;1824:542-549.
86. Traxlmayr MW, et al. Construction of a stability landscape of the CH3 domain of human IgG1 by combining directed evolution with high throughput sequencing. J Mol Biol 2012;423:397-412.
87. Traxlmayr MW, et al. Directed evolution of Her2/neu-binding IgG1-Fc for improved stability and resistance to aggregation by using yeast surface display. Protein Eng Des Sel 2013;26:255-265.
88. Schaefer JV, Pluckthun A. Engineering aggregation resistance in IgG by two independent mechanisms: lessons from comparison of Pichia pastoris and mammalian cell expression. J Mol Biol 2012;417:309-335.
89. Wozniak-Knopp G, Stadlmann J, Ruker F. Stabilisation of the Fc fragment of human IgG1 by engineered intradomain disulfide bonds. PLoS ONE 2012;7:e30083.
90. Wozniak-Knopp G, Ruker F. A C-terminal interdomain disulfide bond significantly stabilizes the Fc fragment of IgG. Arch Biochem Biophys 2012;526:181-187.
91. Gong R, et al. Engineered human antibody constant domains with increased stability. J Biol Chem 2009;284:14203-14210.
92. Bloom JD, Labthavikul ST, Otey CR, Arnold FH. Protein stability promotes evolvability. Proc Natl Acad Sci USA 2006;103:5869-5874.
93. Ponsel D, Neugebauer J, Ladetzki-Baehs K, Tissot K. High affinity, developability and functional size: the holy grail of combinatorial antibody library generation. Molecules 2011;16:3675-3700.
94. Hasenhindl C, et al. Stability assessment on a library scale: a rapid method for the evaluation of the commutability and insertion of residues in C-terminal loops of the CH3 domains of IgG1-Fc. Protein Eng Des Sel 2013;26:675-682.
95. Koide A, Jordan MR, Horner SR, Batori V, Koide S. Stabilization of a fibronectin type III domain by the removal of unfavorable electrostatic interactions on the protein surface. Biochemistry 2001;40:10326-10333.
96. Xu L, et al. Directed evolution of high-affinity antibody mimics using mRNA display. Chem Biol 2002;9:933-942.
97. Parker MH, et al. Antibody mimics based on human fibronectin type three domain engineered for thermostability and high-affinity binding to vascular endothelial growth factor receptor two. Protein Eng Des Sel 2005;18:435-444.
98. Lipovsek D, et al. Evolution of an interloop disulfide bond in high-affinity antibody mimics based on fibronectin type III domain and selected by yeast surface display: molecular convergence with single-domain camelid and shark antibodies. J Mol Biol 2007;368:1024-1041.
99. Gong R, Wang Y, Feng Y, Zhao Q, Dimitrov DS. Shortened engineered human antibody CH2 domains: increased stability and binding to the human neonatal Fc receptor. J Biol Chem 2011;286:27288-27293.
100. Gong R, et al. N-terminal truncation of an isolated human IgG1 CH2 domain significantly increases its stability and aggregation resistance. Mol Pharm 2013;10:2642-2652.
101. Gong R, Wang Y, Ying T, Dimitrov DS. Bispecific engineered antibody domains (nanoantibodies) that interact noncompetitively with an HIV-1 neutralizing epitope and FcRn. PLoS ONE 2012;7:e42288.
102. North B, Lehmann A, Dunbrack RL Jr. A new clustering of antibody CDR loop conformations. J Mol Biol 2011;406:228-256.
103. Desiderio SV, et al. Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature 1984;311:752-755.
104. Furukawa K, Shirai H, Azuma T, Nakamura H. A role of the third complementarity-determining region in the affinity maturation of an antibody. J Biol Chem 2001;276:27622-27628.
105. Hasenhindl C, et al. Creating stable stem regions for loop elongation in Fcabs - insights from combining yeast surface display, in silico loop reconstruction and molecular dynamics simulations. Biochim Biophys Acta 2014;1844:1530-1540.
106. Batori V, Koide A, Koide S. Exploring the potential of the monobody scaffold: effects of loop elongation on the stability of a fibronectin type III domain. Protein Eng 2002;15:1015-1020.
107. Hackel BJ, Kapila A, Wittrup KD. Picomolar affinity fibronectin domains engineered utilizing loop length diversity, recursive mutagenesis, and loop shuffling. J Mol Biol 2008;381:1238-1252.
108. Lloyd C, et al. Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens. Protein Eng Des Sel 2009;22:159-168.
109. Vaughan TJ, et al. Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nat Biotechnol 1996;14:309-314.
110. Knappik A, et al. Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. J Mol Biol 2000;296:57-86.
111. Prassler J, et al. HuCAL PLATINUM, a synthetic Fab library optimized for sequence diversity and superior performance in mammalian expression systems. J Mol Biol 2011;413:261-278.
112. Zemlin M, et al. Expressed murine and human CDR-H3 intervals of equal length exhibit distinct repertoires that differ in their amino acid composition and predicted range of structures. J Mol Biol 2003;334:733-749.
113. Fellouse FA, Barthelemy PA, Kelley RF, Sidhu SS. Tyrosine plays a dominant functional role in the paratope of a synthetic antibody derived from a four amino acid code. J Mol Biol 2006;357:100-114.
114. Fellouse FA, Li B, Compaan DM, Peden AA, Hymowitz SG, Sidhu SS. Molecular recognition by a binary code. J Mol Biol 2005;348:1153-1162.
115. Fellouse FA, Wiesmann C, Sidhu SS. Synthetic antibodies from a four-amino-acid code: a dominant role for tyrosine in antigen recognition. Proc Natl Acad Sci USA 2004;101:12467-12472.
116. Fellouse FA, et al. High-throughput generation of synthetic antibodies from highly functional minimalist phage-displayed libraries. J Mol Biol 2007;373:924-940.
117. Hackel BJ, Ackerman ME, Howland SW, Wittrup KD. Stability and CDR composition biases enrich binder functionality landscapes. J Mol Biol 2010;401:84-96.
118. Hackel BJ, Wittrup KD. The full amino acid repertoire is superior to serine/tyrosine for selection of high affinity immunoglobulin G binders from the fibronectin scaffold. Protein Eng Des Sel 2010;23:211-219.
119. Kiyoshi M, et al. Structural basis for binding of human IgG1 to its high-affinity human receptor FcγRI. Nat Commun 2015;6:6866.
120. James LC, Keeble AH, Khan Z, Rhodes DA, Trowsdale J. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc Natl Acad Sci USA 2007;104:6200-6205.
121. Schneider S, Zacharias M. Atomic resolution model of the antibody Fc interaction with the complement C1q component. Mol Immunol 2012;51:66-72.
122. Saphire EO, et al. Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design. Science 2001;293:1155-1159.