Selection of IgG variants with increased FcRn binding using random and directed mutagenesis: Impact on effector functions

Frontiers in Immunology

Volumn 6, Issue FEB, 2015, Pages

  Monnet, Céline ^a   Jorieux, Sylvie ^a   Urbain, Rémi ^b   Fournier, Nathalie ^a   Bouayadi, Khalil ^c   De Romeuf, Christophe ^a   Behrens, Christian K ^b   Fontayne, Alexandre ^a   Mondon, Philippe ^a  

^a LFB Biotechnologies Research Department   (France)

^b LFB Biotechnologies   (France)

^c MilleGen   (France)

Author keywords

Complement C1q; Directed mutagenesis; Fc engineering; Fc gamma receptors; FcRn; IgG; Random mutagenesis; Therapeutic mAbs

Indexed keywords

FC RECEPTOR; IMMUNOGLOBULIN G;

ARTICLE; CONTROLLED STUDY; CRYSTALLOGRAPHY; CYTOTOXICITY; ENZYME LINKED IMMUNOSORBENT ASSAY; GENE EXPRESSION SYSTEM; HUMAN; HUMAN CELL; POLYMERASE CHAIN REACTION; SITE DIRECTED MUTAGENESIS; SURFACE PLASMON RESONANCE;

EID: 84926659212     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2015.00039     Document Type: Article

References (79)

1. Reichert JM. Antibodies to watch in 2014: mid-year update. MAbs (2014) 6:799-802. doi: 10.4161/mabs.29282
2. Ward ES, Ober RJ. Chapter 4: multitasking by exploitation of intracellular transport functions the many faces of FcRn. Adv Immunol (2009) 103:77-115. doi:10.1016/S0065-2776(09)03004-1
3. Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, Lencer WI, et al. Neonatal Fc receptor: from immunity to therapeutics. J Clin Immunol (2010) 30:777-89. doi:10.1007/s10875-010-9468-4
4. Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella VJ, et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci U S A (2004) 101:9763-8. doi:10.1073/pnas.0403235101
5. Ye L, Zeng R, Bai Y, Roopenian DC, Zhu X. Efficient mucosal vaccination mediated by the neonatal Fc receptor. Nat Biotechnol (2011) 29:158-63. doi:10.1038/nbt.1742
6. Pridgen EM, Alexis F, Kuo TT, Levy-Nissenbaum E, Karnik R, Blumberg RS, et al. Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci Transl Med (2013) 5:213ra167. doi:10.1126/scitranslmed.3007049
7. Qiao SW, Kobayashi K, Johansen FE, Sollid LM, Andersen JT, Milford E, et al. Dependence of antibody-mediated presentation of antigen on FcRn. Proc Natl Acad Sci U S A (2008) 105:9337-42. doi:10.1073/pnas.0801717105
8. Baker K, Qiao SW, Kuo TT, Aveson VG, Platzer B, Andersen JT, et al. Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cells. Proc Natl Acad Sci U S A (2011) 108:9927-32. doi:10.1073/pnas.1019037108
9. Hoffmann E, Kotsias F, Visentin G, Bruhns P, Savina A, Amigorena S. Autonomous phagosomal degradation and antigen presentation in dendritic cells. Proc Natl Acad Sci U S A (2012) 109:14556-61. doi:10.1073/pnas.1203912109
10. Vidarsson G, Stemerding AM, Stapleton NM, Spliethoff SE, Janssen H, Rebers FE, et al. FcRn: an IgG receptor on phagocytes with a novel role in phagocytosis. Blood (2006) 108:3573-9. doi:10.1182/blood-2006-05-024539
11. Rath T, Baker K, Dumont JA, Peters RT, Jiang H, Qiao SW, 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
12. Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. MAbs (2011) 3:422-30. doi:10.4161/mabs.3.5.16983
13. Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, 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) 276:6591-604. doi:10.1074/jbc.M009483200
14. 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) 7:867-77. doi:10.1016/S1097-2765(01)00230-1
15. Dall'acqua WF, Woods RM, Ward ES, Palaszynski SR, Patel NK, Brewah YA, et al. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J Immunol (2002) 169:5171-80. doi:10.4049/jimmunol.169.9.5171
16. Hinton PR, Johlfs MG, Xiong JM, Hanestad K, Ong KC, Bullock C, et al. Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem (2004) 279:6213-6. doi:10.1074/jbc.C300470200
17. Hinton PR, Xiong JM, Johlfs MG, Tang MT, Keller S, Tsurushita N. An engineered human IgG1 antibody with longer serum half-life. J Immunol (2006) 176:346-56. doi:10.4049/jimmunol.176.1.346
18. Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IW, Sproule TJ, et al. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol (2010) 28:157-9. doi:10.1038/nbt.1601
19. Dall'acqua WF, Cook KE, Damschroder MM, Woods RM, Wu H. Modulation of the effector functions of a human IgG1 through engineering of its hinge region. J Immunol (2006) 177:1129-38. doi:10.4049/jimmunol.177.2.1129
20. Petkova SB, Akilesh S, Sproule TJ, Christianson GJ, Al KH, Brown AC, et al. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol (2006) 18:1759-69. doi:10.1093/intimm/dxl110
21. Yeung YA, Leabman MK, Marvin JS, Qiu J, Adams CW, Lien S, et al. Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol (2009) 182:7663-71. doi:10.4049/jimmunol.0804182
22. Yeung YA, Wu X, Reyes AE, Vernes JM, Lien S, Lowe J, et al. A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life. Cancer Res (2010) 70:3269-77. doi:10.1158/0008-5472.CAN-09-4580
23. Finch DK, Sleeman MA, Moisan J, Ferraro F, Botterell S, Campbell J, et al. Whole-molecule antibody engineering: generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics. J Mol Biol (2011) 411:791-807. doi:10.1016/j.jmb.2011.06.031
24. Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi Y, Shimaoka S, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol (2010) 28:1203-7. doi:10.1038/nbt.1691
25. Bernett MJ, Chu SY, Leung I, Moore GL, Lee SH, Pong E, 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(3):384-96. doi:10.4161/mabs.23976
26. Robbie GJ, Criste R, Dall'acqua WF, Jensen K, Patel NK, Losonsky GA, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother (2013) 57:6147-53. doi:10.1128/AAC.01285-13
27. Albanesi M, Daeron M. The interactions of therapeutic antibodies with Fc receptors. Immunol Lett (2012) 143:20-7. doi:10.1016/j.imlet.2012.02.005
28. Gillis C, Gouel-Cheron A, Jonsson F, Bruhns P. Contribution of human FcgammaRs to disease with evidence from human polymorphisms and transgenic animal studies. Front Immunol (2014) 5:254. doi:10.3389/fimmu.2014.00254
29. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood (2002) 99:754-8. doi:10.1182/blood.V99.3.754
30. Cooper N, Stasi R, Cunningham-Rundles S, Cesarman E, McFarland JG, Bussel JB. Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia. Br J Haematol (2012) 158:539-47. doi:10.1111/j.1365-2141.2012.09184.x
31. Ruyssen-Witrand A, Rouanet S, Combe B, Dougados M, Le Loët X, Sibilia J, et al. Fcgamma receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis (2012) 71:875-7. doi:10.1136/annrheumdis-2011-200337
32. Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol (2008) 26:1789-96. doi:10.1200/JCO.2007.14.8957
33. Bibeau F, Lopez-Crapez E, Di FF, Thezenas S, Ychou M, Blanchard F, et al. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol (2009) 27:1122-9. doi:10.1200/JCO.2008.18.0463
34. Moroi R, Endo K, Kinouchi Y, Shiga H, Kakuta Y, Kuroha M, et al. FCGR3A-158 polymorphism influences the biological response to infliximab in Crohn's disease through affecting the ADCC activity. Immunogenetics (2013) 65:265-71. doi:10.1007/s00251-013-0679-8
35. Strohl WR. Optimization of Fc-mediated effector functions of monoclonal antibodies. Curr Opin Biotechnol (2009) 20:685-91. doi:10.1016/j.copbio.2009.10.011
36. Lu Y, Vernes JM, Chiang N, Ou Q, Ding J, Adams C, et al. Identification of IgG(1) variants with increased affinity to FcgammaRIIIa and unaltered affinity to FcgammaRI and FcRn: comparison of soluble receptor-based and cell-based binding assays. J Immunol Methods (2011) 365:132-41. doi:10.1016/j.jim.2010.12.014
37. Stavenhagen JB, Gorlatov S, Tuaillon N, Rankin CT, Li H, Burke S, et al. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcgamma receptors. Cancer Res (2007) 67:8882-90. doi:10.1158/0008-5472.CAN-07-0696
38. Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A (2006) 103:4005-10. doi:10.1073/pnas.0508123103
39. Shields RL, Lai J, Keck R, O'Connell LY, Hong K, Meng YG, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem (2002) 277:26733-40. doi:10.1074/jbc.M202069200
40. Beck A, Reichert JM. Marketing approval of mogamulizumab: a triumph for glyco-engineering. MAbs (2012) 4:419-25. doi:10.4161/mabs.20996
41. Monnet C, Jorieux S, Souyris N, Zaki O, Jacquet A, Fournier N, et al. Combined glyco-and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody. MAbs (2014) 6:422-36. doi:10.4161/mabs.27854
42. Popov S, Hubbard JG, Kim J, Ober B, Ghetie V, Ward ES. The stoichiometry and affinity of the interaction of murine Fc fragments with the MHC class I-related receptor, FcRn. Mol Immunol (1996) 33:521-30. doi:10.1016/0161-5890(96)00004-1
43. Kabat EA, Wu TT. Identical V region amino acid sequences and segments of sequences in antibodies of different specificities. Relative contributions of VH and VL genes, minigenes, and complementarity-determining regions to binding of antibody-combining sites. J Immunol (1991) 147:1709-19.
44. Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science (1985) 228:1315-7. doi:10.1126/science.4001944
45. Behrens CK, Jorieux S, Kharrat A, Bouayadi K, Mondon P, Monnet-Mars C. Optimized Fc Variants. WO/2010/106180 (2010).
46. Fontayne A, Jorieux S, Monnet-Mars C, Mondon P, Kharrat A, Bouayadi K. Fc Variants with Reduced Effector Functions. WO2012175751 (2012).
47. Idusogie EE, Wong PY, Presta LG, Gazzano-Santoro H, Totpal K, Ultsch M, et al. Engineered antibodies with increased activity to recruit complement. J Immunol (2001) 166:2571-5. doi:10.4049/jimmunol.166.4.2571
48. Richards JO, Karki S, Lazar GA, Chen H, Dang W, Desjarlais JR. Optimization of antibody binding to FcgammaRIIa enhances macrophage phagocytosis of tumor cells. Mol Cancer Ther (2008) 7:2517-27. doi:10.1158/1535-7163.MCT-08-0201
49. Chu SY, Vostiar I, Karki S, Moore GL, Lazar GA, Pong E, et al. Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies. Mol Immunol (2008) 45:3926-33. doi:10.1016/j.molimm.2008.06.027
50. Polyak MJ, Deans JP. Alanine-170 and proline-172 are critical determinants for extracellular CD20 epitopes; heterogeneity in the fine specificity of CD20 monoclonal antibodies is defined by additional requirements imposed by both amino acid sequence and quaternary structure. Blood (2002) 99:3256-62. doi:10.1182/blood.V99.9.3256
51. Mondon P, Souyris N, Douchy L, Crozet F, Bouayadi K, Kharrat H. Method for generation of human hyperdiversified antibody fragment library. Biotechnol J (2007) 2:76-82. doi:10.1002/biot.200600205
52. Clark MR. IgG effector mechanisms. Chem Immunol (1997) 65:88-110. doi:10.1159/000319350
53. Kim JK, Firan M, Radu CG, Kim CH, Ghetie V, Ward ES. Mapping the site on human IgG for binding of the MHC class I-related receptor, FcRn. Eur J Immunol (1999) 29:2819-25. doi:10.1002/(SICI)1521-4141(199909)29:09<2819::AID-IMMU2819>3.0.CO;2-6
54. de Romeuf C, Dutertre CA, Le Garff-Tavernier M, Fournier N, Gaucher C, Glacet A, et al. Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16. Br J Haematol (2008) 140:635-43. doi:10.1111/j.1365-2141.2007.06974.x
55. Le Garff-Tavernier M, Decocq J, de Romeuf C, Parizot C, Dutertre CA, Chapiro E, et al. Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies. Leukemia (2011) 25:101-9. doi:10.1038/leu.2010.240
56. Abdelwahed RB, Donnou S, Ouakrim H, Crozet L, Cosette J, Jacquet A, et al. Preclinical study of ublituximab, a glycoengineered anti-human CD20 antibody, in murine models of primary cerebral and intraocular B-cell lymphomas. Invest Ophthalmol Vis Sci (2013) 54:3657-65. doi:10.1167/iovs.12-10316
57. Siberil S, de Romeuf C, Bihoreau N, Fernandez N, Meterreau JL, Regenman A, et al. Selection of a human anti-RhD monoclonal antibody for therapeutic use: impact of IgG glycosylation on activating and inhibitory Fc gamma R functions. Clin Immunol (2006) 118:170-9. doi:10.1016/j.clim.2005.10.008
58. Beliard R, Waegemans T, Notelet D, Massad L, Dhainaut F, Romeuf C, et al. A human anti-D monoclonal antibody selected for enhanced FcgammaRIII engagement clears RhD+ autologous red cells in human volunteers as efficiently as polyclonal anti-D antibodies. Br J Haematol (2008) 141:109-19. doi:10.1111/j.1365-2141.2008.06985.x
59. Martin WL, Bjorkman PJ. Characterization of the 2:1 complex between the class I MHC-related Fc receptor and its Fc ligand in solution. Biochemistry (1999) 38:12639-47. doi:10.1021/bi9913505
60. Dall'acqua WF, Kiener PA, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem (2006) 281:23514-24. doi:10.1074/jbc.M604292200
61. Oganesyan V, Damschroder MM, Woods RM, Cook KE, Wu H, Dall'acqua WF. Structural characterization of a human Fc fragment engineered for extended serum half-life. Mol Immunol (2009) 46:1750-5. doi:10.1016/j.molimm.2009.01.026
62. Oganesyan V, Damschroder MM, Cook KE, Li Q, Gao C, Wu H, et al. Structural insights into neonatal Fc receptor-based recycling mechanisms. J Biol Chem (2014) 289(11):7812-24. doi:10.1074/jbc.M113.537563
63. Vaccaro C, Zhou J, Ober RJ, Ward ES. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol (2005) 23:1283-8. doi:10.1038/nbt1143
64. Igawa T, Maeda A, Haraya K, Tachibana T, Iwayanagi Y, Mimoto F, et al. Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PLoS One (2013) 8:e63236. doi:10.1371/journal.pone.0063236
65. Tam SH, McCarthy SG, Brosnan K, Goldberg KM, Scallon BJ. Correlations between pharmacokinetics of IgG antibodies in primates vs. FcRn-transgenic mice reveal a rodent model with predictive capabilities. MAbs (2013) 5(3):397-405. doi:10.4161/mabs.23836
66. Proetzel G, Roopenian DC. Humanized FcRn mouse models for evaluating pharmacokinetics of human IgG antibodies. Methods (2014) 65(1):148-53. doi:10.1016/j.ymeth.2013.07.005
67. Ober RJ, Radu CG, Ghetie V, Ward ES. Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. Int Immunol (2001) 13:1551-9. doi:10.1093/intimm/13.12.1551
68. Vaccaro C, Bawdon R, Wanjie S, Ober RJ, Ward ES. Divergent activities of an engineered antibody in murine and human systems have implications for therapeutic antibodies. Proc Natl Acad Sci U S A (2006) 103:18709-14. doi:10.1073/pnas.0606304103
69. Deng R, Loyet KM, Lien S, Iyer S, DeForge LE, Theil FP, et al. Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-{alpha} antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab Dispos (2010) 38:600-5. doi:10.1124/dmd.109.031310
70. Andersen JT, Daba MB, Berntzen G, Michaelsen TE, Sandlie I. Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding. J Biol Chem (2010) 285:4826-36. doi:10.1074/jbc.M109.081828
71. Hessell AJ, Hangartner L, Hunter M, Havenith CE, Beurskens FJ, Bakker JM, et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature (2007) 449:101-4. doi:10.1038/nature06106
72. Hiatt A, Bohorova N, Bohorov O, Goodman C, Kim D, Pauly MH, et al. Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy. Proc Natl Acad Sci U S A (2014) 111:5992-7. doi:10.1073/pnas.1402458111
73. Zeitlin L, Pettitt J, Scully C, Bohorova N, Kim D, Pauly M, et al. Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant. Proc Natl Acad Sci U S A (2011) 108:20690-4. doi:10.1073/pnas.1108360108
74. Moore GL, Chen H, Karki S, Lazar GA. Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions. MAbs (2010) 2:181-9. doi:10.4161/mabs.2.2.11158
75. Horton HM, Bernett MJ, Pong E, Peipp M, Karki S, Chu SY, et al. Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res (2008) 68:8049-57. doi:10.1158/0008-5472.CAN-08-2268
76. Loo D, Alderson RF, Chen FZ, Huang L, Zhang W, Gorlatov S, et al. Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Clin Cancer Res (2012) 18:3834-45. doi:10.1158/1078-0432.CCR-12-0715
77. Labrijn AF, Aalberse RC, Schuurman J. When binding is enough: nonactivating antibody formats. Curr Opin Immunol (2008) 20:479-85. doi:10.1016/j.coi.2008.05.010
78. Reichert JM. Antibodies to watch in 2014. MAbs (2013) 6(1):5-14. doi:10.4161/mabs.27333
79. Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol (2010) 10:301-16. doi:10.1038/nri2761