Optimization of Fc-mediated effector functions of monoclonal antibodies

Current Opinion in Biotechnology

Volumn 20, Issue 6, 2009, Pages 685-691

  Strohl, William R ^a  

^a CENTOCOR INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID SEQUENCE; FUSION PROTEINS; GLYCOFORMS; PHARMACOLOGICAL ACTIVITY; RESEARCH AND DEVELOPMENT;

AMINES; AMINO ACIDS; MONOCLONAL ANTIBODIES; ORGANIC ACIDS; SURFACE PLASMON RESONANCE;

PROTEINS;

ABATACEPT; ADALIMUMAB; ALEMTUZUMAB; BEVACIZUMAB; CATUMAXOMAB; CD19 ANTIBODY; CD20 ANTIBODY; CETUXIMAB; CLENOLIXIMAB; ECULIZUMAB; EPITOPE; ETANERCEPT; FC RECEPTOR; IMMUNOGLOBULIN FC FRAGMENT; IMMUNOGLOBULIN HEAVY CHAIN; INFLIXIMAB; MONOCLONAL ANTIBODY; OKT 3; OTELIXIZUMAB; RITUXIMAB; ROMIPLOSTIM; TOLERX; TRASTUZUMAB; UNCLASSIFIED DRUG; VISILIZUMAB;

AMINO ACID SEQUENCE; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; BINDING AFFINITY; COMPLEMENT DEPENDENT CYTOTOXICITY; DRUG DISTRIBUTION; DRUG MECHANISM; DRUG RESEARCH; DRUG SAFETY; DRUG TARGETING; HUMAN; IMMUNE RESPONSE; INSULIN DEPENDENT DIABETES MELLITUS; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN ENGINEERING; PROTEIN MODIFICATION; RECEPTOR BINDING; REVIEW;

AMINO ACID SEQUENCE; ANIMALS; ANTIBODIES, MONOCLONAL; BIOPHARMACEUTICS; BIOTECHNOLOGY; DRUG DESIGN; GENE SILENCING; GLYCOPROTEINS; HUMANS; IMMUNOGLOBULIN G; MOLECULAR SEQUENCE DATA; PROTEIN ENGINEERING; PROTEIN ISOFORMS; PROTEIN STRUCTURE, TERTIARY; RECOMBINANT FUSION PROTEINS;

EID: 70449727004     PISSN: 09581669     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.copbio.2009.10.011     Document Type: Review

References (61)

1. Carter P.J. Potent antibody therapeutics by design. Nat Rev Immunol 6 (2006) 343-357
2. Presta L.G. Molecular engineering and design of therapeutic antibodies. Curr Opin Immunol 20 (2008) 460-470
3. Strohl W.R. Therapeutic monoclonal antibodies-past, present, and future. In: An Z. (Ed). Therapeutic Monoclonal Antibodies: From Bench to Clinic (2009), John Wiley & Sons, New York 4-50
4. Jefferis R. Antibody therapeutics: isotype and glycoform selection. Expert Opin Ther 7 (2007) 1401-1413
5. Bruhns P., Iannascoli B., England P., Mancardi D.A., Fernandez N., Jorieux S., and Daeron M. Specificity and affinity of human Fcγ receptors and their polymorphic variants for human IgG subclasses. Blood 113 (2009) 3716-3725. The binding kinetics of all human IgG isotypes to all of the various polymorphs of the human Fcγ receptors is determined, compared, and described in comprehensive detail.
6. Shields R.L., Namenuk A.K., Hog K., Meng Y.G., Rae J., Briggs J., Xie D., Lai J., Stadlen A., Li B., 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 276 (2001) 6591-6604
7. Lazar G.A., Dang W., Karki S., Vafa O., Peng J.S., Hyun L., Chan C., Chung H.S., Eivazi A., Yoder S.C., et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 103 (2006) 4005-4010. Based on a comprehensive set of data analyzing Fc mutations for enhanced effector functions, a pair of mutations that provide the best effector function activity, as well as a third that strongly reduces complement-mediated activity, are described.
8. Stavenhagen J.B., Gorlatov S., Tuaillon N., Rankin C.T., Li H., Burke S., Huang L., Johnson S., Bonvini E., and Koenig S. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fcγ receptors. Cancer Res 67 (2007) 8882-8890
9. Richards J.O., Karki S., Lazar G.A., Chen H., Dang W., and Desjarlais J.R. Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells. Mol Cancer Ther 7 (2008) 2517-2527
10. Idusogie E.E., Wong P.Y., Presta L.G., Gazzano-Santoro H., Totpal K., Ultsch M., and Mulkerrin M.G. Engineered antibodies with increased activity to recruit complement. J Immunol 166 (2001) 2571-2575
11. Hayden-Ledbetter M.S., Cerveny C.G., Espling W., Brady W.A., Grosmaire L.S., Tan P., Bader R., Slater S., Nilsson C.A., Barone D.S., et al. CD20-directed small modular immunopharmaceutical TRU-015, depletes normal and malignant B cells. Clin Cancer Res 15 (2009) 2739-2746. The in vitro activity of the small modular immunopharmaceutical (SMIP) furthest advanced in clinical trials, TRU-015, is described in detail. Also noted is the mutation reducing complement-mediated cytotoxicity intended to reduce injection site reactions.
12. Horton H.M., Bernett M.J., Pong E., Piepp M., Karki S., Chu S.Y., Richards J.O., Vostiar I., Joyce P.F., Repp R., et al. Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res 68 (2008) 8049-8057
13. Zalevsky J., Leung I.W.L., Karki S., Chu S.Y., Zhukovsky E.A., Desjarlais J.R., Carmichael D.F., and Lawrence C.E. The impact of Fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates. Blood 113 (2009) 3735-3743
14. Bruckheimer E.M., Fazenbaker C.A., Gallagher S., Mulgrew K., Furmann S., Coffman K.T., Walsh W., Ready S., Cook K., Damschroder M., et al. Antibody-dependent cell-mediated cytotoxicity effector-enhanced EphA2 agonist monoclonal antibody demonstrates potent activity against human tumors. Neoplasia 11 (2009) 509-517
15. Allan B, Jiang W, Tang Y, Watkins JD: Variant Fc regions. WO 2006/020114. Publ. 2/23/2006.
16. Watkins JD, Allan B: Fc region variants. WO 2004/074455 A2. Publ 9/2/2004.
17. Natsume A., In M., Takamura H., Nakagawa T., Shimizu Y., Kitajima K., Wakitani M., Ohta S., Satoh M., Shitara K., et al. Engineered antibodies of IgG1/IgG3 mixed isotype with enhanced cytotoxic activities. Cancer Res 68 (2008) 3863-3872
18. Sazinsky S.L., Ott R.G., Silver N.W., Tidor B., Ravetch J.V., and Wittrup K.D. Aglycosylated immunoglobulin G1 variants productively engage activating Fc receptors. Proc Natl Acad Sci USA 105 (2008) 20167-20172. The generation, characterization, and activity of novel aglycosyl-IgGs that retain effector function are described in detail, including Fc mutants that provide higher than wild-type effector activity.
19. Oganesyan V., Damschroder M.M., Leach W., Wu H., and Dall'Acqua W.F. Structural characterization of a mutated ADCC-enhanced human Fc fragment. Mol Immunol 45 (2008) 1872-1882
20. Raju T.S. Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr Opin Immunol 20 (2008) 471-476
21. Shields R.L., Lai J., Keck R., O'Connell L.Y., Hong K., Meng Y.G., Weikert S.H., and Presta L.G. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma Rlll and antibody-dependent cellular toxicity. J Biol Chem 277 (2002) 26733-26740
22. Niwa R., Hatanaka S., Shoji-Hosaka E., Sakurada M., Kobayashi Y., Uehara A., Yodoi H., Nakamura K., and Shitara K. Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 is independent of FcgammaRllla functional polymorphism. Clin Cancer Res 10 (2004) 6248-6255
23. Masuda K., Kubota T., Kaneko E., Iida S., Wakitani M., Kobayashi-Natsume Y., Kubota A., Shitara K., and Nakamura K. Enhanced binding affinity for FcgammaRIIIa of fucose-negative antibody is sufficient to induce maximal antibody-dependent cellular cytotoxicity. Mol Immunol 44 (2007) 3122-3131
24. Scallon B.J., McCarthy S., Radewonuk J., Cai A., Naso M., Raju T.S., and Capocasale R. Quantitative in vivo comparisons of the Fcγ receptor-dependent agonist activities of different fucosylation variants of an immunoglobulin G antibody. Int Immunopharmacol 7 (2007) 761-772
25. Iida S., Kuni-Kamochi R., Mori K., Misaka H., Inoue M., Okazaki A., Shitara K., and Satoh M. Two mechanisms of enhanced antibody-dependent cellular cytotoxicity (ADCC) efficacy of non-fucosylated therapeutic antibodies in human blood. BMC Cancer 9 (2009) 58
26. Shibata-Koyama M., Iida S., Misaka H., Mori K., Yano K., Shitara K., and Satoh M. Nonfucosylated rituximab potentiates human neutrophil phagocytosis through its high binding for FcγRIIIb and MHC class II expression on the phagocytotic neutrophils. Exp Hematol 37 (2009) 309-321
27. Rother R.P., Rollins S.A., Mojcik C.J., Brodsky R.A., and Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25 (2007) 1256-1264
28. Davis P.M., Abraham R., Xu L., Nadler S.G., and Suchard S.J. Abatacept binds to the Fc receptor CD64 but does not mediate complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. J Rheumatol 34 (2007) 2204-2210
29. Bolt S., Routledge E., Lloyd I., Chatenoud L., Pope H., Gorman S.D., Clark M., and Waldmann H. The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 23 (1993) 403-411
30. Alegre M.L., Peterson L.J., Xu D., Sattar H.A., Jeyarajah D.R., Kowalkowski K., Thistlewaite J.R., Zivin R.A., Jolliffe L., and Bluestone J.A. A non-activating "humanized" anti-CD3 monoclonal antibody retains innunosuppressive properties in vivo. Transplantation 57 (1994) 1537-1543
31. Xu D., Alegre M.L., Varga S.S., Rothermel A.L., Collins A.M., Pulito V.L., Hanna L.S., Dolan K.P., Parren P.W., Bluestone J.A., et al. In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell Immunol 200 (2000) 16-26
32. Cole M.S., Stellrecht K.E., Shi J.D., Homola M., Hsu D.H., Anasetti C., Vasquez M., and Tso J.Y. HuM291, a humanized anti-CD3 antibody, is immunosuppressive to T cells while exhibiting reduced mitogenicity in vitro. Transplantation 68 (1999) 563-571
33. Hutchins J.T., Kull Jr. F.C., Bynum J., Knick V.C., Thurmond L.M., and Ray P. Improved biodistribution, tumor targeting, and reduced immunogenicity in mice with gamma 4 variant of Campath-1H. Proc Natl Acad Sci USA 92 (1995) 11980-11984
34. Reddy M.P., Kinney C.A.S., Chaikin M.A., Payne A., Fishman-Lobell J., Tsui P., Dal Monte P.R., Doyle M.L., Brigham-Burke M.R., Anderson D., et al. Elimination of Fc receptor-dependent effector functions of a modified IgG4 mAb to human CD4. J Immunol 164 (2000) 1925-1933
35. Mueller JP, Evans MJ, Mueller EE, Rollins S, Rother RP, Matis, LA: Porcine cell interaction proteins. WO 1997/11971. Publ 4/3/1997.
36. Bell L, Rother RP: Treatment of paroxysmal nocturnal hemoglobinuria patients by an inhibitor of complement. WO 2007/106585. Publ. 9/20/2007.
37. Strohl WR: Non-immunostimulatory antibody and compositions containing the same. US 2007/0148167A1. Publ. 6/28/2007.
38. McEarchern J.A., Oflazoglu E., Francisco L., McDonagh C.F., Gordon K.A., Stone I., Klussman K., Turcott E., van Rooijen N., Carter P., et al. Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities. Blood 109 (2007) 1185-1192
39. Kumagai Y., Fujita T., Ozaki M., Sahashi K., Ohkura M., Ohtsu T., Arai Y., Sonehara Y., and Nichol J.L. Pharmacodynamics and pharmacokinetics of AMG 531, a thrombopoiesis-stimulating peptibody, in healthy Japanese subjects: a randomized, placebo-controlled study. J Clin Pharmacol 47 (2007) 1489-1497
40. Chu S.Y., Vostiar I., Kaki S., Moore G.L., Lazar G.A., Pong E., Joyce P.F., Szymkowski D.E., and Desjarlais J.R. Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcγRIIb with Fc-engineered antibodies. Mol Immunol 45 (2008) 3926-3933. Generation and characterization of an Fc mutant antibody that selectively binds FcγRIIb over the activating Fcγ receptors are described. Additionally, the co-engagement of an anti-CD19 antibody possessing that FcγRIIb-selectively binding mutation with CD19 and FcγRIIb on B cells is demonstrated to block B-cell activation.
41. Angal S., King D.J., Bodmer M.W., Turner A., Lawson A.D., Roberts G., Pedley B., and Adair J.R. A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody. Mol Immunol 30 (1993) 105-108
42. Oganesyan V., Gao C., Shirinian L., Wu H., and Dall'Acqua W.F. Structural characterization of a human Fc fragment engineered for lack of effector functions. Acta Crystallogr D64 (2008) 700-704
43. Walker M.R., Lund J., Thompson K.M., and Jefferis R. Aglycosylation of human IgG1 and IgG3 monoclonal antibodies can eliminate recognition by human cells expressing FcγRI and/or FcγRII receptors. Biochem J 259 (1989) 347-353
44. Keymeulen B., Vandemeulebroucke E., Ziegler A.G., Mathieu C., Kaufman L., Hale G., Gorus F., Goldman M., Walter M., Candon S., et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. New Engl J Med 352 (2005) 2598-2608
45. Fiege M.J., Nath S., Catharino S.R., Weinfurtner D., Steinbacher S., and Buchner J. Structure of the murine unglycosylated IgG1 Fc fragment. J Mol Biol 391 (2009) 599-608
46. Clynes R.A., Towers T.L., Presta L.G., and Ravetch J.V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6 (2000) 443-446
47. Kaneko Y., Nimmerjahn F., and Ravetch J.V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313 (2006) 670-673
48. Anthony R.M., Nimmerjahn F., Ashline D.J., Reinhold V.N., Paulson J.C., and Ravetch J.V. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320 (2008) 373-376. Demonstration that terminally sialylated mouse IgG is responsible for immunosuppressive effects of IVIG using a monoclonal antibody proves the important biological function of sialylated antibodies.
49. Nimmerjahn F., and Ravetch J.V. The anti-inflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 204 (2007) 11-15
50. Anthony R.M., Wermeling F., Karlsson M.C.I., and Ravetch J.V. Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 105 (2008) 19571-19578. Elucidation of the target of sialylated IgGs in mice, SIGN-R1, which may help to understand mechanistically how sialylated IgGs may have immunosuppressive effects.
51. Scallon B.J., Tam S.H., McCarthy S.G., Cai A.N., and Raju T.S. Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol 44 (2007) 1524-1534. Demonstration that sialylated IgGs not only have lower affinity to activating FcγRs but also to their target antigen offers additional insight into how sialylation affects the pharmacology of human IgGs.
52. Petkova S.B., Akilesh S., Sproule T.J., Christianson G.J., Al Khabbaz H., Brown A.C., Presta L.G., Meng Y.G., and Roopenian D.C. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 18 (2006) 1759-1769
53. Dall'Acqua W.F., Woods R.M., Ward E.S., Palaszynski S.R., Patel N.K., Brewah Y.A., Wu H., Kiener P.A., and Langermann S. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J Immunol 169 (2002) 5171-5180
54. Dall'Acqua W.F., Kiener P.A., and Wu H. Properties of human IgG1 engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem 281 (2006) 23514-23524. Detailed description and analysis of the 'YTE' mutation that binds FcRn 10-fold better than wild-type in a pH-dependent manner and confers a four-fold increased half-life to an antibody bearing that Fc mutation in non-human primates.
55. Oganesyan V., Damschroder M.M., Woods R.M., Cook K.E., Wu H., and Dall'Acqua W.F. Structural characterization of a human Fc fragment engineered for extended serum half-life. Mol Immunol 46 (2009) 1750-1755
56. Hinton P.R., Xiong J.M., Johlfs M.J., Tang M.T., Keller S., and Tsurushita N. An engineered human IgG1 antibody with longer serum half-life. J Immunol 176 (2006) 346-356
57. Datta-Mannan A., Wichter D.R., Tang Y., Watkins J., Jiang W., and Wroblewski V.J. Humanized IgG1 variants with differential binding properties to the neonatal Fc receptor: relationship to pharmacokinetics in mice and primates. Drug Metab Dispos 35 (2007) 86-94
58. Datta-Mannan A., Wichter D.R., Tang Y., Watkins J., and Wroblewski V.J. Monoclonal antibody clearance. Impact of modulating the interaction of IgG with the neonatal Fc receptor. J Biol Chem 282 (2007) 1709-1717. Detailed description of the kinetics of IgG-Fc and FcRn interaction and demonstration that pH-dependent binding alone may not be enough to confer loger half-life on IgGs. Also showed that the QL mutation previously described by Hinton et al. [56] may not confer half-life to all antibodies
59. Yeung Y.A., Leabman M.K., Marvin J.S., Qiu J., Adams C.W., Lien S., Starovasnik M.A., and Lowman H.B. Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol 182 (2009) 7663-7671
60. Ward ES: Immunoglobulin molecules with improved characteristics. WO 2006/130834. 31 pp.
61. Vaccaro C., Zhou J., Ober R.J., and Ward E.S. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 23 (2005) 1283-1288