A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway

Immunology and Cell Biology

Volumn 93, Issue 4, 2015, Pages 396-405

  Helling, Bianca ^a   König, Martin ^a   Dälken, Benjamin ^a   Engling, Andre ^a   Krömer, Wolfgang ^a   Heim, Katharina ^a   Wallmeier, Holger ^b   Haas, Jürgen ^c   Wildemann, Brigitte ^c   Fritz, Brigitte ^c   Jonuleit, Helmut ^d   Kubach, Jan ^d   Dingermann, Theodor ^e   Radeke, Heinfried H ^f   Osterroth, Frank ^a   Uherek, Christoph ^a   Czeloth, Niklas ^a   Schüttrumpf, Jörg ^a  

^a BIOTEST AG   (Germany)

^b Condor Scientific Computing and Consulting ^*  (Germany)

^c UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^d JOHANNES GUTENBERG UNIVERSITY   (Germany)

^e GOETHE UNIVERSITY   (Germany)

^f UNIVERSITY HOSPITAL FRANKFURT   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; CYCLIC AMP; FOCAL ADHESION KINASE 2; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 2; INTERLEUKIN 5; LAT PROTEIN; LATENCY ASSOCIATED PEPTIDE; MEK PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; OKT 3; OKT 4; PROTEIN; PROTEIN KINASE ZAP 70; PROTEIN TYROSINE PHOSPHATASE SHP 2; T LYMPHOCYTE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; TREGALIZUMAB; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; BT-061; EPITOPE; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 2 RECEPTOR ALPHA; MONOCLONAL ANTIBODY; PROTEIN BINDING;

ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ARTICLE; CELL PROLIFERATION; COMPLEMENTARITY DETERMINING REGION; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYTOKINE RELEASE; HUMAN; HUMAN CELL; HYDROGEN BOND; MIXED LYMPHOCYTE REACTION; PERIPHERAL BLOOD MONONUCLEAR CELL; POINT MUTATION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; UPREGULATION; AMINO ACID SEQUENCE; CELL CULTURE; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; METABOLISM; MOLECULAR GENETICS; PHOSPHORYLATION; PROTEIN CONFORMATION; T LYMPHOCYTE SUBPOPULATION; X RAY CRYSTALLOGRAPHY;

AMINO ACID SEQUENCE; ANTIBODIES, MONOCLONAL; ANTIGENS, CD4; CELLS, CULTURED; CRYSTALLOGRAPHY, X-RAY; EPITOPES, B-LYMPHOCYTE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; LYMPHOCYTE ACTIVATION; MOLECULAR SEQUENCE DATA; PHOSPHORYLATION; PROTEIN BINDING; PROTEIN CONFORMATION; SIGNAL TRANSDUCTION; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY; TRANSFORMING GROWTH FACTOR BETA;

EID: 84928208326     PISSN: 08189641     EISSN: 14401711     Source Type: Journal    
DOI: 10.1038/icb.2014.102     Document Type: Article

References (57)

1. Sakaguchi S, Sakaguchi N, Asano M, Itoh M. Toda M Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-1164.
2. Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH. Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med 2002; 196: 255-260.
3. Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J et al. "Infectious" transplantation tolerance. Science 1993; 259: 974-977.
4. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001; 182: 18-32.
5. Fontenot JD, Gavin M. A, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-336.
6. Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998; 188: 287-296.
7. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001; 193: 1285-1294.
8. Levings MK, Sangregorio R, Roncarolo MG. Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001; 193: 1295-1302.
9. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 2009; 30: 636-645.
10. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 1998; 10: 1969-1980.
11. Lin C. H, Hunig T. Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 2003; 33: 626-638.
12. Chatenoud L, Ferran C, Legendre C, Thouard I, Merite S, Reuter A et al. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation 1990; 49: 697-702.
13. Römer PS, Berr S, Avota E, Na SY, Battaglia M, ten Berge I et al. Preculture of PBMCs at high cell density increases sensitivity of T-cell responses, revealing cytokine release by CD28 superagonist TGN1412. Blood 2011; 118: 6772-6782.
14. Becker C, Taube C, Bopp T, Michel K, Kubach J, Reuter S et al. Protection from graftversus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells. Blood 2009; 114: 1263-1269.
15. Waldmann H, Cobbold S. How do monoclonal antibodies induce tolerance? A role for infectious tolerance? Annu Rev Immunol 1998; 16: 619-644.
16. Mayer CT, Tian L, Hesse C, Kühl AA, Swallow M, Kruse F et al. Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals. J Autoimmun 2014; 50: 23-32.
17. Becker C, Bopp T, Jonuleit H. Boosting regulatory T cell function by CD4 stimulation enters the clinic. Front Immunol 2012; 3: 164.
18. Chirmule N, Avots A, LakshmiTamma SM, Pahwa S, Serfling E. CD4-mediated signals induce T cell dysfunction in vivo. J Immunol 1999; 163: 644-649.
19. Fehervari Z, Cooke A, Brett S, Turner J. Perturbation of naive TCR transgenic T cell functional responses and upstream activation events by anti-CD4 monoclonal antibodies. Eur J Immunol 2012; 32: 333-340.
20. Harding S, Lipp P, Alexander DR. A therapeutic CD4 monoclonal antibody inhibits TCRzeta chain phosphorylation, zeta-associated protein of 70-kDa Tyr319 phosphorylation, and TCR internalization in primary human T cells. J Immunol 2002; 169: 230-238.
21. Choy EH, Panayi GS, Emery P, Madden S, Breedveld FC, Kraan MC et al. Repeat-cycle study of high-dose intravenous 4162W94 anti-CD4 humanized monoclonal antibody in rheumatoid arthritis. A randomized placebo-controlled trial. Rheumatology (Oxford) 2002; 41: 1142-1148.
22. Hepburn TW, Totoritis MC, Davis CB. Antibody-mediated stripping of CD4 from lymphocyte cell surface in patients with rheumatoid arthritis. Rheumatology (Oxford) 2003; 42: 54-61.
23. Scheerens H, Su Z, Irving B, Townsend MJ, Zheng Y, Stefanich E et al. MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments. Arthritis Res Ther 2011; 13: R177.
24. Kendal AR, Chen Y, Regateiro FS, Ma J, Adams E, Cobbold SP et al. Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance. J Exp Med 2011; 208: 2043-2053.
25. Oliveira V, Sawitzki B, Chapman S, Appelt C, Gebuhr I, Wieckiewicz J et al. Anti-CD4-mediated selection of Treg in vitro-in vitro suppression does not predict in vivo capacity to prevent graft rejection. Eur J Immunol 2008; 38: 1677-1688.
26. Oliveira VG, Caridade M, Paiva RS, Demengeot J, Graca L. Sub-optimal CD4+ T-cell activation triggers autonomous TGF-beta-dependent conversion to Foxp3+ regulatory T cells. Eur J Immunol 2011; 41: 1249-1255.
27. Kon OM, Sihra BS, Loh LC, Barkans J, Compton C. H, Barnes NC et al. The effects of an anti-CD4 monoclonal antibody, keliximab, on peripheral blood CD4+ T-cells in asthma. Eur Respir J 2001; 18: 45-52.
28. Villadsen LS, Skov L, Dam TN, Dagnaes-Hansen F, Rygaard J., Schuurman J et al. In situ depletion of CD4+ T cells in human skin by Zanolimumab. Arch Dermatol Res 2007; 298: 449-455.
29. Carteron NL, Wofsy D, Seaman WE. Induction of immune tolerance during administration of monoclonal antibody to L3T4 does not depend on depletion of L3T4+ cells. J Immunol 1998; 140: 713-716.
30. Qin SX, Wise M, Cobbold SP, Leong L, Kong YC, Parnes JR, Waldmann H. Induction of tolerance in peripheral T cells with monoclonal antibodies. Eur J Immunol 1990; 20: 2737-2745.
31. van Oosten BW, Lai M, Hodgkinson S, Barkhof F, Miller DH, Moseley IF et al. Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 1997; 49: 351-3571997.
32. Czeloth N, Dälken B, Engling A, Osterroth F, Aigner S, Abufarag A et al. Selective activation of naturally occurring regulatory T cells (Tregs) by the monoclonal antibody BT-061 as a novel therapeutic opportunity: preclinical and early clinical results. Ann Rheum Dis 2010; 69: 99 (OP0138; abstract).
33. Abufarag A, Aigner S, Czeloth N, Dälken B, Koch H, Niemann G et al. Selective activation of naturally occurring regulatory T cells (Tregs) by the monoclonal antibody BT-061 as a novel therapeutic opportunity in psoriasis: early clinical results after single doses. J Invest Dermatol 2010; 130: 64 (abstract).
34. Uherek C, Engling A, Dälken B, Becker C, Jonuleit H, Wallmeier H et al. The novel regulatory T cell (Treg) agonistic monoclonal antibody (mAb) tregalizumab (BT-061): further characterization of mechanism of action, epitope binding, and clinical effects in patients with rheumatoid arthritis. IBC Life Sciences 2011 (http://www.biotest.de/shared/data/pdf/biotherapeutics/ibc-2011.pdf).
35. Kwong PD, Ryu SE, Hendrickson WA, Axel R, Sweet RM, Folena-Wasserman G et al. Molecular characteristics of recombinant human CD4 as deduced from polymorphic crystals. Proc Natl Acad Sci USA 1990; 87: 6423-6427.
36. Kjer-Nielsen L, Dunstone M. A, Kostenko L, Ely LK, Beddoe T, Mifsud NA et al. Crystal structure of the human T cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3. Proc Natl Acad Sci USA 2004; 101: 7675-7680.
37. Healey D, Dianda L, Moore JP, McDougal JS, Moore MJ, Estess P et al. Novel anti-CD4 monoclonal antibodies separate human immunodeficiency virus infection and fusion of CD4+ cells from virus binding. J Exp Med 1990; 172: 1233-1242.
38. Howie SE, Fernandes ML, Heslop I, Hewson TJ, Cotton GJ, Moore MJ et al. A functional, discontinuous HIV-1 gp120 C3/C4 domain-derived, branched, synthetic peptide that binds to CD4 and inhibits MIP-1alpha chemokine binding. FASEB J 1999; 13: 503-511.
39. Li Q, Mei Z, Riethmuller G, Rieber P, Yinghua C. Monoclonal Anti-CD4 Antibody MT310 Binds HIV-1 gp120 Binding Site on CD4. Tsinghua Sci Technol 2001; 6: 257-259.
40. Hong YL, Wu LH, Cui M, McMaster G, Hunt SW 3rd, Chung FZ et al. New reporter cell lines to study macrophage-tropic HIV envelope protein-mediated cell-cell fusion. AIDS Res Hum Retroviruses 1999; 15: 1667-1672.
41. Song R, Franco D, Kao CY, Yu F, Huang Y, Ho DD. Epitope mapping of ibalizumab, a humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients. J Virol 2010; 84: 6935-6942.
42. Moebius U, Clayton LK, Abraham S, Diener A, Yunis JJ, Harrison SC et al. Human immunodeficiency virus gp120 binding C'C" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules. Proc Natl Acad Sci USA 1992; 89: 12008-12012.
43. Baldari CT, Milia E, Di Somma MM, Baldoni F, Valitutti S, Telford JL. Distinct signaling properties identify functionally different CD4 epitopes. Eur J Immunol 1995; 25: 1843-1850.
44. Sgro C. Side-effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: bibliographic review. Toxicology 1995; 105: 23-29.
45. Haas J, Hug A, Viehover A, Fritzsching B, Falk CS, Filser A et al. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 2005; 35: 3343-3352.
46. Scurr M., Ladell K, Besneux M, Christian A, Hockey T, Smart K et al. Highly prevalent colorectal cancer-infiltrating LAP Foxp3 T cells exhibit more potent immunosuppressive activity than Foxp3 regulatory T cells. Mucosal Immunol 2013; 7: 428-439.
47. Tran D.Q., Andersson J, Hardwick D, Bebris L, Illei GG, Shevach EM. Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood 2009; 113: 5125-5133.
48. Gleizes P.E., Munger JS, Nunes I, Harpel JG, Mazzieri R, Noguera I et al. TGF-beta latency: biological significance and mechanisms of activation. Stem Cells 1997; 15: 190-197.
49. Lawrence DA. Identification and activation of latent transforming growth factor beta. Methods Enzymol 1991; 198: 327-336.
50. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998; 393: 648-659.
51. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 2007; 204: 1303-1310.
52. Lahl K, Mayer CT, Bopp T, Huehn J, Loddenkemper C, Eberl G et al. Nonfunctional regulatory T cells and defective control of Th2 cytokine production in natural scurfy mutant mice. J Immunol 2009; 183: 5662-5672.
53. Mayer CT, Huntenburg J, Nandan A, Schmitt E, Czeloth N, Sparwasser T. CD4 blockade directly inhibits mouse and human CD4 T cell functions independent of Foxp3 Tregs. J Autoimmun 2013; 47: 73-82.
54. Diamond DC, Sleckman BP, Gregory T, Lasky LA, Greenstein JL, Burakoff SJ. Inhibition of CD4+ T cell function by the HIV envelope protein, gp120. J Immunol 1998; 141: 3715-3717.
55. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345-352.
56. Joshi A, Garg H, Tompkins MB, Tompkins WA. Different thresholds of T cell activation regulate FIV infection of CD4+CD25+ and CD4+CD25-cells. Virology 2005; 335: 212-221.
57. Rudnev A, Ragavan S, Trollmo C, Malmstrom V, Becker C, Jonuleit H et al. Selective activation of naturally occurring regulatory T cells (Tregs) by the monoclonal antibody (mAb) BT-061. Markers of clinical activity and early phase II results in patients with rheumatoid arthritis (RA). Arthritis Rheum 2010; 62: 1125 (abstract).