A human CD4 monoclonal antibody for the treatment of T-cell lymphoma combines inhibition of T-cell signaling by a dual mechanism with potent Fc-dependent effector activity

Cancer Research

Volumn 67, Issue 20, 2007, Pages 9945-9953

  Rider, David A ^a   Havenith, Carin E G ^b   De Ridder, Ruby ^b   Schuurman, Janine ^b   Favre, Cedric ^a   Cooper, Joanne C ^a   Walker, Simon ^a   Baadsgaard, Ole ^d   Marschner, Susanne ^e   VandeWinkel, Jan G J ^b,c   Cambier, John ^e   Parren, Paul W H I ^b,f   Alexander, Denis R ^a  

^a BABRAHAM INSTITUTE   (United Kingdom)

^b Genmab BV   (Netherlands)

^c UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^d Genmab   (Denmark)

^e NATIONAL JEWISH MEDICAL AND RESEARCH CENTER   (United States)

^f GENMAB   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

CD45RO ANTIGEN; OKT 4; PLACEBO; T LYMPHOCYTE RECEPTOR; ZANOLIMUMAB;

ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG EFFICACY; DRUG INHIBITION; DRUG MECHANISM; DRUG SAFETY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; PRIORITY JOURNAL; PSORIASIS; T CELL LYMPHOMA;

ANTIBODIES, MONOCLONAL; ANTIBODY-DEPENDENT CELL CYTOTOXICITY; ANTIGENS, CD3; ANTIGENS, CD4; CD4 LYMPHOCYTE COUNT; CD4-POSITIVE T-LYMPHOCYTES; DOUBLE-BLIND METHOD; DOWN-REGULATION; HUMANS; LYMPHOCYTE ACTIVATION; LYMPHOCYTE SPECIFIC PROTEIN TYROSINE KINASE P56(LCK); LYMPHOMA, T-CELL, CUTANEOUS; PHOSPHORIC MONOESTER HYDROLASES; PHOSPHORYLATION; PSORIASIS; RECEPTORS, ANTIGEN, T-CELL; SIGNAL TRANSDUCTION;

EID: 35448960750     PISSN: 00085472     EISSN: None     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-07-1148     Document Type: Article

References (49)

1. Vignali DA, Moreno J, Schiller D, Hammerling GJ. Does CD4 help to maintain the fidelity of T cell receptor specificity? Int Immunol 1992;4:621-6.
2. Ranges GE, Sriram S, Cooper SM, et al. Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J Exp Med 1985;162:1105-10.
3. Hutchings P, O'Reilly L, Parish NM, Waldmann H, Cooke A. The use of a non-depleting anti-CD4 monoclonal antibody to re-establish tolerance to β cells in NOD mice. Eur J Immunol 1992;22:1913-8.
4. Herzog C, Walker C, Muller W, et al. Anti-CD4 antibody treatment of patients with rheumatoid arthritis: I. Effect on clinical course and circulating T cells. J Autoimmun 1989;2:627-42.
5. Choy EH, Connolly DJ, Rapson N, et al. Pharmacokinetic, pharmacodynamic, and clinical effects of a humanized IgG1 anti-CD4 monoclonal antibody in the peripheral blood and synovial fluid of rheumatoid arthritis patients. Rheumatology (Oxford) 2000;39: 1139-46.
6. Winsor-Hines D, Merrill C, O'Mahony M, et al. Induction of immunological tolerance/hyporesponsiveness in baboons with a nondepleting CD4 antibody. J Immunol 2004;173:4715-23.
7. Reimann KA, Khunkhun R, Lin W, Gordon W, Fung M. A humanized, nondepleting anti-CD4 antibody that blocks virus entry inhibits virus replication in rhesus monkeys chronically infected with simian immunodeficiency virus. AIDS Res Hum Retroviruses 2002;18: 747-55.
8. Knox SJ, Levy R, Hodgkinson S, et al. Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides. Blood 1991;77:20-30.
9. Knox S, Hoppe RT, Maloney D, et al. Treatment of cutaneous T-cell lymphoma with chimeric anti-CD4 monoclonal antibody. Blood 1996;87:893-9.
10. Fishwild DM, O'Donnell SL, Bengoechea T, et al. High-avidity human IgGn monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat Biotechnol 1996;14:845-51.
11. Fishwild DM, Hudson DV, Deshpande U, Kung AH. Differential effects of administration of a human anti-CD4 monoclonal antibody, HM6G, in nonhuman primates. Clin Immunol 1999;92:138-52.
12. Skov L, Kragballe K, Zachariae C, et al. HuMax-CD4: a fully human monoclonal anti-CD4 antibody for the treatment of psoriasis vulgaris. Arch Dermatol 2003;139: 1433-9.
13. Kim YH, Duvic M, Obitz E, et al. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood 2007;109: 4655-62.
14. + peripheral T-cell lymphoma of non-cutaneous type. In: 47th Annual Meeting of The American Society of Hematology; 2005; Atlanta, USA; 2005.
15. Neuberger MS, Rajewsky K. Activation of mouse complement by monoclonal mouse antibodies. Eur J Immunol 1981;11:1012-6.
16. Reddy MP, Kinney CA, Chaikin MA, et al. Elimination of Fc receptor-dependent effector functions of a modified IgG4 monoclonal antibody to human CD4. J Immunol 2000;164:1925-33.
17. van der Lubbe PA, Reiter C, Miltenburg AM, et al. Treatment of rheumatoid arthritis with a chimeric CD4 monoclonal antibody (cM-T412): immunopharmacological aspects and mechanisms of action. Scand J Immunol 1994;39:286-94.
18. Choy EH, Panayi GS, Emery P, 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;41:1142-8.
19. Bartholomew M, Brett S, Barber K, Rossman C, Crowe S, Tite J. Functional analysis of the effects of a fully humanized anti-CD4 antibody on resting and activated human T cells. Immunology 1995;85:41-8.
20. Newell MK, Haughn LJ, Maroun CR, Julius MH. Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen. Nature 1990;347:286-9.
21. Choy EH, Adjaye J, Forrest L, Kingsley GH, Panayi GS. Chimaeric anti-CD4 monoclonal antibody cross-linked by monocyte Fc γ receptor mediates apoptosis of human CD4 lymphocytes. Eur J Immunol 1993;23:2676-81.
22. Hashimoto F, Oyaizu N, Kalyanaraman VS, Pahwa S. Modulation of Bcl-2 protein by CD4 cross-linking: a possible mechanism for lymphocyte apoptosis in human immunodeficiency virus infection and for rescue of apoptosis by interleukin-2. Blood 1997;90:745-53.
23. Tite JP, Sloan A, Janeway CA, Jr. The role of L3T4 in T cell activation: L3T4 may be both an Ia-binding protein and a receptor that transduces a negative signal. J Mol Cell Immunol 1986;2:179-90.
24. Bank I, Chess L. Perturbation of the T4 molecule transmits a negative signal to T cells. J Exp Med 1985; 162:1294-303.
25. Veillette A, Bookman MA, Horak EM, Bolen JB. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell 1988;55:301-8.
26. Chan AC, Desai DM, Weiss A. The role of protein tyrosine kinases and protein tyrosine phosphatases in T cell antigen receptor signal transduction. Annu Rev Immunol 1994;12:555-92.
27. van Oers NS, Killeen N, Weiss A. Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. J Exp Med 1996;183: 1053-62.
28. Weiss A, Littman DR. Signal transduction by lymphocyte antigen receptors. Cell 1994;76:263-74.
29. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 1998; 92:83-92.
30. Harding S, Lipp P, Alexander DR. A Therapeutic CD4 monoclonal antibody inhibits TCR-ζ chain phosphorylation, ζ-associated protein of 70-kDa Tyr(319) phosphorylation, and TCR internalization in primary human T cells. J Immunol 2002;169:230-8.
31. Duchesne M, Schweighoffer F, Parker F, et al. Identification of the SH3 domain of GAP as an essential sequence for Ras-GAP-mediated signaling. Science 1993;259:525-8.
32. + human T cells. Eur J Immunol 2003;33:666-75.
33. Chirmule N, Avots A, Tamma SML, Pahwa S, Serfling E. CD4-mediated signals induce T cell dysfunction in vivo. J Immunol 1999;163:644-9.
34. Woods M, Guy R, Waldmann H, Glennie M, Alexander DR. A humanised therapeutic CD4 mAb inhibits TCR-induced IL-2, IL-4, and IL-10 secretion and expression of CD25, CD40L, and CD69. Cell Immunol 1998;185:101-13.
35. Veillette A, Bookman MA, Horak EM, Samelson LE, Bolen JB. Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature 1989;338:257-9.
36. Janssen E, Zhang W. Adaptor proteins in lymphocyte activation. Curr Opin Immunol 2003;15:269-76.
37. Sattler M, Verma S, Pride YB, Salgia R, Rohrschneider LR, Griffin JD. SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL. J Biol Chem 2001;276:2451-8.
38. Berger CL, Tigelaar R, Cohen J, et al. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 2005;105:1640-7.
39. Teeling JL, Mackus WJ, Wiegman LJ, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 2006;177:362-71.
40. Morel P, Vincent C, Wijdenes J, Revillard JP. Internalization and degradation of anti-CD4 monoclonal antibodies bound to human peripheral blood lymphocytes. Mol Immunol 1993;30:649-57.
41. Friedman LM, Rinon A, Schechter B, et al. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci U S A 2005;102:1915-20.
42. Nemorin JG, Laporte P, Berube G, Duplay P. p62dok negatively regulates CD2 signaling in Jurkat cells. J Immunol 2001;166:4408-15.
43. Damen JE, Liu L, Rosten P, et al. The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc Natl Acad Sci U S A 1996;93:1689-93.
44. Toker A, Cantley LC. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 1997; 387:673-6.
45. Carver DJ, Aman MJ, Ravichandran KS. SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization. Blood 2000;96:1449-56.
46. Kane LP, Andres PG, Howland KC, Abbas AK, Weiss A. Akt provides the CD28 costimulatory signal for upregulation of IL-2 and IFN-γ but not TH2 cytokines. Nat Immunol 2001;2:37-44.
47. Cantrell D. Protein kinase B (Akt) regulation and function in T lymphocytes. Semin Immunol 2002;14: 19-26.
48. Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A. Akt-dependent phosphorylation specifically regulates Cot induction of NF-κB-dependent transcription. Mol Cell Biol 2002;22:5962-74.
49. Sanzenbacher R, Kabelitz D, Janssen O. SLP-76 binding to p56lck: a role for SLP-76 in CD4-induced desensitization of the TCR/CD3 signaling complex. J Immunol 1999;163:3143-52.