A humanized monoclonal antibody against interleukin-2 that can inactivate the cytokine/receptor complex.
Inhibition of the interleukin-2 (IL-2) pathway has potent immunosuppressive activity in humans as is evident from the broad therapeutic utility of cyclosporine, rapamycin, tacrolimus, and monoclonal antibodies blocking the high-affinity subunit of the IL-2 receptor (CD25). Here we describe a humanized antibody, MT204, interfering with IL-2 signaling by a novel mechanism. Although MT204 did not prevent IL-2 from binding to CD25, it potently antagonized downstream signaling events of IL-2 at sub-nanomolar concentrations, such as STAT3 tyrosine phosphorylation, expression of CD124, production of gamma-interferon and cell proliferation. While MT204 and the anti-CD25 mAb daclizumab were equally effective in inhibiting autocrine growth of human CD4(+) T cells, MT204 was far superior in preventing proliferation of NKL lymphoma cells, production of gamma-interferon by natural killer (NK) cells and proliferation of primary NK cells. MT204 has potential as a novel immunosuppressive and anti-proliferative therapy with an apparently broader spectrum of activities than anti-CD25 antibodies.
Volkland
Jörg
J
Micromet, Inc., 2110 Rutherford Road, Carlsbad, CA 92008, USA.
Lumsden
John
J
Mølhøj
Michael
M
Raum
Tobias
T
Hausmann
Susanne
S
Wissing
Sandra
S
Wissinger
Monika
M
Hoffmann
Patrick
P
Sriskandarajah
Mirnaalini
M
Kvesic
Majk
M
Baeuerle
Patrick A
PA
Pflanz
Stefan
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001681:Biological Assay; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors; D000077561:Daclizumab; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D007074:Immunoglobulin G; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C517847:MT204 antibody, human; D018121:Receptors, Cytokine; D007371:Interferon-gamma; D000077561:Daclizumab