Activating Fc receptors are required for antitumor efficacy of the antibodies directed toward CD25 in a murine model of adult t-cell leukemia.
We previously showed therapeutic efficacy of humanized anti-Tac (HAT), murine anti-Tac (MAT), and 7G7/B6 monoclonal antibodies, which recognize CD25, for human adult T-cell leukemia (ATL) in a murine model. In this study, we investigated the mechanism underlying the tumor-killing action mediated by these antibodies on an ATL model in nonobese diabetic/severe combined immunodeficient (SCID/NOD) wild-type mice that lack effective T and natural killer (NK) cells and in SCID/NOD Fc receptor common gamma chain knockout (FcRgamma-/-) mice. The ATL model was established by i.p. injection of human ATL cells (MET-1) into SCID/NOD wild-type or SCID/NOD FcRgamma-/- mice. HAT, MAT, and 7G7/B6 were given to the leukemia-bearing mice at a dose of 100 microg weekly for 4 weeks. The three antibodies inhibited the leukemia growth significantly in SCID/NOD wild-type mice, as monitored by serum levels of human beta2-microglobulin (P < 0.01), and prolonged survival of the leukemia-bearing SCID/NOD wild-type mice (P < 0.01) as compared with the control group. However, none of the antibodies manifested efficacy on the leukemia growth and survival of the SCID/NOD FcRgamma-/- mice bearing MET-1 leukemia. In a pharmacokinetics study, the blood concentrations of the radiolabeled antibodies decreased with time similarly in SCID/NOD wild-type and SCID/NOD FcRgamma-/- mice. Although NK cells may play a role in humans, in this murine model FcRgamma receptors on non-NK cells, such as polymorphonuclear leukocytes or monocytes, are required for the tumor-killing action of the antibodies directed toward CD25.
Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-1374, USA.
Meili
M
Zhang
Zhuo
Z
Zhang
Kayhan
K
Garmestani
Carolyn K
CK
Goldman
Jeffrey V
JV
Ravetch
Martin W
MW
Brechbiel
Jorge A
JA
Carrasquillo
Thomas A
TA
Waldmann
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000077561:Daclizumab; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007457:Iodine Radioisotopes; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017452:Receptors, IgG / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D017452:Receptors, IgG; D015375:Receptors, Interleukin-2; D000077561:Daclizumab