Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells

被引：408

作者：

Jin, Liqing ^{[2
]}

Lee, Erwin M. ^{[1
]}

Ramshaw, Hayley S. ^{[3
]}

Busfield, Samantha J. ^{[4
]}

Peoppl, Armando G. ^{[2
]}

Wilkinson, Lucy ^{[5
]}

Guthridge, Mark A. ^{[3
]}

Thomas, Daniel ^{[3
]}

Barry, Emma F. ^{[3
]}

Boyd, Andrew ^{[5
]}

Gearing, David P. ^{[4
]}

Vairo, Gino ^{[4
]}

Lopez, Angel F. ^{[3
]}

Dick, John E. ^{[2
]}

Lock, Richard B. ^{[1
]}

机构：

[1] Univ New S Wales, Childrens Canc Inst Australia Med Res, Sydney, NSW 2031, Australia

[2] Univ Hlth Network, Div Cell & Mol Biol, Toronto, ON M5G 1L7, Canada

[3] Inst Med & Vet Sci, Div Human Immunol, Ctr Canc Biol, Adelaide, SA 5000, Australia

[4] CSL Ltd, Melbourne, Vic 3052, Australia

[5] Queensland Inst Med Res, Brisbane, Qld 4029, Australia

来源：

CELL STEM CELL | 2009年 / 5卷 / 01期

关键词：

ACUTE MYELOGENOUS LEUKEMIA; COLONY-STIMULATING FACTOR; ACUTE LYMPHOBLASTIC-LEUKEMIA; INTERLEUKIN-3; RECEPTOR; HEMATOPOIETIC-CELL; BONE-MARROW; SHORT-TERM; G-CSF; INTRAFEMORAL TRANSPLANTATION; GROWTH-FACTORS;

D O I：

10.1016/j.stem.2009.04.018

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor a chain (CD123)-neutralizing antibody (7133) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7133 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with preestablished disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7133 inhibited IL-3-mediated intracellular signaling of isolated AML CD34(+) CD38(-) cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.

引用

页码：31 / 42

页数：12

共 53 条

[1] Monoclonal antibodies for the treatment of acute myeloid leukemia [J].

Abutalib, Syed A. ;

Tallman, Martin S. .

CURRENT PHARMACEUTICAL BIOTECHNOLOGY, 2006, 7 (05) :343-369

[2]

Aribi A, 2006, CANCER J, V12, P77

[3] The structural and functional basis of cytokine receptor activation: Lessons from the common beta subunit of the granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 receptors [J].

Bagley, CJ ;

Woodcock, JM ;

Stomski, FC ;

Lopez, AF .

BLOOD, 1997, 89 (05) :1471-1482

[4] Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice [J].

Bhatia, M ;

Wang, JCY ;

Kapp, U ;

Bonnet, D ;

Dick, JE .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (10) :5320-5325

[5] Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell [J].

Bonnet, D ;

Dick, JE .

NATURE MEDICINE, 1997, 3 (07) :730-737

[6]

BUDEL LM, 1989, BLOOD, V74, P565

[7] Characterization of CD34+ subsets derived from bone marrow, umbilical cord blood and mobilized peripheral blood after stem cell factor and interleukin 3 stimulation [J].

De Bruyn, C ;

Delforge, A ;

Lagneaux, L ;

Bron, D .

BONE MARROW TRANSPLANTATION, 2000, 25 (04) :377-383

[8]

Elbaz Osama, 2001, Hematology, V5, P383

[9] Acute myeloid leukaemia [J].

Estey, Elihu ;

Doehner, Hartmut .

LANCET, 2006, 368 (9550) :1894-1907

[10] Detection of molecular targets on the surface of CD34+/CD38-stem cells in various myeloid malignancies [J].

Florian, S ;

Sonneck, K ;

Hauswirth, AW ;

Krauth, MT ;

Schernthaner, GH ;

Sperr, WR ;

Valent, P .

LEUKEMIA & LYMPHOMA, 2006, 47 (02) :207-222

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