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

Liqing Jin, Erwin M. Lee, Hayley S. Ramshaw, Samantha J. Busfield, Armando G. Peoppl, Lucy Wilkinson, Mark A. Guthridge, Daniel Thomas, Emma F. Barry, Andrew Boyd, David P. Gearing, Gino Vairo, Angel F. Lopez, John E. Dick, Richard B. Lock

Research output: Contribution to journalArticle

324 Citations (Scopus)

Abstract

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 α chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 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.

LanguageEnglish
Pages31-42
Number of pages12
JournalCell Stem Cell
Volume5
Issue number1
DOIs
Publication statusPublished - 2 Jul 2009
Externally publishedYes

Keywords

  • STEMCELL

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Jin, L., Lee, E. M., Ramshaw, H. S., Busfield, S. J., Peoppl, A. G., Wilkinson, L., ... Lock, R. B. (2009). Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells. Cell Stem Cell, 5(1), 31-42. https://doi.org/10.1016/j.stem.2009.04.018
Jin, Liqing ; Lee, Erwin M. ; Ramshaw, Hayley S. ; Busfield, Samantha J. ; Peoppl, Armando G. ; Wilkinson, Lucy ; Guthridge, Mark A. ; Thomas, Daniel ; Barry, Emma F. ; Boyd, Andrew ; Gearing, David P. ; Vairo, Gino ; Lopez, Angel F. ; Dick, John E. ; Lock, Richard B. / Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells. In: Cell Stem Cell. 2009 ; Vol. 5, No. 1. pp. 31-42.
@article{6d1bc81082324807befef9a8bb99e910,
title = "Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells",
abstract = "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 α chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 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.",
keywords = "STEMCELL",
author = "Liqing Jin and Lee, {Erwin M.} and Ramshaw, {Hayley S.} and Busfield, {Samantha J.} and Peoppl, {Armando G.} and Lucy Wilkinson and Guthridge, {Mark A.} and Daniel Thomas and Barry, {Emma F.} and Andrew Boyd and Gearing, {David P.} and Gino Vairo and Lopez, {Angel F.} and Dick, {John E.} and Lock, {Richard B.}",
year = "2009",
month = "7",
day = "2",
doi = "10.1016/j.stem.2009.04.018",
language = "English",
volume = "5",
pages = "31--42",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "1",

}

Jin, L, Lee, EM, Ramshaw, HS, Busfield, SJ, Peoppl, AG, Wilkinson, L, Guthridge, MA, Thomas, D, Barry, EF, Boyd, A, Gearing, DP, Vairo, G, Lopez, AF, Dick, JE & Lock, RB 2009, 'Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells', Cell Stem Cell, vol. 5, no. 1, pp. 31-42. https://doi.org/10.1016/j.stem.2009.04.018

Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells. / Jin, Liqing; Lee, Erwin M.; Ramshaw, Hayley S.; Busfield, Samantha J.; Peoppl, Armando G.; Wilkinson, Lucy; Guthridge, Mark A.; Thomas, Daniel; Barry, Emma F.; Boyd, Andrew; Gearing, David P.; Vairo, Gino; Lopez, Angel F.; Dick, John E.; Lock, Richard B.

In: Cell Stem Cell, Vol. 5, No. 1, 02.07.2009, p. 31-42.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells

AU - Jin, Liqing

AU - Lee, Erwin M.

AU - Ramshaw, Hayley S.

AU - Busfield, Samantha J.

AU - Peoppl, Armando G.

AU - Wilkinson, Lucy

AU - Guthridge, Mark A.

AU - Thomas, Daniel

AU - Barry, Emma F.

AU - Boyd, Andrew

AU - Gearing, David P.

AU - Vairo, Gino

AU - Lopez, Angel F.

AU - Dick, John E.

AU - Lock, Richard B.

PY - 2009/7/2

Y1 - 2009/7/2

N2 - 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 α chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 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.

AB - 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 α chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 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.

KW - STEMCELL

UR - http://www.scopus.com/inward/record.url?scp=67649200331&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2009.04.018

DO - 10.1016/j.stem.2009.04.018

M3 - Article

VL - 5

SP - 31

EP - 42

JO - Cell Stem Cell

T2 - Cell Stem Cell

JF - Cell Stem Cell

SN - 1934-5909

IS - 1

ER -