Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells.
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 alpha 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.
Jin
Liqing
L
Division of Cell and Molecular Biology, University Health Network, Toronto, ON M5G 1L7, Canada.
Lee
Erwin M
EM
Ramshaw
Hayley S
HS
Busfield
Samantha J
SJ
Peoppl
Armando G
AG
Wilkinson
Lucy
L
Guthridge
Mark A
MA
Thomas
Daniel
D
Barry
Emma F
EF
Boyd
Andrew
A
Gearing
David P
DP
Vairo
Gino
G
Lopez
Angel F
AF
Dick
John E
JE
Lock
Richard B
RB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D018952:Antigens, CD34 / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous; D047368:Tumor Burden
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D053650:Interleukin-3 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins