Monoclonal antibody targeting of IL-3 receptor α with CSL362 effectively depletes CML progenitor and stem cells.

Abstract

Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) in eliminating differentiated chronic myeloid leukemia (CML) cells, recent evidence suggests that leukemic stem and progenitor cells (LSPCs) persist long term, which may be partly attributable to cytokine-mediated resistance. We evaluated the expression of the interleukin 3 (IL-3) receptor α subunit (CD123), an established marker of acute myeloid leukemia stem cells, on CML LSPCs and the potential of targeting those cells with the humanized anti-CD123 monoclonal antibody CSL362. Compared with normal donors, CD123 expression was higher in CD34(+)/CD38(-) cells of both chronic phase and blast crisis CML patients, with levels increasing upon disease progression. CSL362 effectively targeted CML LSPCs by selective antibody-dependent cell-mediated cytotoxicity (ADCC)-facilitated lysis of CD123(+) cells and reduced leukemic engraftment in mice. Importantly, not only were healthy donor allogeneic natural killer (NK) cells able to mount an effective CSL362-mediated ADCC response, but so were CML patients' autologous NK cells. In addition, CSL362 also neutralized IL-3-mediated rescue of TKI-induced cell death. Notably, combination of TKI- and CSL362-induced ADCC caused even greater reduction of CML progenitors and further augmented their preferential elimination over normal hematopoietic stem and progenitor cells. Thus, our data support the further evaluation of CSL362 therapy in CML.

• Authors: Eva Nievergall, Hayley S Ramshaw, Agnes S M Yong, Mark Biondo, Samantha J Busfield, Gino Vairo, Angel F Lopez, Timothy P Hughes, Deborah L White, Devendra K Hiwase
• Journal: Blood (Blood) Vol. 123 Issue 8 Pg. 1218-28 (Feb 20 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24363400 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Antigens, CD34
• IL3RA protein, human
• Interleukin-3 Receptor alpha Subunit
• Receptors, Interleukin-3
• ADP-ribosyl Cyclase 1

Topics

• ADP-ribosyl Cyclase 1 (metabolism)
• Adult
• Aged
• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antibodies, Neutralizing (immunology, pharmacology)
• Antigens, CD34 (metabolism)
• Cell Line
• Female
• Humans
• Interleukin-3 Receptor alpha Subunit (immunology, metabolism)
• Killer Cells, Natural (immunology, pathology)
• Leukemia, Erythroblastic, Acute (immunology, pathology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (immunology, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Receptors, Interleukin-3 (immunology)
• Stem Cells (immunology, metabolism, pathology)