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A radiolabeled antibody targeting CD123(+) leukemia stem cells - initial radioimmunotherapy studies in NOD/SCID mice engrafted with primary human AML.

Leyton JV, Gao C, Williams B, Keating A, Minden M, Reilly RM - Leuk Res Rep (2015)

Bottom Line: Radioimmunotherapy (RIT) with anti-CD123 monoclonal antibody CSL360 modified with nuclear translocation sequence (NLS) peptides and labeled with the Auger electron-emitter, (111)In ((111)In-NLS-CSL360) was studied in the prevalent NOD/SCID mouse AML engraftment assay.Significant decreases in CD123(+) leukemic cells and impairment of leukemic stem cell self-renewal were achieved with high doses of RIT.At low non-toxic treatment doses, (111)In-NLS-CSL360 demonstrated a trend towards improved survival associated with decreased spleen/body weight ratio, an indicator of leukemia burden, and almost complete eradication of leukemia from the bone marrow in some mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.

ABSTRACT
Radioimmunotherapy (RIT) with anti-CD123 monoclonal antibody CSL360 modified with nuclear translocation sequence (NLS) peptides and labeled with the Auger electron-emitter, (111)In ((111)In-NLS-CSL360) was studied in the prevalent NOD/SCID mouse AML engraftment assay. Significant decreases in CD123(+) leukemic cells and impairment of leukemic stem cell self-renewal were achieved with high doses of RIT. However, NOD/SCID mice were very radiosensitive to these doses. At low non-toxic treatment doses, (111)In-NLS-CSL360 demonstrated a trend towards improved survival associated with decreased spleen/body weight ratio, an indicator of leukemia burden, and almost complete eradication of leukemia from the bone marrow in some mice.

No MeSH data available.


Related in: MedlinePlus

Effect of treatment of NOD/SCID mice engrafted with AML specimen 080179 with radioimmunoconjugates (4–5 MBq; 13–15 μg) on leukemic cells in the bone marrow (BM). (A) Percentage of human hCD45+ cells. (B) Percentage of human CD34+/CD38−/CD123+ stem cells. Bars represent the mean±SD and values for individual mice are shown. Significant differences (P<0.05) are indicated by an asterisk.
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f0010: Effect of treatment of NOD/SCID mice engrafted with AML specimen 080179 with radioimmunoconjugates (4–5 MBq; 13–15 μg) on leukemic cells in the bone marrow (BM). (A) Percentage of human hCD45+ cells. (B) Percentage of human CD34+/CD38−/CD123+ stem cells. Bars represent the mean±SD and values for individual mice are shown. Significant differences (P<0.05) are indicated by an asterisk.

Mentions: To examine the longer term anti-leukemic effects of RIT, we treated NOD/SCID mice engrafted with AML specimen 080179 with a single lower non-toxic dose of 111In-NLS-CSL360 (4.5±0.2 MBq; 13–15 μg). Specimen 080179 engrafts reproducibly and aggressively into the BM of NOD/SCID mice and produces increased levels of leukemic blasts in the blood and impairment of normal murine hematopoiesis by week 8 [12]. Analysis of the BM at 8 weeks revealed that in 1/5 mice 111In-NLS-CSL360 decreased the proportion of hCD45+ cells compared to untreated mice by 10-fold to <10% and the mean proportion of hCD45+ cells in all 5 mice was moderately decreased by 23.5% relative to 111In-CSL360 and 111In-NLS-chIgG1 (Fig. 2A). No mice treated with 111In-CSL360 (without NLS) or irrelevant 111In-NLS-chIgG1 exhibited decreased hCD45+ cells in the BM. 111In-NLS-CSL360 significantly reduced the proportion of CD34+/CD38−/CD123+ LSCs in the BM by 2.1-fold (P<0.01) compared to untreated mice. This finding suggests that Auger electron RIT with 111In-NLS-CSL360 impairs LSC long term survival and the NOD/SCID mouse assay is suitable to monitor this effect at reduced doses. However, the dose of radioactivity employed in these experiments most likely was insufficient to completely eradicate LSCs, which have inherent resistance properties to radiation [15] and overexpression of proteins involved in DNA repair [16].


A radiolabeled antibody targeting CD123(+) leukemia stem cells - initial radioimmunotherapy studies in NOD/SCID mice engrafted with primary human AML.

Leyton JV, Gao C, Williams B, Keating A, Minden M, Reilly RM - Leuk Res Rep (2015)

Effect of treatment of NOD/SCID mice engrafted with AML specimen 080179 with radioimmunoconjugates (4–5 MBq; 13–15 μg) on leukemic cells in the bone marrow (BM). (A) Percentage of human hCD45+ cells. (B) Percentage of human CD34+/CD38−/CD123+ stem cells. Bars represent the mean±SD and values for individual mice are shown. Significant differences (P<0.05) are indicated by an asterisk.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4588397&req=5

f0010: Effect of treatment of NOD/SCID mice engrafted with AML specimen 080179 with radioimmunoconjugates (4–5 MBq; 13–15 μg) on leukemic cells in the bone marrow (BM). (A) Percentage of human hCD45+ cells. (B) Percentage of human CD34+/CD38−/CD123+ stem cells. Bars represent the mean±SD and values for individual mice are shown. Significant differences (P<0.05) are indicated by an asterisk.
Mentions: To examine the longer term anti-leukemic effects of RIT, we treated NOD/SCID mice engrafted with AML specimen 080179 with a single lower non-toxic dose of 111In-NLS-CSL360 (4.5±0.2 MBq; 13–15 μg). Specimen 080179 engrafts reproducibly and aggressively into the BM of NOD/SCID mice and produces increased levels of leukemic blasts in the blood and impairment of normal murine hematopoiesis by week 8 [12]. Analysis of the BM at 8 weeks revealed that in 1/5 mice 111In-NLS-CSL360 decreased the proportion of hCD45+ cells compared to untreated mice by 10-fold to <10% and the mean proportion of hCD45+ cells in all 5 mice was moderately decreased by 23.5% relative to 111In-CSL360 and 111In-NLS-chIgG1 (Fig. 2A). No mice treated with 111In-CSL360 (without NLS) or irrelevant 111In-NLS-chIgG1 exhibited decreased hCD45+ cells in the BM. 111In-NLS-CSL360 significantly reduced the proportion of CD34+/CD38−/CD123+ LSCs in the BM by 2.1-fold (P<0.01) compared to untreated mice. This finding suggests that Auger electron RIT with 111In-NLS-CSL360 impairs LSC long term survival and the NOD/SCID mouse assay is suitable to monitor this effect at reduced doses. However, the dose of radioactivity employed in these experiments most likely was insufficient to completely eradicate LSCs, which have inherent resistance properties to radiation [15] and overexpression of proteins involved in DNA repair [16].

Bottom Line: Radioimmunotherapy (RIT) with anti-CD123 monoclonal antibody CSL360 modified with nuclear translocation sequence (NLS) peptides and labeled with the Auger electron-emitter, (111)In ((111)In-NLS-CSL360) was studied in the prevalent NOD/SCID mouse AML engraftment assay.Significant decreases in CD123(+) leukemic cells and impairment of leukemic stem cell self-renewal were achieved with high doses of RIT.At low non-toxic treatment doses, (111)In-NLS-CSL360 demonstrated a trend towards improved survival associated with decreased spleen/body weight ratio, an indicator of leukemia burden, and almost complete eradication of leukemia from the bone marrow in some mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.

ABSTRACT
Radioimmunotherapy (RIT) with anti-CD123 monoclonal antibody CSL360 modified with nuclear translocation sequence (NLS) peptides and labeled with the Auger electron-emitter, (111)In ((111)In-NLS-CSL360) was studied in the prevalent NOD/SCID mouse AML engraftment assay. Significant decreases in CD123(+) leukemic cells and impairment of leukemic stem cell self-renewal were achieved with high doses of RIT. However, NOD/SCID mice were very radiosensitive to these doses. At low non-toxic treatment doses, (111)In-NLS-CSL360 demonstrated a trend towards improved survival associated with decreased spleen/body weight ratio, an indicator of leukemia burden, and almost complete eradication of leukemia from the bone marrow in some mice.

No MeSH data available.


Related in: MedlinePlus