TY - JOUR
T1 - ImmunoPET, [64Cu]Cu-DOTA-anti-CD33 PET-CT, imaging of an AML xenograft model
AU - Srideshikan, Sargur Madabushi
AU - Brooks, Jamison
AU - Zuro, Darren
AU - Kumar, Bijender
AU - Sanchez, James
AU - Parra, Liliana Echavarria
AU - Orellana, Marvin
AU - Vishwasrao, Paresh
AU - Nair, Indu
AU - Chea, Junie
AU - Poku, Kofi
AU - Bowles, Nicole
AU - Miller, Aaron
AU - Ebner, Todd
AU - Molnar, Justin
AU - Rosenthal, Joseph
AU - Vallera, Daniel A.
AU - Wong, Jeffrey Y.C.
AU - Stein, Anthony S.
AU - Colcher, David
AU - Shively, John E.
AU - Yazaki, Paul J.
AU - Hui, Susanta K.
N1 - Funding Information:
We appreciate administrative support at our institutions. Research reported in this publication included work performed by the Small Animal Imaging Core for PET-CT imaging and imaging precision radiation delivery system supported by the NCI of the NIH under award number P30CA033572 and partly supported by NIH grant 1R01CA154491-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - Purpose: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET. Experimental Design: We evaluated whether [64Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibody-specific targeting with an antibody–drug conjugate (ADC) and radioimmunotherapy (RIT). Results: [64Cu]Cu-DOTA-anti-CD33–based PET-CT imaging detected CD33+ AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33+ PET activity was significantly higher in specific skeletal niches [femur (P < 0.00001), tibia (P = 0.0001), humerus (P = 0.0014), and lumber spine (P < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (P = 0.02) and [225Ac]Ac-anti-CD33-RIT (P < 0.00001) significantly reduced disease burden over that of respective controls. Conclusions: We have successfully developed a novel anti-CD33 immunoPET-CT–based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche.
AB - Purpose: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET. Experimental Design: We evaluated whether [64Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibody-specific targeting with an antibody–drug conjugate (ADC) and radioimmunotherapy (RIT). Results: [64Cu]Cu-DOTA-anti-CD33–based PET-CT imaging detected CD33+ AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33+ PET activity was significantly higher in specific skeletal niches [femur (P < 0.00001), tibia (P = 0.0001), humerus (P = 0.0014), and lumber spine (P < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (P = 0.02) and [225Ac]Ac-anti-CD33-RIT (P < 0.00001) significantly reduced disease burden over that of respective controls. Conclusions: We have successfully developed a novel anti-CD33 immunoPET-CT–based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche.
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U2 - 10.1158/1078-0432.CCR-19-1106
DO - 10.1158/1078-0432.CCR-19-1106
M3 - Article
C2 - 31548348
AN - SCOPUS:85076501648
SN - 1078-0432
VL - 25
SP - 7463
EP - 7474
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -
