ImmunoPET, [64Cu]Cu-DOTA-anti-CD33 PET-CT, imaging of an AML xenograft model

Sargur Madabushi Srideshikan, Jamison Brooks, Darren Zuro, Bijender Kumar, James Sanchez, Liliana Echavarria Parra, Marvin Orellana, Paresh Vishwasrao, Indu Nair, Junie Chea, Kofi Poku, Nicole Bowles, Aaron Miller, Todd Ebner, Justin Molnar, Joseph Rosenthal, Daniel A. Vallera, Jeffrey Y.C. Wong, Anthony S. Stein, David ColcherJohn E. Shively, Paul J. Yazaki, Susanta K. Hui

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7463-7474
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number24
DOIs
StatePublished - Dec 15 2019

Bibliographical note

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.

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