ImmunoPET, [64Cu]Cu-DOTA-Anti-CD33 PET-CT, Imaging of an AML Xenograft Model

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 [ 64 Cu]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 antibodyspecific targeting with an antibody-drug conjugate (ADC) and radioimmunotherapy (RIT). Results:[ 64 Cu]Cu-DOTA-anti-CD33-based PET-CT imaging detected CD33 þ AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33 þ PET activity was significantly higher in specific skeletal niches [femur (P < 0.00001), tibia (P ¼ 0.0001), humerus (P ¼ 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 ¼ 0.02) and [ 225 Ac]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.

Review of Palliative Radiation Therapy Patterns of Practice for Adrenal Metastases in British Columbia

“…Therefore, the GVHD mouse model in allogeneic BMT settings using TMI would enable us to further understand the role of radiation-induced gut damage in GVHD. (iv) A recent study using an anti-CD33-PET imaging modality showed that AML disease localizes mostly in the skeletal system and is highly heterogeneous (41). The PET-guided functional TMI (fTMI) could allow localized radiation boosts to sites of high disease burden to enhance increased tumor cell killing without damaging the entire skeletal system(11,42).…”

ImmunoPET: Concept, Design, and Applications

“…In two recent studies, researchers reported the feasibility and satisfactory treatment efficacy of 90 Y-rituximab in patients with relapsed or refractory NHL. , Furthermore, several preclinical and clinical studies have reported the superior effectiveness of pRIT or RIT in treating lymphomas by targeting several targets, such as CD20, , CD38, and CD45 . CD33 is another alternative target for RIT of hematological malignancies , and for immunoPET imaging . Continuous innovation of the pRIT systems and incorporation of immunoPET techniques may reinvigorate the enthusiasm for managing hematologic malignancies with nuclear medicine approaches.…”

“…913 CD33 is another alternative target for RIT of hematological malignancies 914,915 and for immunoPET imaging. 916 Continuous innovation of the pRIT systems and incorporation of immunoPET techniques may reinvigorate the enthusiasm for managing hematologic malignancies with nuclear medicine approaches. Readers are recommended to refer to an excellent review parsing RIT for more information.…”

89Zr-immuno-PET in translational development of biopharmaceuticals

“…PDCs with a toxic payload attached, DM4 in the case of CX-2009, aim at delivering selectively their payload to tumors via widely expressed antigens, such as CD166. We evaluated the potential of CX-2009 by performing 89 Zr-immuno-PET and biodistribution studies in a CD166-positive H292 lung cancer mouse model in comparison with its radiolabeled benchmark compounds, the Probody therapeutic without DM4 (CX-191), the unmasked antibody drug conjugate (ADC) CX-1031, and the parental mAb CX-090 at three different doses (10,110, or 510 µg) and different time points (24,72, and 168 hours post-injection (p.i.)). Tumor uptake was similar for all constructs at 72 hrs p.i.…”

“…the different experimental groups, being 264 ± 145 mm 3 . As a first step, the biodistribution of [89 Zr]Zr-CX-2009 was assessed as a function of dose (10, 110, or 510 µg; Figure3Aand TableS1) and time(24,72, and 168 h p.i. ; Figure3Band TableS2).…”