AML ImmunoPET:⁶⁴Cu-DOTA-anti-CD33 PET-CT imaging of AML in Xenograft mouse model

Abstract

provides consulting for Amgen and Stemline and is on the speakers' bureau for the former company. Joseph Rosenthal receives honoraria from and consults for Shire and Bayer, and receives research funding from Daiichi Sankyo and Kite Pharma. All other authors declare no competing financial interests. Abstract: 245 words Translational relevance: 153 words Abstract: Purpose:Acute myeloid leukemia (AML) is a highly aggressive form of leukemia that 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 non-invasive imaging method to assess disease in the whole body, including in extramedullary organs, representing an unmet clinical need. About 85-90% of human myeloid leukemia cells express CD33 (an accepted biomarker for AML) cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET. Experimental Design:In this study, we evaluated if 64 Cu-DOTA-anti-CD33 murine monoclonal antibody (mAb) can be used for ImmunoPET-CT imaging of AML in preclinical model. For translational purpose, a humanized anti-CD33 antibody was produced, and after confirming its anti-CD33 PET-CT imaging ability we further explored its therapeutic potential. Results:64 Cu-DOTA-anti-CD33 based PET-CT imaging detected CD33 + AML in mice with high sensitivity (95.65%) and specificity (100%). In the entire skeletal system, CD33 + PET activity was significantly high in the bones of AML bearing mice over non-leukemic control mice; femur (p<0.00001), tibia (p=0.0001), humerus (p=0.0014), and lumber spine (p<0.00001).Interestingly, the imaging showed CD33 + PET activity prevelant in epiphysis/diaphysis of the bones, indicating spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC (p=0.02) and 225 Ac-anti-CD33-RIT (p<0.00001), significantly reduced disease burden over that of respective controls. Conclusion:We have successfully developed a novel anti-CD33 immunoPET-CT based non-invasive imaging tool for diagnosis of AML and its spatial distribution, which indicates a preferential skeletal niche.

PET/CT in leukemia: utility and future directions

“…The findings support the potential use of this imaging modality for noninvasive detection of AML in humans and monitoring treatment response [139]. Subsequent research by Allen et al focused on [ 89 Zr]Zr-labeled lintuzumab molecule, showing promising results in PET imaging of CD33 positive human AML tumors [140].…”

“…The results showed high sensitivity and specificity, highlighting spatial heterogeneity in the disease based on disease burden [139]. This suggests caution in interpreting results from single bone marrow biopsies [139].…”

“…Alternatively, Madabushi et al conducted a study using [ 64 Cu]Cu-DOTA-anti-CD33 murine mAb for immu-noPET imaging of AML in a preclinical model [139].…”

“…conducted a study using [ 64 Cu]Cu-DOTA-anti-CD33 murine mAb for immunoPET imaging of AML in a preclinical model [139]. The results showed high sensitivity and specificity, highlighting spatial heterogeneity in the disease based on disease burden [139]. This suggests caution in interpreting results from single bone marrow biopsies [139].…”

In Vitro and In Vivo Characterization of 89Zirconium-Labeled Lintuzumab Molecule

“…Currently, two PET enabling radionuclides are routinely available to the nuclear medicine community: Gallium-68 ( 68 Ga), a trivalent positron radiometal with a short physical half-life of 68 min and Zirconium-89 ( 89 Zr), tetravalent radiometal with a half-life of 78.4 h. 68 Ga half-life does not match the several days long biological half-life of full-size antibodies; 89 Zr half-life provides a better match. Recently pre-clinical imaging of acute myeloid leukemia (AML) models with Copper-64 ( 64 Cu) has been reported [ 4 ], however, both short-physical half-life of 64 Cu (12.7 h) and its not being readily available limit its use as a research tool for biodistribution and pharmacokinetics of antibodies. It has been demonstrated that targeting CD33 with lintuzumab antibody radiolabeled with 225 Ac has promising activity in patients with relapsed/refractory AML in phase 1/2 clinical trials [ 5 , 6 , 7 ].…”