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Clin Cancer Res ; 25(24): 7463-7474, 2019 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-31548348

RESUMEN

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.


Asunto(s)
Radioisótopos de Cobre/química , Compuestos Heterocíclicos con 1 Anillo/química , Inmunoconjugados/farmacocinética , Leucemia Mieloide Aguda/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Lectina 3 Similar a Ig de Unión al Ácido Siálico/inmunología , Animales , Anticuerpos Monoclonales Humanizados/farmacocinética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Lectina 3 Similar a Ig de Unión al Ácido Siálico/antagonistas & inhibidores , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
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