Abstract 2650: Radioimmunotherapy for acute myeloid leukemia targeting human aspartyl (asparaginyl) β-hydroxylase
Notice bibliographique
Résumé
Abstract Treatment options for acute myeloid leukemia (AML) are limited and have modest impact on 5-year survival rates in patients <60 years of age (~35-40%) and on median survival of older patients (< 1 year). The incidence of AML has been rising, with an anticipated 19,950 new cases in 2016. Thus, the need for novel, more efficacious and better tolerated therapy for AML is urgent. Human aspartyl (asparaginyl) β-hydroxylase (HAAH) is an embryonic/developmental protein, which is down-regulated in normal cells after birth but overexpressed on the surface of many malignant cells, where it has been demonstrated to be sufficient to induce cancer cell proliferation, motility and invasiveness. We hypothesized that HAAH is selectively overexpressed on leukemia cells and thus targeting it with a fully human monoclonal antibody (mAb) conjugated to the short half-life α-emitter 213Bi could provide a novel radioimmunotherapy (RIT) treatment option with a reasonable therapeutic index. Using immunocytochemistry and flow cytometry with anti-HAAH mouse mAbs as well as a fully human mAb, PAN-622, we investigated the expression of HAAH on a variety of cytogenetically- and mutationally heterogeneous leukemia cell lines, including MV4-11, MOLM-14, HL-60, KG1α, Kasumi-1, K562, J45.1, and CCRF-CEM, as well as on normal human leukocytes. PAN-622 was further modified with DTPA-maleimide to allow chelation of radionuclides, specifically 213Bi, to the antibody. The 213Bi-DTPA-PAN-622 was then employed in killing assays to measure selective dose-dependent killing of leukemic cells. HAAH was highly expressed, as detected by flow cytometry, on all tested leukemia cell lines with KG1α and HL-60 demonstrating the highest levels of expression amongst the AML lines. Binding was observed by both PAN-622 and the modified DTPA-PAN-622 conjugate. Interestingly, expression of HAAH was not detected on CD45+ normal human leukocytes, including in subpopulations of monocytes (CD14+), B-cells (CD19+), T-cells (CD3+) or hematopoietic stem cells (CD34+). To determine whether PAN-622 could selectively target leukemia cells in a background of normal human blood, flow cytometry was performed on leukemia cells spiked into whole blood. Only leukemia cells were stained with the PAN-622 antibody as indicated by simultaneous staining for surface markers specific to the various leukocyte subpopulations. Selective killing of leukemia cell lines was demonstrated following incubation with 213Bi-DTPA-PAN-622 which induced dose dependent specific killing over a 6.7-670 pM concentration range. No killing was detected when using 213Bi conjugated to an isotype-matched control antibody at a similar specific activity and dose range. Thus, HAAH is a novel oncogenic target expressed on leukemia cells, which can be selectively targeted for RIT via the fully-human PAN-622 mAb. Experiments targeting primary leukemia cells in patient-derived bone marrow aspirates are ongoing. Citation Format: Michael S. Lebowitz, Ekaterina Revskaya, Kanam Malhotra, Amir Shahlaee, Steven Fuller, Maria R. Baer, Noa G. Holtzman, Ashkan Emadi, Ekaterina Dadachova, Hossein A. Ghanbari. Radioimmunotherapy for acute myeloid leukemia targeting human aspartyl (asparaginyl) β-hydroxylase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2650. doi:10.1158/1538-7445.AM2017-2650
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».