Abstract 2650: Radioimmunotherapy for acute myeloid leukemia targeting human aspartyl (asparaginyl) β-hydroxylase
Bibliographic record
Abstract
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
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".