Anti-CD44 antibody, ARH460-16-2, binds to human AML CD34+CD38- cancer stem cells and demonstrates anti-tumor activity in an AML xenograft model
Bibliographic record
Abstract
3976 The CD44 glycoprotein was first identified in cells of hematopoietic origin. CD44 has been found expressed in several hematologic malignancies including AML, ALL, CLL and multiple myeloma. Further, CD44 has been shown to be expressed on the CD34+CD38- cancer stem cells in these malignancies. These findings suggest that targeting CD44 in leukemia may be an effective therapeutic strategy. Using Arius’ FunctionFIRST™ platform, ARH460-16-2, a monoclonal antibody targeting CD44, was discovered. This antibody has potent anti-tumor activity in solid tumor models of breast (CD44+CD24-/lo), liver and prostate cancer. Using flow cytometry, chimeric ARH460-16-2 (chARH460-16-2) was shown to bind to cancer cells from patients with AML, CLL, ALL (B and T), multiple myelomas and to cells from patients with Monoclonal Gammopathies of Undetermined Significance (MGUS), albeit at varying levels of binding. chARH460-16-2 also bound to various leukemia, lymphoma and multiple myeloma cell lines including KG-1, HL-60, CCRF-CEM and OPM, respectively. To determine whether ARH460-16-2 also recognizes CD44 on hemopoietic stem cells, flow cytometry was carried out on peripheral blood samples from patients with AML. The results showed that the antibody bound to all AML CD34+CD38- cancer stem cells. While ARH460-16-2 also bound normal hematopoietic CD34+CD38- stem cells, albeit to a lower degree, these data raise the possibility that ARH460-16-2 can target AML cancer stem cells in a therapeutic setting. Consistent with this notion, a non-GLP cynomolgus dose-ranging toxicology study using chARH460-16-2, did not detect abnormalities in the hematopoietic compartment even though chARH460-16-2 bound to variety of blood cell types. To assess the therapeutic potential in hematologic cancers chARH460-16-2 was tested in two established in vivo subcutaneous models of promyelocytic leukemia (HL-60) and AML (KG-1) in SCID mice. In these experiments, chARH460-16-2 had significant dose-responsive tumor growth inhibition in the KG-1 model (57% at 10 mg/kg) and an increase in the median survival of 62 days compared to 49 days in the control group. The antibody did not have anti-tumor activity in the HL-60 model. Because the maximum levels of binding to KG-1and HL-60, as determined by flow cytometry, were 100 and 4.5 fold above isotype respectively, it is possible that the therapeutic activity of the antibody may directly correlate with CD44 levels. ARH460-16-2 is being developed as a therapeutic monoclonal antibody for solid tumors and hematologic malignancies based on its effectiveness in pre-clinical models. Its target, CD44, is expressed in a variety of hematologic malignancies and CD34+CD38- cancer stem cells in AML and extends its therapeutic utility.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".