Preclinical development of huARH460-16-2, a humanized antibody to the CD44 cancer stem cell target
Bibliographic record
Abstract
3975 CD44 has been identified on cancer stem cells in several solid and liquid tumors (breast, colon, prostate, pancreatric cancer and AML) where it is thought to play key roles in tumor maintenance, adhesion, migration and invasion. A monoclonal antibody targeting CD44, ARH460-16-2, was generated using the ARIUS’ FunctionFIRST™ platform. Murine and chimeric ARH460-16-2 (chARH460-16-2) demonstrated potent anti-tumor efficacy in models of human breast (CD44+CD24-/lo), liver and prostate cancer as well as AML. With respect to mechanism of action, chARH460-16-2 induced apoptosis and suppressed phosphorylation of the Tie-1 receptor tyrosine kinase in breast cancer cells. Immunohistochemistry showed that the epitope for ARH460-16-2 is present on the majority of human adenocarcinomas including breast, prostate, colon, and liver cancers. Limited binding to normal human tissues was observed, predominantly to myeloid cells in bone marrow, with no binding observed to erythroid cells, megakaryocytes, endothelium, fibroblasts, smooth muscle, eye, heart, liver, ovary and colon epithelium. The binding pattern was not substantially different in cynomolgus monkey tissues, although some differences in intensity were seen. A dose-ranging toxicology study was carried out in cynomolgus monkeys with chARH460-16-2. In the first phase, monkeys (2 per group) were given a single 1 hr infusion of 10, 30 or 95 (high dose) mg/kg chARH460-16-2. A second cohort of 3 monkeys was infused with 25 mg/kg chARH460-16-2 once per week for 2 doses. There were no drug related effects on clinical chemistry parameters, coagulation, or hematology (blood cell counts or morphology). In one of the high-dose treated monkeys, and in 3 monkeys of the second cohort there was transient reddening of the skin which resolved after a few days. Histopathology of the second cohort, sacrificed 15 days after the first dose, revealed no findings in the skin of 2 tested animals, while the third had a crusting dermatitis. In all cases there no findings in bone marrow smears or in lung sections. A CHO cell line producing the humanized version of the antibody (huARH460-16-2) has been developed. huARH460-16-2 is equivalent to chARH460-16-2 using the following criteria: affinity to recombinant CD44 by BiaCore and ELISA, FACS binding to cancer cell lines, ability to induce apoptosis, and ability to induce tumor regression in the established MDA-MB-231 breast cancer model. In addition, the EC50 of huARH460-16-2 binding to lymphocytes, monocytes and granulocytes of human and cynomolgus monkeys was similar as assessed by FACS. Taken together, these results support the clinical development of a humanized therapeutic monoclonal antibody targeting the cancer stem cell antigen CD44
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".