Toxicology and pharmacokinetics of chimeric ARH460-16-2, a therapeutic monoclonal antibody targeting CD44
Bibliographic record
Abstract
B41 CD44 is a widely distributed cancer-associated membrane glycoprotein, believed to play a critical role in cellular adhesion, migration, invasion and tumorigenicity. CD44 was recently shown to be expressed in cancer stem cells from several cancer types, including breast, colon, prostate, pancreas and AML. A monoclonal antibody targeting CD44, ARH460-16-2, was identified using the Arius’ FunctionFirst™ platform. The chimeric version of the antibody demonstrated potent dose-dependent tumor growth inhibition in an in vivo established subcutaneous model of breast cancer and in an established orthotopic model of metastatic liver cancer at all doses tested (20, 2 and 0.2 mg/kg). IHC staining of human cancers from breast, prostate, colon, and liver demonstrated that the epitope for ARH460-16-2 is present on the majority of human adenocarcinomas. Limited binding to normal human tissues was observed, predominantly in the bone marrow myeloid series with no binding 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. To enable the clinical development of ARH460-16-2, a dose-finding toxicology study was carried out in cynomolgus monkeys using the chimeric version of the antibody. 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. Animals were observed daily, and clinical chemistry, hematology and coagulation parameters were assessed 24 hr after injection, and then twice more after 9 and 28 days for the first cohort. For the second cohort, analysis was similar except that the final blood collection was carried out at Day 15, at which point the repeat-dose animals were sacrificed for necropsy. In one of the high-dose treated monkeys, and all subjects in the repeat-dose group, there was a transient reddening of the skin which resolved after a few days. There were small decreases in the indicators of circulating erythrocyte mass which were attributable to blood sampling for clinical pathology and toxicokinetic assessments. These changes were accompanied by expected and appropriately increased reticulocyte counts. Other fluctuations in hematology, coagulation, body weight and clinical chemistry parameters were sporadic, transient, observed prestudy, and/or of a magnitude of change that is commonly observed in laboratory-housed cynomolgus monkeys undergoing similar study procedures. Together with the potent anti-tumor effect in models of human cancer, these results support the clinical development of a therapeutic monoclonal antibody targeting the cancer stem cell antigen CD44.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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) | 0.001 | 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".