An alpha-fetoprotein-maytansine conjugate for the treatment of AFP receptor expressing tumors.
Bibliographic record
Abstract
e15056 Background: The alpha fetoprotein (AFP) receptor is an oncofetal antigen and a novel target for cancer therapeutics. It is highly expressed on the surfaces of many cancers and myeloid derived suppressor cells (MDSCs) but absent on normal tissues. By conjugating a novel maytansinoid toxin to a recombinant form of human AFP (ACT-101), we can selectively deliver the toxin to cancer and MDSC cells while sparing normal cells, thereby enabling a combination of targeted and immune activating approaches against the tumor. Methods: Four ACT-101-maytansinoid conjugates with different protein-toxin ratios and different linker chemistries were initially investigated in a mouse COLO-205 xenograft model, resulting in the selection of ACT-903 as the lead candidate for further development. A second study performed in the same tumor model compared the effects of single intravenous doses of ACT-903 (10-50 mg/kg) to control groups receiving either vehicle or the unconjugated protein, ACT-101 (25 mg/kg). Tumor growth, survival and clinical observations were assessed for 60 days post tumor implantation. Both serum ACT-101 and maytansinoid levels were measured following the single dose. Results: In the first study, a statistically significant reduction in tumor volume was seen for all four conjugates compared to vehicle control (p < 0.05). For ACT-903, tumors continued shrinking even after treatment completion, becoming undetectable in 9 of 10 animals. All 10 mice in this group survived through Day 60 with no obvious signs of toxicity. In contrast, there were no survivors in the control group. In the single dose study of ACT-903, a significant reduction of tumor burden compared to vehicle was achieved by Day 14 (p < 0.05) in both the 40 and 50 mg/kg dose groups. Mice in these 2 groups received a second dose 15 days after the first dose, based on observed tumor re-growth. Survival was significantly prolonged in the 50 mg/kg (p = 0.0037) and 40 mg/kg group (p < 0.0001) with 7 of 10 in the 50 mg/kg group and 9 of 10 animals in the 40 mg/kg group surviving to Day 60. Similar doses of ACT-101 and ACT-903 produced comparable ACT-101 serum levels, suggesting that the pharmacokinetic profile of the conjugate is driven primarily by the protein component. Free maytansinoid levels at 4 hours were less than 0.01% of the injected dose of the conjugate, indicating that the conjugate is stable in circulation. Conclusions: The efficacy and tolerability of ACT-903 in an animal tumor model supports advancing this conjugate toward clinical use with a regimen of either once a week or once every other week administration.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".