AR47A6.4.2, a naked monoclonal antibody targeting Trop-2, exhibits anti-tumor efficacy in multiple human cancer models as a monotherapeutic agent and demonstrates efficacy in combination therapy
Bibliographic record
Abstract
3990 Trop-2 is a putative signal transduction molecule with widespread expression reported in a number of human carcinomas. Increasing evidence supports the role of Trop-2 in cancer, and over-expression studies suggest Trop-2 plays a role in cancer cell proliferation both in vitro and in vivo. In human colorectal cancer, high levels of Trop-2 have been associated with poor prognosis and a decrease in patient survival. Most recently, Trop-2 was suggested to play an important role in metastasis and high levels of Trop-2 were reported in metastatic tumors from breast cancer patients. Taken together, these findings suggest that targeting Trop-2 in cancer patients may be an effective therapeutic strategy. Using the ARIUS FunctionFIRST™ anti-cancer antibody discovery platform, AR47A6.4.2, a functional monoclonal antibody targeting human Trop-2, was identified. To examine the potential anti-tumor effect of this antibody in vivo, AR47A6.4.2 was administered in both prophylactic and established xenograft models of human solid tumors. Significant tumor growth inhibition was observed in models of breast, pancreatic, colon, and prostate cancers, concomitant with an increase in the survival of mice in the antibody treatment groups. The potency of AR47A6.4.2 was enhanced in an established model of pancreatic cancer when administered in combination with Gemcitabine®, a standard of care in pancreatic cancer. The combination therapy resulted in tumor regression during the treatment period, and 97 % tumor growth inhibition was observed 27 days after treatment ended. Mechanism of action studies have revealed that AR47A6.4.2 treatment diminishes MAPK phosphorylation in response to serum stimulation, suggesting that AR47A6.4.2 may exert some of its anti-tumor effects by inhibiting TROP-2 signaling and downstream phosphorylation of MAPK. In addition, in pancreatic cancer cell lines where AR47A6.4.2 has exhibited anti-tumor activity, AR47A6.4.2 was also shown to induce complement dependent cytotoxicity in vitro. In summary, AR47A6.4.2, the first naked therapeutic antibody targeting Trop-2, demonstrates significant anti-tumor in vivo efficacy in xenograft models of human pancreatic, colon, breast and prostate cancer, thereby confirming its potential therapeutic value in treating these solid tumor malignancies. In addition, this antibody can be combined with chemotherapy to enhance its anti-tumor activity. Towards the goal of bringing AR47A6.4.2 to the clinic, the cynomolgus monkey has been identified as a relevant pre-clinical toxicology model and a humanized version of AR47A6.4.2 has been generated with high affinity and potent anti-tumor activity.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.002 | 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".