Abstract 1467: AB-16B5, a therapeutic monoclonal antibody against human clusterin that blocks the epithelial-to-mesenchymal transition
Bibliographic record
Abstract
Abstract Studies are increasingly implicating clusterin (CLU) as an important contributing factor in cancer promotion and invasion. Although there is evidence that secreted (s) CLU plays a pro-survival role in tumors, recently published results demonstrated that sCLU is also a potent stimulator of the epithelial-to-mesenchymal transition (EMT). A family of monoclonal antibodies (mAbs) specific for human sCLU was generated and a subset of these was found to inhibit the migration and invasion of several types of cancer cells. Importantly, this EMT-inhibiting subset of mAbs all bind to a specific amino acid sequence in sCLU and inhibit metastasis in vivo. The variable regions of the lead candidate mAb were modified using an in silico molecular modeling approach to generate a humanized IgG2, designated AB-16B5, which exhibited almost identical binding parameters compared to the original mouse antibody, with an apparent KD of 2 − 5 nM for recombinant human CLU. Treatment of 4T1 carcinoma cells with AB-16B5 inhibited TGFβ-induced EMT indicating that the biological activity in vitro was maintained in the humanized antibody. Moreover, AB-16B5 inhibited the motility of EMT6 cells in scratch assays and reduced the invasion of DU145 and PC-3 hormone-insensitive human prostate cancer cells when cultured in Matrigel. In animal studies, DU145 prostate cancer cells were implanted in SCID mice and treated with 5 mg/kg AB-16B5 twice per week as a monotherapy or in combination with the anti-mitotic drug, docetaxel (TxT). These experiments showed that the tumors in the AB-16B5 treated animals were 55% smaller than those in the control group. Furthermore, combining the AB-16B5 treatment with that of TxT caused a reduction of tumor size by 40% compared to the TxT-only group. PC-3-derived tumors in SCID mice treated with AB-16B5 showed a similar degree of tumor growth inhibition. Importantly, in both prostate cancer models, the mice exposed to AB-16B5 exhibited a marked increase in their overall survival. Furthermore, AB-16B5 treatment of Nude mice with intra-cardiac implantations of MDA-231 breast cancer cells resulted in a reduction of the number of metastatic bone lesions. The pharmacokinetic parameters of AB-16B5 are comparable to other IgG2 antibodies with its half-life being approximately 15 days following a bolus intravenous injection in mice. Finally, mice exposed to AB-16B5 at 10-times the therapeutic dose displayed no observable signs of toxicity and no major changes in serum biochemistry were detected. In conclusion, AB-16B5 is one of the rare therapeutic mAbs that directly targets EMT to reduce the invasion of tumors. Its therapeutic effects hold much promise to control metastasis from breast and prostate tumors, in addition to enhancing the response to chemotherapeutic drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1467.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".