Preventative and therapeutic effects of a novel humanized anti-glycoprotein Ibα fragment of antigen-binding region in a murine model of thrombotic thrombocytopenic purpura
Bibliographic record
Abstract
BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal blood disorder resulting from severe deficiency of plasma ADAMTS-13 activity. Current treatment for immune-mediated TTP includes daily therapeutic plasma exchange plus caplacizumab and immunosuppressives. For hereditary TTP resulting from mutations of ADAMTS-13, plasma infusion or recombinant ADAMTS-13 is the treatment of choice. However, there are still unmet needs for an effective alternative therapy for TTP. OBJECTIVES: The present study aimed to evaluate the therapeutic efficacy of a novel humanized antibody fragment of antigen binding against platelet glycoprotein Ibα (CA1001) in a murine model of TTP. METHODS: Platelet agglutination profiles, microfluidic shear-based assay, intravital microscopy thrombosis model, and lysine histone-induced murine "TTP-like" model were employed. RESULTS: CA1001 exhibited potent inhibition of botrocetin-induced murine platelet agglutination in a dose- and time-dependent manner. CA1001 also significantly inhibited shear-dependent adhesion and aggregation of murine platelets to endothelial von Willebrand factor (VWF) released from calcium ionophore-activated cremaster venules in Adamts-13 null mice and blocked the formation of platelet-VWF rich thrombosis. More importantly, CA1001 appeared to be efficacious in preventing and treating a histone-induced "TTP-like" syndrome in Adamts-13 null mice, demonstrated by the alleviation of thrombocytopenia, prerenal injury, and formation of microvascular thrombosis in major organ tissues. CONCLUSION: CA1001 can effectively inhibit VWF-platelet interaction and thrombus formation under various (patho)physiological conditions. Thus, CA1001 may be a potential candidate for further development as a novel therapeutic for immune-mediated and hereditary TTP and perhaps for other inflammatory thrombotic disorders such as ischemic stroke.
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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 | 0.000 | 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 | 0.000 |
| 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".