Abstract 89: A first-in-class humanized antibody fragment targeting platelet glycoprotein Ibα: a comprehensive preclinical study of CA1001 for the treatment of acute ischemic stroke
Bibliographic record
Abstract
Introduction: Platelet glycoprotein (GP) Ibα is a key receptor for thrombosis. Under high shear conditions, GPIbα-VWF interactions are required for initiating platelet adhesion and vessel occlusion. GPIbα is also an important checkpoint for thrombo-inflammation in acute ischemic stroke. It has been considered as a desirable target against ischemic stroke for decades, but no anti-GPIbα drug has been successfully developed. Methods: CA1001 was humanized from our unique mAb crossing different species, and manufactured under GMP-like conditions with 99.9% purity. The efficacy of CA1001 was assessed using various in vitro platelet functional assays with blood samples and in vivo models, including state-of-the-art intravital microscopy thrombosis and transient middle cerebral artery occlusion (tMCAO) models. Pharmacokinetics (PK), pharmacodynamics (PD), and a 14-day regulatory toxicology study were conducted in rats and rhesus monkeys. Results: CA1001 specifically recognized platelet GPIbα from human, monkeys, rats, mice, rabbits and dogs. Using platelets from rhesus monkeys, healthy volunteers, and patients with peripheral artery disease, CA1001 dose-dependently inhibited ristocetin-induced platelet aggregation in vitro . Using laser injury and FeCl 3 injury intravital microscopy models, CA1001 inhibited thrombosis, prevented vessel occlusion, and importantly, promoted thrombus dissolution (thrombolysis) in vivo . In a 60-min tMCAO models, intravenous injection of CA1001 1 hour after tMCAO significantly reduced the cerebral infarct volume at 24 hours without increasing the risk of intracerebral hemorrhage. The PD studies showed that single bolus injection of CA1001 reached maximal anti-platelet effects within 5 minutes (0.25mg/kg in rats, 4mg/kg in monkeys) which was maintained following intravenous infusion. The extent and duration of the effect were dose-dependent. Plasma concentrations increased linearly with the dose received. In toxicology studies, CA1001 was well tolerated and safe without bleeding nor platelet count reduction. The No Obvious Adverse Event Level in rats and monkeys were 25mg/kg, and 100mg/kg respectively, which are 10 and 25 times the therapeutic targeted doses. Conclusion: The first-in-class humanized anti-GPIbα Fab CA1001 has potent anti-thrombotic effects, consistent PK/PD properties and favorable safety and tolerability profiles warranting further clinical development in healthy volunteers and patients with acute ischemic stroke.
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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) | 0.001 | 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 | 0.001 | 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".