Extremely short bioavailability and fast pharmacodynamic effects of pMHC-based nanomedicines
Bibliographic record
Abstract
Nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHCs) can blunt autoimmune diseases by re-programming cognate effector T-lymphocytes into disease-suppressing regulatory T-cells, followed by massive expansion. Here, a method to quantify the absolute amounts of the active drug product is developed, to understand the relationship between bioavailability and pharmacodynamics. Incubation with plasma results in the formation of a protein corona that stabilizes the directional pMHC coat, shielding it from proteolysis or anti-drug antibody recognition, without any appreciable loss in biological potency. A quantitative method that harnesses these features indicates that the half-life of these compounds in the circulation and organs is an order of magnitude shorter (minutes vs. hours) than that measured using commonly-used semi-quantitative methods. Extensive transmission electron microscopy-based organ scanning and flow cytometry-based enumeration of pMHCII-NP capturing cells confirmed that these compounds are rapidly captured (within 1 min) by liver sinusoidal endothelial cells, Kupffer cells, splenic phagocytes and cognate T-cells, leading to a fast decline in the circulation. Therefore, the powerful pharmacodynamic effects of these compounds are dissociated from long bioavailability, implying a hit-and-run event. Collectively, these data provide a detailed view of the life-cycle of a nanoimmunomedicine, and suggest that the real half-lives of intact nanomedicines may be much shorter than those estimated using indirect approaches.
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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 | 0.001 |
| 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".