Regulation of immune responses to therapeutic factor VIII by transplacental delivery of Fc-fused immunodominant factor VIII domains or peptides
Bibliographic record
Abstract
Patients with severe hemophilia A (HA) often develop undesired immune responses to therapeutic factor VIII (FVIII) that hamper replacement therapy with FVIII-derived products. The transplacental delivery of two Fc-fused FVIII domains in pregnant HA mice was shown to induce partial FVIII-specific immune tolerance in the offspring. Here, we evaluated whether the transplacental delivery of Fc-fused FVIII (rFVIIIFc) induces complete immune tolerance towards FVIII. rFVIIIFc injected to pregnant HA mice was poorly transferred to the fetal circulation and failed to confer tolerance to exogenous FVIII in the offspring. The poor transplacental delivery of rFVIIIFc was associated with the large size of the molecule and with the presence of positive patches at the surface of FVIII. It was, however, independent from the capacity of rFVIIIFc to bind Fcg receptors or von Willebrand factor in the maternal circulation. Conversely, the transplacental delivery of Fc-fused A2 and C2 immunodominant domains of FVIII, as well as of Fc-fused molecules containing seven different immunodominant FVIII-derived peptides decreased the levels of anti-FVIII antibodies following FVIII replacement therapy in the offspring. Our study paves the way towards the development of engineered Fc-fused molecules able to efficiently cross the placenta and confer potent and long-lasting immune tolerance to protein therapeutics.
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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) | 0.001 | 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".