Pre‐clinical development of a blood‐brain barrier (BBB)‐penetrating anti‐amyloid‒β fusion protein
Bibliographic record
Abstract
Abstract Background We have developed a blood‐brain barrier (BBB) crossing anti‐amyloid fusion protein KG207 as a potential AD therapeutic. This humanized bi‐functional molecule was generated by fusing an Aß oligomer (AßO)‐ binding peptide (ABP) with a BBB carrier FC5 via IgG‐1 Fc fragment. Present study shows that KG207 crosses the BBB in vitro and in vivo (mouse, rat and dog), penetrates target regions of the brain (cortex and hippocampus) and engages parenchymal Aß. KG207 neutralizes AßO‐induced toxicity in vitro and does not stimulate pro‐inflammatory cytokine production in mouse microglia. Studies demonstrated that KG207 was safe up to 300 mg/kg. Method Recombinant KG207 was produced in CHO cells. BBB‐permeability was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat, mouse and dog) models. AßO binding was determined by ELISA. Following iv injection, serum, CSF and brain levels of KG207 and Aß were assessed by nanoLC‐ MRM, ELISA and Western blot methods. Aß toxicity studies were done in human neuroblastoma (SH‐SY5Y) cells and rat primary cortical neuronal cells. Following exposure to KG207, cytokine levels in BV2 microglia were measured using Millipore Luminex assay kit. Safety studies were done in Sprague Dawley rats at 30, 100 and 300 mg/kg. Result KG207 retained both Aß‐oligomer binding activity and BBB‐permeability in vitro. When injected iv into rats and mouse, KG207 rapidly appeared in the CSF and brain parenchyma (cortex and hippocampus) indicating active transport of ABP across BBB by FC5 in vivo. In AD transgenic mice, KG207 treatment showed a significant reduction of brain Aß levels. KG207 significantly reduced AßO‐induced toxicity in both human neuroblastoma cells and primary cortical neurons in vitro. KG207 blocked AßO binding to cellular proteins in vitro. KG207 did not activate BV2 mouse microglia and induce pro‐inflammatory cytokines. No adverse effects were seen in rats injected with up to 300 mg/kg, including neurotoxicity. Conclusion Collectively, these results indicate that KG207 can effectivey cross the blood‐brain barrier, penetrate the brain and facilitate Aß clearance in vivo. In vitro data suggest that KG207 can safely clear Aß without eliciting pro‐inflammatory cytokine secretion by microglia.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.001 |
| 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".