P1‐072: PRE‐CLINICAL CHARACTERIZATION OF HUMANIZED, BLOOD‐BRAIN BARRIER (BBB)‐PENETRATING, AMYLOID‐β (Aβ) OLIGOMER‐TARGETING FUSION PROTEIN
Bibliographic record
Abstract
A 40-amino acid peptide (ABP) that selectively binds Aß1-42 oligomers and Aß deposits in brains of Alzheimer's disease (AD) patients and AD transgenic mice, was shown to effectively lower CSF and brain Aß levels after systemic dosing in transgenic mice and rats when fused to the blood-brain barrier (BBB)-crossing single-domain antibody FC5. The fusion protein was subsequently humanized and further engineered for development as human therapeutic (KAL-ABP-BBB). Present studies show pre-clinical characterization of the KAL-ABP-BBB in transgenic mice and aged dogs. Recombinant non-humanized [KAL-ABP-BBB(M)] and humanized [KAL-ABP-BBB(H)] proteins were produced in CHO cells. BBB-permeability was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat and mouse) models. Aß binding was determined by ELISA, Western blot overlay and immunohistochemical methods. Serum, CSF and brain levels of systemically dosed KAL-ABP-BBB constructs and Aß were assessed by nanoLC-MRM, ELISA and Western blot. Both KAL-ABP-BBB bi-functional fusion proteins expressed in CHO cells retained Aß-oligomer binding activity and BBB-permeability in vitro. After systemic dosing, both KAL-ABP-BBB versions demonstrated identical long serum pharmacokinetics in rats and were detected in CSF, cortex and hippocampus of naïve and transgenic mice. In transgenic mice, treatment with either variant of KAL-ABP-BBB resulted in a significant (∼50%) reduction of Aß levels in the CSF suggesting in vivo target engagement. The ability of each variant to engage naturally occurring Aß was further shown after brain microinjection in live animals. Translational studies in aged dogs, which exhibit elevated levels of Aß (identical to human Aß), demonstrated similar serum PK to that observed in rats, >20-fold increased CSF exposure compared to control fusion protein, as well as a reduction in CSF levels of Aß, indicating target engagement. The study demonstrates translation of results (serum PK, enhanced CNS exposure, and lowering of Aß) obtained with KAL-ABP-BBB (M) in rodent species to aged dogs. Chakravarthy et al., J. Neurochem 126, 415, 2013. Biochem. Biophys. Res. Commun. 445, 656, 2014.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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) | 0.001 | 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".