O4‐04‐01: Characterization of a humanized amyloid beta oligomer monoclonal antibody (5E3) under preclinical development for passive immunotherapy of Alzheimer's disease
Bibliographic record
Abstract
Soluble Amyloid βeta oligomers (AβOs) trigger a cascade of toxic signaling in neurons that disrupt neuronal communication, behavior dysfunction and memory loss in Alzheimer's disease (AD). A murine monoclonal antibody (m5E3) has been developed, with demonstrated specificity and selectivity that targets soluble AβOs in vivo and treatment reduced levels in CSF and brain homogenates in Tg2576 and APP/PS1 treated mice. Affinity has been retained across humanized isotype variants and reduced effector functionality has been incorporated by design. Preclinical evaluation is described including a number of physicochemical attributes and pharmacokinetic properties of purified humanized 5E3 in mice. Expression vectors encoding for the IgG1, IgG2 and IgG4 variants were used to transfect CHO K1SV by electroporation or Lipofectiamine®. Immunoreactivity of purified antibodies was characterized by ELISA and immunoblotting, and affinity confirmed against cyclic-SNK (cSNK) and synthetic AβO epitope (Octet analysis and Biacore™ 300). Biodistribution and pharmacokinetic properties were determined in ApoE4 mice using unlabelled and labeled mAbs. Purified isotype variants retained similar affinity and selectivity towards the cSNK epitope and synthetic Aβ42 oligomers. The naturally occurring target recognized by m5E3 in human AD biospecimens was also recognized by all humanized variants. The biodistribution of fluorescent and radio-labelled m5E3 and humanized mAbs was assessed following i.p. injection in mice. The distribution of antibodies was assessed to determine penetration in the CNS and clearance profile in the absence of target (i.e. soluble AβOs). In order to meet the manufacture requirements and advance selection, stable cell lines have been established for each isotype to support manufacturing at commercially relevant levels. The humanization of m5E3 to various isotypic frameworks was completed and affinity to the conformationally constrained cSNK epitope and the selective target of AβO was retained. Systemic administration (i.p.) of humanized variants was assessed to determine penetration across the BBB and clearance. Together, these data provide reassurance towards preclinical evaluation for lead candidate selection and IND enabling studies.
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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) | 0.000 | 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 | 0.000 |
| 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 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".