P4‐371: PRECLINICAL DEVELOPMENT OF AN AMYLOID‐B OLIGMER (ABO) SPECIFIC MONOCLONAL ANTIBODY (5E3) FOR POTENTIAL PASSIVE IMMUNOTHERAPY OF ALZHEIMER'S DISEASE
Bibliographic record
Abstract
Soluble AβOs trigger a cascade of toxic signaling in neurons that disrupt neuronal communication, causing cell death, behavior dysfunction and memory loss in AD. A murine monoclonal antibody (m5E3) against a conformationally constrained epitope (cSNK) has been developed, with demonstrated specificity and selectivity against AβOs (Silverman et al. 2012; Gibbs et al., 2013). The m5E3 specifically recognizes AβOs in AD CSF and TBS brain extracts, while displaying negligible reactivity to healthy controls. This provides a unique opportunity to selectively target and neutralize toxic AβOs implicated in the progression of AD. In the current study, target engagement for m5E3 in the Tg2576 AD mouse model was evaluated. Humanized constructs of m5E3 have been generated and characterization in vitro and in vivo in mouse models is in progress. Aged (12 mo.) Tg2576 mice were treated weekly with mAb5E3 or nonspecific murine IgG1 control for six weeks. At study termination, soluble aggregated Aβ were assayed in plasma, CSF and brain homogenates. The m5E3 was humanized (h5E3) to IgG1, IgG2 and IgG4 frameworks and purified antibodies characterized by Western analysis and affinity confirmed against cSNK epitope (Octet analysis and Biacore™ 300). Treatment with m5E3 antibody was evaluated for impact on the levels of soluble AβOs in CSF and brain homogenates in Tg2576 treated mice. This data is consistent with previous analyses and further supports selective target engagement of pathophysiologically relevant AβOs. Humanized h5E3 variants have been generated and shown to retain the same affinity, specificity and selectivity as m5E3 against the conformational epitope cSNK and AβOs species. The therapeutic potential of m5E3 is under evaluation in preclinical mouse models. These studies suggest intervention with 5E3 selectively targets AβO species and may represent a unique immunotherapeutic approach. Emergent BioSolutions is now positioned to study the h5E3 variants for lead selection and further development.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".