IF the IgV-domain catabody construct nIgV 2E6 (10 mg/kg, IV, weekly for 12 weeks) is co-administered with a sub-stoichiometric priming dose of the N-terminal Aβ1-14 fragment — the endogenous product of nIgV 2E6's own His14-Gln15 cleavage activity — to 15–18 month-old male and female APP/PS1 mice bearing established dense-core amyloid plaques,

THEN cortical and hippocampal plaque burden (% area by 6E10 IHC and thioflavin-S fibrillar density) will be reduced by ≥30% versus vehicle-treated age-matched controls within 12 weeks, and this reduction will occur without elevation of CD11b+/CD45+ microglial activation above untreated age-matched controls or detectable microhemorrhages by ex vivo MRI, compared to an equivalent-dose conventional non-catalytic anti-Aβ1-16 IgG control that will produce equivalent or lesser plaque reduction but significant microglial activation and microhemorrhage incidence,

BECAUSE the following causal chain is operative:

1. Dense-core amyloid plaques in 15–18 month APP/PS1 mice present their outermost fibril surfaces as the initial enzymatic substrate for nIgV 2E6, which functions as a site-specific serine protease cleaving the His14-Gln15 peptide bond (Planque et al., J Biol Chem, 2014 — cited in evidence set); however, the central hydrophobic core of fibrillar Aβ (residues 17–21) is sterically protected in dense β-sheet conformations, limiting initial catabody access to soluble and peri-plaque oligomeric species.

2. [SPECULATIVE — novel synthesis] The Aβ1-14 cleavage product, which retains the charged N-terminal domain but lacks the hydrophobic core required for β-sheet self-assembly (residues 17–21, disrupted by cleavage as noted in the evidence set), acts as a competitive cap on fibril elongation sites: by occupying the Aβ fibril growing ends without itself contributing hydrophobic stacking energy, Aβ1-14 prevents reincorporation of soluble Aβ monomers liberated from the plaque periphery, shifting the monomer-fibril equilibrium toward dissolution. Pre-supplying exogenous Aβ1-14 as a priming dose before nIgV 2E6 administration amplifies this effect by saturating fibril growth termini before catalytic cleavage begins, creating a self-reinforcing degradation loop.

3. nIgV 2E6, operating as an enzyme rather than a stoichiometric binder, achieves high catalytic turnover on the now-exposed soluble and oligomeric Aβ liberated from fibril ends, degrading thousands of substrate molecules per construct molecule (Planque et al., Molecular Medicine, 2021 — cited in evidence set); the resulting fragments (Aβ1-14 and Aβ15-42) do not reform β-sheet amyloid fibrils because cleavage disrupts the central hydrophobic core, and both fragments are non-cytotoxic in neuronal cell assays and do not inhibit hippocampal LTP (Planque et al., J Biol Chem, 2014 — cited in evidence set).

4. nIgV 2E6, engineered as a single-domain IgV fragment (~12–15 kDa) lacking an Fc constant region, cannot engage Fcγ receptors on microglia or acti...

SENS category: GlycoSENS