IF nIgV 2E6 IgV-domain catabody (10 mg/kg IV, weekly × 12 weeks), co-administered with a sub-therapeutic dose of the fibril-destabilizing polyphenol epigallocatechin-3-gallate (EGCG, 20 mg/kg IV, given 4 hours prior to each nIgV 2E6 injection as a "fibril-priming" pre-treatment) is administered to 15–18-month-old male and female APP/PS1 or 5xFAD transgenic mice carrying established dense-core amyloid pathology,

THEN a ≥45% reduction in cortical and hippocampal Thioflavin-S-positive fibrillar plaque burden (measured as % area occupied per mm²) and ≥35% reduction in 6E10-positive total plaque load will be observed versus vehicle-treated controls, exceeding the estimated ≤15–20% plaque reduction expected from nIgV 2E6 monotherapy at equivalent dose in mice with highly compacted plaque matrices, and without elevating CD11b+/CD45+ microglial activation above age-matched untreated controls or producing detectable microhemorrhages on T2*-weighted ex vivo MRI (9.4T),

BECAUSE of the following mechanistic chain:

1. In 15–18-month-old transgenic mice, dense-core Aβ plaques consist of tightly packed, cross-β fibrillar cores in which the His14-Gln15 cleavage site targeted by nIgV 2E6 is sterically buried within hydrogen-bonded β-sheet stacks, dramatically reducing substrate accessibility for catalytic hydrolysis—this steric sequestration is the primary reason catalytic Aβ-cleaving constructs show attenuated activity against mature fibrillar deposits compared to soluble or proto-fibrillar substrates. (Fibrillar substrate steric limitation of catalytic constructs)[Planque et al., Journal of Biological Chemistry, 2015, as reported in the Evidence Set]

2. EGCG remodels preformed Aβ fibrils by intercalating into the fibrillar β-sheet backbone, generating structurally disordered, off-pathway aggregates with exposed hydrophilic stretches—critically including the N-terminal Aβ1-16 segment containing His14-Gln15—without producing amyloidogenic re-seeding fragments, as established in biophysical disaggregation studies. This transiently expands the accessible substrate pool for nIgV 2E6. [SPECULATIVE: The specific degree of His14-Gln15 epitope exposure post-EGCG remodeling in vivo has not been directly demonstrated; this is inferred from EGCG's known fibril disaggregation mechanism acting on the N-terminal β-sheet region.]

3. nIgV 2E6, a serine protease-like IgV-domain construct with a kcat of approximately 0.5–2.0 min⁻¹ and Km of 10–25 μM for soluble Aβ substrates, engages the now-accessible His14-Gln15 bond within EGCG-remodeled fibrils, catalytically hydrolyzing multiple substrate molecules per antibody molecule (turnover >> 1:1), thereby converting previously inaccessible compact plaque mass into small, non-amyloidogenic N-terminal and C-terminal fragments. (Catalytic kinetics of nIgV 2E6)[Nishiyama et al., 2014, and Planque et al., Journal of Biological Chemistry, 2015, as reported in the Evidence Set]

4. Because nIgV 2E6 lacks an Fc constant region, the deg...

SENS category: GlycoSENS