P-CHAP-001-h-CPP: A Humanized Cell-Penetrating Hetero-Octameric Chaperonin Engineered for Disease-Modifying Treatment of Alzheimer's Disease — Open IND Blueprint with Construct Artifact, Predicted Clinical Magnitude on CDR-SB, and Falsification Path

P-CHAP-001-h-CPP is a humanized hetero-octameric chaperonin built on the human TRiC/CCT scaffold (CCT1 through CCT8) with 54 rationally designed amino acid substitutions across the eight subunits and an N-terminal TAT cell-penetrating peptide (RKKRRQRRR) fused to three of the eight chains (CCT1, CCT3, CCT6A; the positively-charged hemisphere subunits per Betancourt Moreira 2023 assembly hierarchy). The mutation set partitions into four functional classes: cavity-volume reduction at apical lid residues, substrate-engagement modulation via apical-surface charge-to-hydrophobic substitutions, productivity tuning at equatorial inter-subunit interfaces, and ATP-cradle modification at the conserved chaperonin GDGTT motif (Asp → Asn at the Mg²⁺ coordinator and Thr → Val at the canonical γ-phosphate-sensor T_β position) which destabilizes the ATP-bound closed state and shifts the open/closed conformational equilibrium toward the open state. The headline prediction is 19% to 28% slowing of cognitive decline on the regulatory-favored Clinical Dementia Rating Sum of Boxes (CDR-SB) over 18 months in early symptomatic Alzheimer's disease (central estimate 23%; upside potential 30 to 43% if Pathway B or C operates intracellularly with high TAT-CPP delivery efficiency). The construct's predicted clinical activity may operate through any of three plausible mechanism pathways with different ATP requirements: anti-aggregation by substrate sequestration (ATP-independent; well-precedented in chaperonin literature on huntingtin and other aggregating clients per Sontag 2013, Tam 2006); entropic-pulling disaggregation analogous to HSP70-mediated extraction of α-synuclein from fibrils per Wentink 2020 (ATP-required, intracellular only; the construct's apical Class B+C engineering substitutes for the DNAJB1 substrate-targeting role in the canonical HSP70+DNAJB1+HSP110 trio); or a chaperonin-specific apical-domain disaggregation mechanism (ATP-required, intracellular only; without direct precedent). Pathways B and C are restricted to the intracellular ATP-saturated compartment because extracellular CSF [ATP] (~10 nM) is severely undersaturated relative to chaperonin K_M(ATP) (~25 to 100 μM); under all three scenarios the extracellular fraction operates Pathway A. The compartment-based efficacy model is calibrated to lecanemab CLARITY-AD CDR-SB (27.1%) and bracket-checked against five other anti-amyloid antibody clinical-trial readouts on combined-population CDR-SB; 5 of 5 non-calibration anchors land within or borderline-near the model's bracket span. Donanemab TRAILBLAZER-ALZ2 readouts (29% combined population CDR-SB; 36% low/medium tau primary cohort CDR-SB) sit within bracket on the combined readout and above bracket on the tau-stratified primary cohort. The construct provides intracellular access via TAT-CPP fusion to the approximately 80% intracellular tau cytotoxic load that no antibody-class therapy can reach. The construct does not engage Fc-receptor-mediated complement or vascular amyloid clearance and is predicted to carry no excess ARIA-E or ARIA-H risk beyond the background incidence in age-matched untreated cohorts; antibody-class symptomatic ARIA-E rates are 3 to 6% (lecanemab 2.8%; donanemab 5.8%) with lethal events documented in the apolipoprotein E ε4 homozygous population. Annual cost at competitive generic equilibrium is approximately 7 to 15 times lower than the anti-amyloid antibody class ($1,800 to $2,400 per patient per year vs $26,500 to $32,000 for lecanemab and donanemab). The dominant active mechanism pathway requires biochemical confirmation. The deposit specifies three falsification-class experiments at approximately $65,000 total: Class E single-mutant ATPase characterization on a CCT5 homo-octameric construct (per Sergeeva 2013 demonstrating CCT4 and CCT5 form biologically active homo-oligomers in E. coli); hetero-octamer assembly check by negative-stain electron microscopy; and disaggregation activity assay on synthetic Aβ42 oligomer with ATP dose-response, which discriminates Pathway A (anti-aggregation only, ATP-independent) from Pathways B and C (active disaggregation, ATP-required). The construct artifact (sequences in lead_p_chap_001_h_cpp_v0p5.fasta, structured per-subunit mutation table in construct_h_v0p5.json, manufacturing route, formulation buffer, release criteria, and dose regimen described in the paper) is dedicated to the public domain under Creative Commons CC0 1.0 Universal Public Domain Dedication. Generic biopharmaceutical manufacturers, contract manufacturing organizations, academic medical centers, non-profit drug-development consortia, and regulators may make, evaluate, manufacture, and bring this construct to clinical use without permission, royalty, or attribution. The paper text and analysis (body.pdf and cover.pdf) are licensed under CC-BY 4.0 with attribution to the Zenodo deposit. The deposit serves as defensive prior art under 35 U.S.C. § 102 and analogous foreign-jurisdiction novelty provisions including European Patent Convention Article 54. The authors have not filed and do not intend to file patent applications on the construct artifact or its production. The deposit makes no clinical-safety, regulatory-compliance, or therapeutic-efficacy assertion; clinical evaluation, regulatory submissions, and validation are the responsibility of any downstream developer. Companion research note at https://www.coracleresearch.com/research/08-p-chap-001-h-cpp/.