Against All Odds: Computational Screening Via Machine Learning Ranking and Generation of Antibody Candidates for Creutzfeldt-Jakob Disease.

Creutzfeldt-Jakob disease (CJD) is a fatal prion disorder with no approved treatments. This study developed a machine learning pipeline trained on 21 literature-curated PrP-targeting CDR sequences to rank 29,574 original and mutation-generated candidate sequences using neutralization, selectivity, and literature-based blood-brain barrier (BBB) proxy scores. The models showed internal performance (neutralization AUC = 0.9239; selectivity AUC = 0.7759), identified 10 high-percentile candidates, and generated 7,309 novel variants. These findings support hypothesis-generating sequence-level prioritization of PrP-targeting candidates, but do not establish native PrP Sc -specific binding, full-antibody efficacy, exact PrP epitope recognition, or in vivo BBB penetration and require further experimental validation and testing.