GII_drug v2: CDR3 Loop Geometric Irregularity as an Anti-Circularity Validated Predictor of Biologic Immunogenicity and Skin irAE (n=18, 7 Target Classes)

This paper presents a full transparency audit and corrected analysis of the original GII_drug paper (v1, DOI:10.5281/zenodo.20115927). The v1 paper reported rho=-0.971 between GII_drug and skin irAE in n=8 ICI drugs, raising anti-circularity concerns. Audit findings: The v1 GII values are a monotone function of CDR3 heavy-chain loop length (CDR3H, SAbDab database), with GII vs CDR3H rho=1.000 for the original 8 drugs. CDR3H is independently accessible from SAbDab before any clinical immunogenicity data is collected. Corrected claim: CDR3H (SAbDab, independent of clinical data) significantly predicts ADA rate (rho=0.737, p=0.0005) and skin irAE (rho=0.821, p<0.0001) across n=18 biologics spanning 7 target classes (PD-1, PD-L1, CTLA-4, TNF, HER2, VEGF, IL-6R). Molecular weight is non-predictive (rho=-0.096, p=0.70). Permutation tests confirm significance (N=10,000, perm-p<0.002). GII_drug operationalizes CDR3H geometric complexity within the Lo-Shu framework.