Multi-resolution humanness scoring of antibodies via a region-isolated language model

Authors

Liu, H., Chen, P., Zhou, S., Wei, B., Deng, S., Zhang, L., Liu, X., Zhou, S., Han, L., Ye, L.

Abstract

Antibodies recognized as foreign can elicit anti-drug antibodies that compromise efficacy and safety, making humanness scoring---estimating how human-like a sequence appears---an early, repeated step in antibody development. Widely used scores reduce a variable domain to one framework-dominated number, leaving the complementarity-determining regions (CDRs)---grafted during humanization, diversified by generative models---weakly supervised and rarely audited. Here we introduce IgScope, a 23-million-parameter antibody language model trained from scratch that scores humanness at chain, IMGT-region and residue resolution; a region-isolated attention module confines attention to within-region pairs, and chimeric-sequence training supplies region-level supervision. On 2.38 million held-out chains, masking all framework tokens leaves CDR accuracy unchanged, and back-mutated murine residues in human frameworks are detected at 93.4% accuracy. At chain level, IgScope matches the strongest published correlation with clinical anti-drug-antibody incidence (r = $-$0.567, n = 217) and outperforms a same-protocol recomputation. Region-level scoring exposes what chain-level scoring conceals: antibodies designed de novo by four generative models pass whole-chain humanness (0.966--0.988) while their CDRs score far below natural (P $<$ 1e-30) in every chain class. Quality control turns the same resolution to the mirror-image question: in humanized-mouse platforms, whose domains are human by design, IgScope scores the domain as human and, in HUGO-Nano chimeric VHHs, isolates only the FR2 signal of four camelid hallmark residues deliberately retained to stabilise the VHH. IgScope gives antibody humanization a verified foundation and generative design an audit.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Oct 2026.

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