Deep learning assessment of nativeness and pairing likelihood for antibody and nanobody design with AbNatiV2

作者：Aubin Ramon, Niccolo Frassetto, Haowen Zhao, Xing Xu, Matthew Greenig, Shimobi Onuoha, Pietro Sormanni · 发表于：mAbs · 年份：2026 · DOI：10.1080/19420862.2026.2646361 · 被引用次数：2 · 研究领域：Monoclonal and Polyclonal Antibodies Research、vaccines and immunoinformatics approaches、Biochemical and Structural Characterization

Most immune-system created antibodies balance good binding and stability with low toxicity and self-reactivity. Quantifying the nativeness of a candidate sequence - its likelihood of belonging to natural immune repertoires - has thus emerged as a valuable strategy for hit selection from synthetic libraries, optimization and humanization, and for guiding de novo design toward developable candidates. We previously introduced AbNatiV, a transformer-based VQ-VAE for nativeness assessment, which proved effective across multiple nanobody engineering tasks. However, AbNatiV1 operated on unpaired sequences, limiting applicability to conventional VH-VL antibodies. Moreover, its performance on nanobody nativeness was constrained by the limited number and diversity of nanobody repertoires available at the time. Here, we sequenced new camelid repertoires, curated additional recent datasets, and present AbNatiV2: an enhanced architecture comprising various models each trained on ≥20 million sequences. AbNatiV2 improves nanobody nativeness classification across held-out and diverse test sets, and more robustly detects nativeness changes upon CDR grafting. We also introduce p-AbNatiV2, a cross-attention model fine-tuned on 3.7 million paired human sequences. p-AbNatiV2 provides residue- and sequence-level humanness for VH/VL pairs and learns pairing-likelihood via noise-contrastive training. On held-out tests, it assigns the native pair a higher score in 74% of cases, substantially outperfo...