Landscape-scale navigation unlocks antibody CDR structural logic for AI-guided rescue and therapeutic optimization

Chun, C.; Sohn, B.-K.; Ki, H.; Jo, J. H.; An, H.-T.; Park, J.; Lee, J.; Choi, S.; Choi, J.; Cho, H.; Lee, S. B.; Yu, B.; Lee, C. Y.; Kim, J. E.; Ban, Y.-j.; Choi, Y.-Y.; Choi, B.; Lee, H.; Chung, J.; Baek, M.; Yoon, T.-Y.

doi:10.64898/2026.04.21.719857

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bioRxiv · 10.64898/2026.04.21.719857

Landscape-scale navigation unlocks antibody CDR structural logic for AI-guided rescue and therapeutic optimization

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Abstract

While AI offers transformative potential for therapeutic antibody design, the lack of ground-truth data fundamentally constrains our ability to model the epistatic topology of fitness landscapes. Here, we establish a high-throughput workflow to characterize tens of thousands of antibody variants per week with gold-standard biophysical precision. By combinatorially assembling functional variants from deep mutational scanning, we charted antibody fitness landscapes comprising over 17,000 data points, which revealed an extremely rugged, non-navigable epistatic topology. Yet, navigating at this unprecedented scale enabled the discovery of rare peak clusters exhibiting simultaneous enhancements in affinity and productivity. Strikingly, ProteinMPNN predicted the CDR-dependent productivity landscape with remarkable accuracy, suggesting that sequence-structure compatibility within CDRs gates cellular productivity. This insight enabled a structure-guided rescue strategy combining AlphaFold3 and ProteinMPNN, which successfully restored the cellular productivity of high-affinity, low-productivity clones via single amino acid substitutions. Two elite variants drawn directly from peak clusters further demonstrated 20- to 100-fold in vivo efficacy gains in a murine psoriasis model. Our findings establish CDR structural fitness as a fundamental determinant of antibody cellular productivity and validate landscape-scale navigation as a powerful framework for therapeutic antibody optimization.

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Chun, C., Sohn, B.-K., Ki, H., Jo, J. H., An, H.-T., Park, J., Lee, J., Choi, S., Choi, J., Cho, H., Lee, S. B., Yu, B., Lee, C. Y., Kim, J. E., Ban, Y.-j., Choi, Y.-Y., Choi, B., Lee, H., Chung, J., Baek, M., Yoon, T.-Y.. 2026-04-23. Landscape-scale navigation unlocks antibody CDR structural logic for AI-guided rescue and therapeutic optimization. https://doi.org/10.64898/2026.04.21.719857

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