CDR Conformation Aware Antibody Sequence Design with ConformAb

Sinha, I.; Stanton, S.; Lillington, S.; Robinson, S. A.; Nerli, S.; Zadorozhny, K.; Kleinhenz, J.; MohammadiPeyhani, H.; Dillon, M.; Chen, Y.; Bevers, J.; Wu, Y.; Watkins, A. M.; Dwyer, H.; Bonneau, R.; Cho, K.; Seeger, F.; Gligorijevic, V.; Kelow, S.

doi:10.1101/2025.11.12.688095

bioRxiv · 10.1101/2025.11.12.688095

CDR Conformation Aware Antibody Sequence Design with ConformAb

Sinha, I.·Stanton, S.·Lillington, S.·Robinson, S. A.·Nerli, S.·Zadorozhny, K.·Kleinhenz, J.·MohammadiPeyhani, H.·Dillon, M.·Chen, Y.·Bevers, J.·Wu, Y.·Watkins, A. M.·Dwyer, H.·Bonneau, R.·Cho, K.·Seeger, F.·Gligorijevic, V.·Kelow, S.

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Abstract

Antibody lead optimization methods seek to enhance a lead candidates therapeutic properties through targeted sequence mutation. However, the mutations introduced during this process can inadvertently induce structural changes that disrupt binding, particularly by altering CDR loop conformations which destabilize CDR-target binding interactions. To address this, we present ConformAb, a guided discrete diffusion model for designing antibody sequences that explicitly conform to the CDR canonical conformation of the lead. With seed sequences as the starting point, we show that our method is capable of generating 3- 5x better binders that conform to the same CDR backbone structure in a one-shot design setup, and in some cases, binders with better affinity than seed repertoire picks without any target-specific data included in training. Across the targets tested, ConformAb demonstrated binding rates ranging from 15 -60% in wet lab experiments, a result obtained using fewer than 100 designs for each target. ConformAb offers a unique one-shot approach for antibody lead optimization in data-scarce scenarios where experimental/repertoire data cannot be leveraged for model training.

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Sinha, I., Stanton, S., Lillington, S., Robinson, S. A., Nerli, S., Zadorozhny, K., Kleinhenz, J., MohammadiPeyhani, H., Dillon, M., Chen, Y., Bevers, J., Wu, Y., Watkins, A. M., Dwyer, H., Bonneau, R., Cho, K., Seeger, F., Gligorijevic, V., Kelow, S.. 2025-11-13. CDR Conformation Aware Antibody Sequence Design with ConformAb. https://doi.org/10.1101/2025.11.12.688095

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