We strongly advocate for the prompt manual selection and rigorous experimental assessment of our curated portfolio of ten novel nanobody sequences. These sequences have been meticulously engineered using established structural scaffolds derived from clinically validated nanobody therapeutics, ensuring inherent stability and favorable pharmacological properties suitable for therapeutic development. The engineering strategy focused specifically on optimizing the three Complementarity-Determining Regions (CDRs) to confer specific, high-affinity antigen recognition that surpasses conventional in silico homology-based screening.

Our design process leveraged the generative capabilities of Boltz-Gen for broad sequence space exploration, combined with a structure-centric validation approach that emphasizes dynamic binding interface evaluation. This methodology mitigates the constraints of static structural predictions and identifies the most physiologically relevant binding geometries. Although the resulting CDR-antigen interaction interfaces may yield lower scores on conventional metrics such as ipTM or PAE—an anticipated outcome when designing sequences beyond existing structural databases—we contend that the robustness of our multi-model optimization supports their candidacy, as it prioritizes functional viability and therapeutic mechanism over purely computational scores.

Therefore, these ten structure-informed candidates represent innovative binding mechanisms and structural solutions that merit expert evaluation. They constitute a significant strategic opportunity to advance the development of next-generation nanobody therapeutics.