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Sarel Fleishman is a Professor at the Weizmann Institute of Science and Chief Scientist at Scala Biodesign. His research team focuses on developing computational protein-design methodology to tackle fundamental and applied challenges in biologics and enzyme design. During his postdoc (2007-2011) with 2024 Nobel Laureate in Chemistry, Prof. David Baker, Sarel pioneered the first accurate methods for designing protein binders, notably designing broad-specificity influenza blockers. Since establishing his lab at the Weizmann Institute in 2011, his team has developed a reliable and general protein design strategy used to optimise numerous classes of enzymes, binders, and antibodies. One such designed antibody is currently in phase II clinical trials as a malaria vaccine. Current work emphasises designing large repertoires of antibodies and enzymes for therapeutic and biocatalyst discovery. Sarel has leveraged his research commercially by co-founding two Israeli biotech companies: Infinite Acres, specialising in agritech, and Scala Biodesign, focused on biologics and enzyme design. His academic recognition includes ongoing European Research Council Starting, Consolidator, and Advanced Grants, the Alon Fellowship, the Henri Gutwirth Prize, and the Weizmann Scientific Council Award.

Synthetic antibody repertoires are a foundational technology in therapeutic research but frequently yield candidates with unacceptable developability profiles. We hypothesize this limitation arises because existing construction methods, reliant on random combinations of human germline genes and mutated CDRs, are likely to produce unstable, misfolded, and aggregation-prone molecules. To overcome this, we introduce CADAbRe (Computational design of Antibody Repertoires), the first structure- and energy-based strategy for de novo repertoire design.

CADAbRe selects antibodies based on calculated foldability and stability while simultaneously optimizing the sequence and structural diversity across the full repertoire. We computationally designed billions of foldable, low-energy antibodies. Our design focused on utilizing fully human V and J genes, concentrating sequence diversity exclusively within the hypervariable CDR H3 loop. We then synthesized a half-billion member repertoire, encompassing hundreds of unique V gene combinations, for phage display.

The isolated binders from the CADAbRe repertoire demonstrated exceptional properties. They exhibited significant sequence diversity, successfully exploiting V genes that are often neglected in state-of-the-art synthetic repertoires. Crucially, these binders showed high developability profiles, comparable to clinical-stage antibodies, alongside high affinities and specificities. CADAbRe enables programmable, accelerated, and improved design of universal and targeted antibody repertoires, thereby significantly advancing the process of therapeutic antibody discovery.