FairJourney Bio has published a peer‑reviewed study in mAbs describing a novel antibody‑engineering approach designed to improve the therapeutic window of IL‑12, one of the most potent anti‑tumor cytokines.
The end‑to‑end discovery and engineering campaign was delivered across the company’s sites in Porto and Cambridge.
IL‑12 development has long been constrained by severe immune‑related systemic toxicity. Previous attempts to improve its therapeutic window, including intratumoral dosing and protease‑cleavable pro‑drugs, have shown limited clinical success.
The paper, ‘Conditional activation of IL‑12 through a Fibronectin‑EDB dependent switch gate’, details the generation of a dual‑specificity Fab engineered to bind competitively to IL‑12 and fibronectin‑EDB, a tumor‑associated matrix antigen. This reversible switch masks IL‑12 until it encounters fibronectin‑EDB, enabling conditional activation within the tumor microenvironment.
The authors describe what they report as the first demonstration of a reversible trans‑activation logic gate for tumor‑conditional cytokine delivery. In vitro data shows fibronectin‑EDB‑dependent IL‑12 availability and activity. Quantitative systems pharmacology modeling predicts a substantially improved therapeutic window.
The format combines a dual‑specificity switch arm with a separate, higher‑affinity fibronectin‑EDB targeting arm. Modeling was used to define binding parameters before a candidate existed. Working to this predefined affinity window, FairJourney Bio introduced IL‑12 binding into existing fibronectin‑EDB binders using targeted mutagenesis, then optimised both specificities through a two‑stage combinatorial engineering campaign. Affinities were tuned against one another to enable competitive binding while supporting avidity‑driven tumor localisation and conditional IL‑12 activation.
Teresa Barata, Chief Scientific Officer and co‑author, said: “Harnessing the potent anti‑tumor activity of IL‑12 while limiting systemic toxicity has challenged researchers for almost 30 years.”
She added: “We are proud of the role our teams played in engineering this complex antibody format, developing a switch molecule that unmasks IL‑12 only where it is needed.”
