FairJourney Bio delivers antibody engineering for novel tumor-conditional IL-12 therapeutic approach that unlocks the potential of localized cytokine activation

FairJourney Bio ("FJBio"), a global antibody discovery expert, today announced the publication of a peer-reviewed study in mAbs describing a novel approach with the potential to improve the therapeutic window of IL-12, a potent anti-tumor cytokine. FJBio delivered the end-to-end antibody discovery and engineering campaign for the venture-backed oncology program across its sites in Porto, Portugal, and Cambridge, UK.

IL-12 is one of the most potent anti-tumor cytokines, but its development has been limited by severe immune-related systemic toxicity. Previous strategies to improve its therapeutic window, including intratumoral dosing, half-life extension and protease-cleavable pro-drugs, have had limited clinical success.

The paper, 'Conditional activation of IL-12 through a Fibronectin-EDB dependent switch gate', reports the generation of a dual-specificity antigen-binding fragment (Fab) engineered to bind competitively to IL-12 and fibronectin-EDB (FN-EDB), a tumor-associated matrix antigen. This reversible switch is designed to mask IL-12 until it encounters FN-EDB, enabling its conditional activation in the tumor microenvironment.

The study describes what the authors report as the first demonstration of a reversible trans-activation logic gate for tumor-conditional cytokine delivery. In vitro data demonstrates FN-EDB-dependent IL-12 availability and activity, while quantitative systems pharmacology (QSP) modeling predicts a substantially improved therapeutic window for the approach.

The novel format combines a dual-specificity switch arm with a separate, higher-affinity FN-EDB targeting arm. QSP modeling was used to define the binding parameters required for the switch to function before a candidate existed. Working to this predefined affinity window, FJBio introduced IL-12 binding into existing FN-EDB binders using targeted mutagenesis, before optimizing both specificities through a two-stage combinatorial engineering campaign. The resulting affinities were then tuned against one another, enabling the switch arm to bind competitively to IL-12 or FN-EDB, while the targeting arm supports avidity-driven localization to the tumor and conditional activation of IL-12.

Harnessing the potent anti-tumor activity of IL-12 while limiting systemic toxicity has challenged researchers for almost 30 years. 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. This campaign demonstrates FJBio's ability to partner at the most challenging end of discovery, engineering to a narrow, pre-defined specification and delivering a solution that recognizes two completely unrelated targets and holds them in balance. We are hugely excited by the potential this has in oncology and future treatments."

Teresa Barata, PhD, Chief Scientific Officer and Co-Author, FairJourney Bio