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

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

Study in mAbs describes the first reported demonstration of a reversible trans-activation logic gate for tumour-conditional cytokine delivery
FJBio engineered dual-specificity Fabs to meet model-defined affinity window through an end-to-end campaign across Porto and Cambridge

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-tumour cytokine¹. FJBio delivered the end-to-end antibody discovery and engineering campaign for the venture-backed oncology programme across its sites in Porto, Portugal and Cambridge, UK.

IL-12 is one of the most potent anti-tumour 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 ofa dual-specificity antigen-binding fragment (Fab) engineered to bind competitively to IL-12 and fibronectin-EDB (FN-EDB), a tumour-associated matrix antigen. This reversible switch is designed to mask IL-12 until it encounters FN-EDB, enabling its conditional activation in the tumour 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 optimising 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 localisation to the tumour and conditional activation of IL-12.

Teresa Barata, PhD, Chief Scientific Officer and co-author, FairJourney Bio, commented: “Harnessing the potent anti-tumour 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 recognises two completely unrelated targets and holds them in balance. We are hugely excited by the potential this has in oncology and future treatments.”