mAbs · Available online 23 Jul 2026 · In press · DOI 10.1080/19420862.2026.2700812
Josephine D. Kahn, Kothai Parthiban, Peter Slavny, Aaron Arvey, Marc Presler, Jamie Nosbisch, Adrienne Rothschilds, Allan Capili, Teresa Barata, Joana Martins, Jiang Zhu, Robert Kamen, Robert Tepper, Ton N. Schumacher, Lioudmila Tchistiakova, Divya Mathur
Potent immune-activators, such as interleukin-12 (IL-12) have been challenging to develop for the treatment of solid tumors due to high systemic toxicity. To expand the therapeutic window achievable with IL-12, we engineered a novel and reversible antibody format, comprising a switch arm and targeting arm, that permits conditional activation of IL12 only in the presence of the pan-tumor matrix antigen Fibronectin-EDB (FN-EDB). The switch arm is formed by a dual specificity Fab that binds to tethered IL-12 or FN-EDB in a competitive manner. The FN-EDB targeting arm promotes the avidity‑driven unveiling of IL-12 that is tethered to the switch arm. We employed a quantitative systems pharmacology (QSP) model to define binding parameters required for Switch-IL-12 activity and use a phage screening and rational library design process to generate switch binders with the desired binding profiles. We show that our in vitro functional data support FN-EDB dependent Switch-IL-12 activity and incorporate these data into our QSP model to further refine and expand the therapeutic index of Switch-IL-12.
Abstract from DOAJ. Public domain (CC0 1.0).
Read the article at the publisher →
Kahn, J., Parthiban, K., Slavny, P., et al. (2026). Conditional activation of IL-12 through a Fibronectin-EDB dependent switch gate. mAbs. https://doi.org/10.1080/19420862.2026.2700812