Abstract Background: MDNA113 comprises of a core anti-PD1-IL-2SK with ‘β-enhanced, not-α’ receptor selectivity, a removable IL-2 masking domain and an IL-13SK tumor targeting moiety. Anti-PD1-IL-2SK is designed to facilitate cis-binding to maximize synergy between IL-2R signaling and PD1/PDL1 blockade. The IL-2 masking domain blocks binding to IL-2R to minimize systemic toxicity until removal by proteases enriched within the tumor microenvironment (TME). The IL-13SK selectively binds the IL-13Rα2 decoy receptor overexpressed in a broad range tumors but not normal tissues, thereby effectively promoting accumulation at the tumor sites. We present preliminary characterization of MDNA113, designed to enhance systemic tolerability while maximizing therapeutic efficacy within the TME. Methods: Receptor binding was measured using the Octet Biolayer Interferometry (BLI) platform. IL-2R signaling and PD1/PDL1 blockade were assessed using in vitro cell reporter assays. In vivo pharmacodynamic and efficacy studies were conducted in the MC38 mouse syngeneic colon tumor model. Results: MDNA113 binds IL-2Rβ with a 150-fold lower affinity than a non-masked anti-PD1-IL-2SK (MDNA223). Binding to IL-13Rα2 and PD1 are not affected. The potency of MDNA113 in IL-2R signaling is reduced by 1000-fold with no change in PD1/PDL1 blockade. Removal of the masking domain by metalloproteases fully restores IL-2R signaling. Mice treated with MDNA113 showed significantly reduced lymphocyte expansion compared to equimolar dose of MDNA223, correlating with enhanced tolerability. In an MC38 colon tumor model, MDNA113 significantly inhibited tumor growth whereas efficacy was compromised when mice were treated with an uncleavable version of MDNA113, indicating that removal of the masking domain activates immune effector cells within the TME. Accordingly, treatment with cleavable MDNA113 resulted in increased tumor infiltration effector CD8+ T cells expressing Granzyme B. MDNA113 variants comprising of approved human anti-PD1 antibodies show similar characteristics and studies in non-human primate to evaluate safety, pharmacodynamics and pharmacokinetics are underway. Conclusions: MDNA113 is a novel Bifunctional SuperKine for Immunotherapy (BiSKIT) with tumor targeting capability to enhance tolerability and maximize therapeutic response by synergizing IL-2R agonism and PD1/PDL1 blockade within the TME. Citation Format: Minh D. To, Rosemina Merchant, Aanchal Sharma, Fahar Merchant. MDNA113 is a masked conditionally activated tumor-targeted anti-PD1-IL-2SK with superior safety and therapeutic properties abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4342.
To et al. (Fri,) studied this question.