MDNA113是一种经掩蔽、条件性激活的肿瘤靶向抗PD1-IL-2 SK，具有卓越的安全性和治疗特性

Background: MDNA113 comprises of a core anti-PD1-IL-2 SK with ‘beta-enhanced, not-alpha' receptor selectivity, a removable IL-2 masking domain and an IL-13 SK tumor targeting moiety. Anti-PD1-IL-2 SK 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-13 SK selectively binds the IL-13Ralpha2 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-2Rbeta with a >150-fold lower affinity than a non-masked anti-PD1-IL-2 SK (MDNA223). Binding to IL-13Ralpha2 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.