The clinical impact of PD-1/PD-L1 inhibitors remains limited, as the vastmajority of cancer patients ultimately experience relapse or lack a durable response.Conversely, the therapeutic potential of IL-2, a pioneering immunotherapy cytokine,has been historically overshadowed by its severe toxicity and narrow therapeuticwindow. While past efforts to develop safer IL-2 variants with reduced Treg bias(non-alpha IL-2) have seen scant clinical success, they have spurred the development of anew class of PD-1/IL-2 bispecific molecules. These agents are engineered to achievecis-engagement and deliver alpha biased IL-2 signal specifically to PD-1-high andCD25-high CD8+ T cells within the tumor microenvironment.MBS309 was engineered to enhance the safety of IL-2 in cancers relapsed orresistant to PD-1/PD-L1 therapy. It consists of an alpha-biased IL-2 variant fused to theC-terminus of pembrolizumab (Keytruda). This design retains IL-2's binding toIL-2Ralpha while significantly reducing its interaction with IL-2Rbetagamma. In vitro studiesdemonstrated that MBS309 exhibits activity restricted to PD-1 targets. As amonotherapy, MBS309 elicited robust anti-tumor responses across a range ofpreclinical xenograft models, regardless of their intrinsic sensitivity to PD-1 inhibition.In mice, MBS309 showed a favorable safety profile, characterized by a longerhalf-life compared to a clinical-stage benchmark and significantly reduced systemictoxicity. At a dose of 20 mg/kg, it exhibited less toxicity. Pharmacodynamic investigations revealed the mechanistic basis for this improved therapeutic window:MBS309 induced dampened T cell activation in normal tissues while achieving potentintra-tumoral CD8+ T cell expansion comparable to the benchmark.The compelling preclinical profile of MBS309, characterized by robustanti-tumor efficacy and a favorable safety window, warrants its further clinicalinvestigation as a promising therapeutic candidate for oncology.Disclosures: All the authors are employees from Beijing Mabworks Biotech Co. Ltd