Kazia Therapeutics Unveils NDL2 to Address Immunotherapy Resistance

Kazia Therapeutics announced "compelling" preclinical and translational data supporting the development of NDL2, a potentially first-in-class protein degrader that is designed to selectively eliminate nuclear PD-L1, a previously unrecognized intracellular driver of immunotherapy resistance and metastatic progression that is not addressed by currently approved PD-1/PD-L1 antibodies. Across multiple preclinical models and patient-derived samples, NDL2 demonstrated reversal of immune exhaustion, suppression of metastatic biology, and enhanced anti-tumor activity, including in combination with anti-PD-1 therapy. The data collectively support nuclear PD-L1 as a mechanistically distinct and therapeutically actionable driver of immune evasion, disease progression, and metastasis. Unlike PD-1/PD-L1 antibodies that block extracellular signalling, NDL2 is designed to target nuclear PD-L1 proteins that are linked to aggressive and therapeutically resistant mesenchymal and stem-like cancer phenotypes. In murine triple-negative breast cancer preclinical models, NDL2 reduced primary tumor volume by 49% as monotherapy and 73% in combination with anti-PD-1, with 50% reduction in lung metastases in the combination setting, with no observed toxicity, no hemolysis, preserved immune checkpoint function at the cell surface, and favorable plasma stability. Nuclear PD-L1 was shown to be enriched in immunotherapy-resistant tumor cells, metastatic lesions, and circulating tumor cells, and to regulate gene programs associated with invasion, survival, and immune suppression. These findings support a precision-guided development strategy, integrating therapy and diagnostics from the outset.