Kazia Therapeutics, an oncology-focused pharmaceutical company developing novel therapies for difficult-to-treat cancers, has 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 unrecognised 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-tumour activity, including in combination with anti-PD-1 therapy.
By applying targeted protein degradation to one of the most clinically validated targets in oncology (PD-L1), Kazia aims to address a fundamental limitation of current immunotherapies while advancing a program aligned with growing strategic interest in protein degraders.
Key highlights
Potentially first-in-class nuclear PD-L1 degrader targets a newly discovered epigenetically regulated intracellular PD-L1 species driving immune evasion, metastasis, and resistance to checkpoint inhibitors.
• Clear mechanistic differentiation: 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 (TNBC) preclinical models, NDL2 reduced primary tumour volume by 49% as monotherapy and 73% in combination with anti-PD-1, with 50% reduction in lung metastases in the combination setting.
• Favourable preclinical safety and pharmacokinetics (PK) profile: No observed toxicity, no haemolysis, preserved immune checkpoint function at the cell surface, and favourable plasma stability.
Nuclear PD-L1: a newly identified driver of resistance and metastasis
Despite the transformative impact of immune checkpoint inhibitors, most solid tumours develop primary or acquired resistance, frequently accompanied by metastatic progression. Kazia’s collaborators identified nuclear PD-L1 as a transcriptionally active regulator that promotes:
- Epithelial (benign) to Mesenchymal (aggressive) Transition (EMT)
- Cancer stem-like phenotypes
- Metastatic dissemination
- Immune exhaustion and evasion.
Nuclear PD-L1 was shown to be enriched in immunotherapy-resistant tumour cells, metastatic lesions, and circulating tumour cells (CTCs), and to regulate gene programs associated with invasion, survival, and immune suppression. Importantly, this intracellular PD-L1 pool is not addressed by existing PD-1/PD-L1 antibodies, representing a previously inaccessible resistance mechanism.
Robust translational and liquid biopsy evidence
Using an advanced epigenetic digital pathology and liquid biopsy platform, researchers demonstrated that:
- Nuclear PD-L1 is selectively enriched in resistant and metastatic tumours, including TNBC, melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer.
- Distinct nuclear versus cytoplasmic PD-L1 post-translational modification states can be reliably quantified in circulating tumour cells.
- Longitudinal liquid biopsy analysis showed that reductions in nuclear PD-L1 preceded radiographic tumour responses, supporting its potential utility as an early predictive biomarker of treatment benefit.
These findings support a precision-guided development strategy, integrating therapy and diagnostics from the outset.
