Kazia Therapeutics Limited has entered into an exclusive collaboration and in-licensing agreement with QIMR Berghofer for NDL2, a novel PD-L1 protein degrader that represents a potentially transformative approach to overcoming immunotherapy resistance in cancer treatment.
Novel Mechanism Addresses Immunotherapy Resistance
NDL2, discovered and developed by Professor Sudha Rao at QIMR Berghofer, takes a fundamentally different approach from traditional checkpoint inhibitors. While established therapies like pembrolizumab (Keytruda®) and nivolumab (Opdivo®) use monoclonal antibodies to block PD-L1 surface interactions, NDL2 is designed to specifically recognize and degrade post-translationally modified forms of PD-L1 that contribute to treatment resistance.
These modified PD-L1 proteins are enriched in patients who fail or relapse on checkpoint inhibitor therapy and are found not only on the cell surface but also in the cytoplasm and nucleus, where they drive resistance and tumor progression. By recruiting the cell's natural protein disposal machinery, NDL2 drives the breakdown and clearance of modified PD-L1 across all cellular compartments.
"NDL2 has the potential to redefine immunotherapy by targeting all functional pools of PD-L1 protein, not just the surface expression blocked by current antibodies," said Professor Sudha Rao, Principal Investigator at QIMR Berghofer and inventor of the PD-L1 degrader program.
Promising Preclinical Results
In preclinical models of aggressive triple-negative breast cancer (TNBC), NDL2 demonstrated significant tumor growth reduction both as monotherapy and in combination with anti-PD-1 therapies. Treated tumors showed reduced T-cell exhaustion and enhanced immune activity, consistent with NDL2's dual mechanism of action. Importantly, no toxicity has been observed across the preclinical work to date.
The comprehensive degradation strategy is believed to offer two major clinical advantages: overcoming resistance in both primary non-responders and patients who relapse on antibody therapies, and providing durable immune reactivation by restoring cytotoxic T-cell function and reducing T-cell exhaustion in the tumor microenvironment.
Development Timeline and Target Indications
The program will initially target advanced breast cancer and non-small cell lung cancer (NSCLC), where PD-1/PD-L1 immunotherapies are widely used but resistance remains common. IND-enabling studies are expected to commence within six months, with a goal of initiating first-in-human studies within approximately 15 months.
Professor Rao and QIMR Berghofer are working with world-leading oncology peptide manufacturers to optimize the stability, potency, pharmacokinetics and pharmacodynamics of the NDL2 formulation.
Strategic Combination Opportunities
Kazia intends to explore synergistic opportunities to combine NDL2 with its existing pipeline assets, including paxalisib (a pan-PI3K/mTOR inhibitor) and EVT801 (a selective VEGFR3 inhibitor), given their complementary mechanisms of action in modulating the tumor microenvironment.
"This Agreement positions Kazia at the forefront of next-generation immuno-oncology," commented Dr. John Friend, Chief Executive Officer of Kazia Therapeutics. "NDL2 is a truly first-in-class asset, representing an advanced PD-L1 degrader, and what we believe one of the most exciting innovations in targeted protein degradation."
Financial Terms
Under the collaboration agreement, Kazia will make a one-time payment of approximately $1.39 million 15 business days after signing and is responsible for all development costs. Kazia will share a percentage of commercialization revenue, which includes any out-licensing payments received from third parties.
