Beyond Checkpoints: How PD-L1 Degraders Could Revolutionize Cancer Immunotherapy
For decades, the promise of immunotherapy – harnessing the body’s own immune system to fight cancer – has been tantalizingly close. While checkpoint inhibitors like Keytruda and Opdivo have delivered remarkable results for some, a significant portion of patients either don’t respond or develop resistance. Now, a new frontier is emerging: not just blocking PD-L1, but actively degrading it. This shift, exemplified by Kazia Therapeutics’ recent collaboration with QIMR Berghofer on the NDL2 program, could redefine treatment paradigms and unlock benefits for a wider range of cancer patients.
The Limitations of Current Immunotherapy Approaches
Traditional checkpoint inhibitors work by preventing PD-L1 on tumor cells from binding to PD-1 on T cells, effectively releasing the brakes on the immune system. However, this approach primarily targets PD-L1 expressed on the cell surface. Emerging research reveals that PD-L1 also exists in modified forms, residing not just on the surface but also within the cell itself – in the cytoplasm and nucleus. These intracellular pools contribute to resistance, allowing cancer cells to evade immune attack even when surface PD-L1 is blocked. This is where the concept of PD-L1 degradation comes into play.
NDL2: A Novel Approach to PD-L1 Targeting
NDL2, a first-in-class bicyclic peptide degrader developed by Professor Sudha Rao at QIMR Berghofer, represents a fundamentally different strategy. Unlike antibodies that simply block PD-L1, NDL2 is designed to actively seek out and destroy all functional forms of the protein, both on the cell surface and within the cell. It achieves this by binding to PD-L1 and recruiting the cell’s natural protein disposal machinery – a process known as targeted protein degradation (TPD). This comprehensive approach has the potential to overcome resistance mechanisms that antibody therapies can’t reach.
The Science Behind Targeted Protein Degradation
Targeted protein degradation is a rapidly evolving field in drug discovery. Instead of inhibiting a protein’s function, TPD aims to eliminate the protein altogether. This can be particularly effective for proteins like PD-L1, where resistance often arises from increased expression or the presence of modified forms. Recent advancements in PROTACs (Proteolysis-Targeting Chimeras) and molecular glues have highlighted the potential of TPD, and NDL2 represents a novel application of this technology in immuno-oncology.
Preclinical Promise and Future Development
Preclinical studies of NDL2 in aggressive triple-negative breast cancer (TNBC) have shown significant tumor growth reduction, both as a standalone therapy and in combination with anti-PD-1 treatments. Importantly, these studies also demonstrated reduced T-cell exhaustion and enhanced immune activity, supporting NDL2’s dual mechanism of action. Kazia Therapeutics plans to initiate IND-enabling studies within six months, with the goal of starting first-in-human trials within approximately 15 months. The initial focus will be on advanced breast cancer and non-small cell lung cancer (NSCLC), two cancers where PD-1/PD-L1 therapies are widely used but resistance remains a major challenge.
Synergistic Potential with Existing Therapies
Kazia isn’t just developing NDL2 in isolation. The company intends to explore synergistic combinations with its existing pipeline assets, including paxalisib (a PI3K/mTOR inhibitor) and EVT801 (a VEGFR3 inhibitor). These combinations could modulate the tumor microenvironment, further enhancing the effectiveness of NDL2 and potentially overcoming additional resistance mechanisms. This strategic approach highlights the growing trend towards combination immunotherapies designed to address the complexity of cancer.
Implications for the Future of Cancer Treatment
The development of PD-L1 degraders like NDL2 signals a significant shift in the landscape of cancer immunotherapy. By targeting the root cause of resistance – the presence of both surface and intracellular PD-L1 – these therapies offer the potential to benefit a broader patient population and achieve more durable responses. While still in the early stages of development, NDL2 represents a compelling example of how innovative approaches to targeted protein degradation could revolutionize cancer treatment in the years to come. The success of this program will likely spur further investment and research into similar degrader technologies, accelerating the development of next-generation immunotherapies.
What are your predictions for the role of protein degraders in future cancer treatments? Share your thoughts in the comments below!
