Oncoleader

PD-L1-Targeting Lipid Nanoparticles

Northwestern researchers developed PD-L1-targeting lipid nanoparticles to directly neutralize or eliminate immunosuppressive cells in the tumor. This transforms PD-L1 from a checkpoint protein into a target for precise drug delivery.

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The Challenge:

Immune checkpoint inhibitors have low response rates in the clinic.

Immune checkpoint inhibitors (ICIs), such as PD-1 or PD-L1 antibodies, revolutionized cancer treatment by inhibiting the interaction between PD-1 and PD-L1, thereby preventing tumor cells from suppressing T cells.

However, many solid tumors contain abundant immunosuppressive cells – especially tumor-associated myeloid cells (TAMCs) – which express high levels of PD-L1 but can promote cancer through multiple mechanisms beyond PD-L1-mediated suppression.

By simply inhibiting PD-1/PD-L1, traditional ICIs alone often fall short.

But! What if, instead of merely inhibiting PD-L1 engagement, we use it as a target to aim at. This would enable the design of precision therapeutics that selectively eliminate PD-L1-high cells like cancer cells and TAMCs.

In other words, we transform PD-L1 from a checkpoint molecule into a bullseye…

The Invention:

This is exactly what researchers in Maciej Lesniak’s lab at Northwestern University have done. They have developed a therapeutic strategy that turns PD-L1 expression from a challenge into an advantage.

How?

Instead of simply blocking PD-L1 interactions, they designed lipid nanoparticles (LNPs) that are coated with anti-PD-L1 antibodies, actively directing these nanoparticles toward PD-L1-rich immunosuppressive cells like tumor-associated myeloid cells (TAMCs). Once bound, the nanoparticles efficiently deliver their therapeutic payload, dinaciclib (a potent CDK5 inhibitor) directly into these cells.

At very low concentrations, dinaciclib suppresses PD-L1 expression and inhibits multiple immunosuppressive pathways within TAMCs – at higher concentrations, it can even induce apoptosis, facilitating their complete elimination.

This approach doesn’t just reignite the immune system, it actively dismantles the immunosuppressive infrastructure tumors rely on, offering a multi-dimensional approach to immune checkpoint inhibition.

Differentiation & Potential Risks

Differentiation:

Novel mechanism: Transforms PD-L1 from a checkpoint to a targeted delivery address, enabling precision elimination of immunosuppressive PD-L1+ cells.
Multi-dimensional immune modulation: Unlike traditional checkpoint inhibitors, this actively removes cells responsible for multiple immunosuppressive mechanisms, going beyond mere checkpoint blockade.
Avoiding systemic toxicities: plenty of healthy cells throughout the body express PD-L1, so something like a PD-L1 targeting ADC would be toxic, but these LNPs are injected into the tumor, avoiding systemic toxicities.
Advanced LNP technology: Leverages recent advances in antibody-LNP conjugation.

Potential Risks:

Manufacturing complexity: LNP formulation and antibody-conjugation processes can be technically challenging and expensive at large scale.
Limited tissue penetration: Antibody-coated LNPs (~100 nm in diameter) may struggle to diffuse deeply into dense tumor microenvironments, likely requiring direct intratumoral injection, restricting clinical applications, complicating re-dosing, and adding burden to the overall process.

Why This Matters Now

Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 antibodies have revolutionized oncology, but even in easily accessible solid tumors, such as melanoma, lung, and renal cancers, response rates rarely surpass 20-40%.

With ICIs now used in approximately 50% of cancer treatment regimens for these tumor types, there’s an urgent need for innovative approaches that tackle broader mechanisms of immune suppression.

This new therapeutic paradigm offers a timely and transformative opportunity to meaningfully enhance response rates and patient outcomes across multiple indications.

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Key Scientist

Maciej Lesniak, MD

Chair of Neurological Surgery | Feinberg School of Medicine

Key Publications

Published: 11 Nov 2019

Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma

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