Surreal illustration of targeted cancer imaging with glowing protein structures.

Revolutionizing Cancer Imaging: How a Novel Protein Could Unlock New Treatment Strategies

Soraya Malik in Health & Wellness June 2025 • 4 min read.

"A breakthrough in positron emission tomography (PET) imaging offers new hope for personalized cancer therapy by targeting Programmed Death Ligand-1 (PD-L1)"

In the ever-evolving landscape of cancer treatment, immunotherapy has emerged as a beacon of hope, harnessing the body's own defenses to combat tumors. Central to this approach is understanding the intricate interactions between cancer cells and the immune system, particularly the role of immune checkpoints. These checkpoints, such as Programmed Death Ligand-1 (PD-L1), act as brakes on immune cells, preventing them from attacking cancer cells. However, predicting which patients will respond to therapies targeting these checkpoints remains a significant challenge.

Current methods rely heavily on analyzing biopsied tumor tissue, a process that, while informative, has limitations. Biopsies only capture a snapshot of a tumor's characteristics at a specific location and time, potentially missing the broader picture. Factors like tumor heterogeneity (variations within the tumor itself) and changes in biomarker expression due to prior treatments can lead to inconsistent results. Furthermore, obtaining adequate tissue samples, especially in patients with metastatic disease, can be difficult.

To overcome these limitations, researchers are turning to innovative imaging techniques that can non-invasively visualize PD-L1 expression throughout the body. Among these, positron emission tomography (PET) imaging holds great promise, offering a way to repeatedly assess PD-L1 levels, track changes over time, and improve lesion detection and characterization. The development of a novel engineered small protein for PET imaging of human PD-L1 represents a significant step forward in this field.

What Makes this Novel Protein So Promising for Cancer Imaging?

Surreal illustration of targeted cancer imaging with glowing protein structures.

The newly engineered protein, known as FN3hPD-L1, is designed to bind specifically to PD-L1, allowing it to be visualized using PET scans. This protein is based on a fibronectin type-3 domain (FN3) scaffold, a small and stable structure that offers several advantages over traditional antibody-based imaging agents. Notably, FN3hPD-L1 is significantly smaller than a typical antibody (approximately one-tenth the size), enabling it to clear from the body more quickly and potentially provide clearer images.

The creation and validation of FN3hPD-L1 involved rigorous engineering and testing, including:

Protein Engineering: FN3hPD-L1 was engineered using a human fibronectin type-3 domain (FN3) scaffold.
Affinity Testing: The binder's affinity was assayed in CT26 mouse colon carcinoma cells stably expressing hPD-L1 (CT26/hPD-L1).
Radiolabeling: The protein was labeled with copper-64 (64Cu), a radioactive isotope suitable for PET imaging.
In Vivo Imaging: The radiolabeled protein was injected into mice bearing different types of tumors, and PET scans were performed to assess its ability to target PD-L1.
Immunohistochemistry: The protein's ability to detect PD-L1 in human cancer tissue samples was compared to that of validated PD-L1 antibodies.

The results of these experiments were highly encouraging. FN3hPD-L1 bound to PD-L1 with high affinity, and the radiolabeled protein successfully targeted PD-L1-expressing tumors in mice. Moreover, its performance in human tissue samples was comparable to that of established PD-L1 antibodies, suggesting its potential for clinical use.

Why This Matters: The Potential Impact on Cancer Treatment

The development of FN3hPD-L1 holds significant implications for the future of cancer treatment. By providing a non-invasive and repeatable way to assess PD-L1 expression, this novel protein could help clinicians identify patients who are most likely to benefit from immunotherapy. This personalized approach could lead to more effective treatment strategies, improved patient outcomes, and reduced healthcare costs. Further research and clinical trials are needed to fully realize the potential of FN3hPD-L1, but this innovative imaging agent represents a major step forward in the fight against cancer.

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This article is based on research published under:

DOI-LINK: 10.1158/1078-0432.ccr-18-1871, Alternate LINK

Title: A Novel Engineered Small Protein For Positron Emission Tomography Imaging Of Human Programmed Death Ligand-1: Validation In Mouse Models And Human Cancer Tissues

Subject: Cancer Research

Journal: Clinical Cancer Research

Publisher: American Association for Cancer Research (AACR)

Authors: Arutselvan Natarajan, Chirag B. Patel, Sindhuja Ramakrishnan, Paramjyot S. Panesar, Steven R. Long, Sanjiv S. Gambhir

Published: 2018-10-29

Everything You Need To Know

What is Programmed Death Ligand-1 (PD-L1) and why is it important in cancer treatment?

Programmed Death Ligand-1 (PD-L1) is a protein found on the surface of cancer cells and some immune cells. It acts as a 'brake' on the immune system, preventing immune cells from attacking cancer cells. In cancer treatment, specifically immunotherapy, understanding PD-L1 expression is crucial. Therapies targeting PD-L1 aim to release this brake, allowing the immune system to recognize and destroy cancer cells. Predicting which patients will respond to these therapies depends on accurate PD-L1 assessment, which is where the novel protein FN3hPD-L1 becomes valuable.

How does the newly engineered protein, FN3hPD-L1, improve upon current methods of assessing PD-L1 expression?

Current methods of assessing Programmed Death Ligand-1 (PD-L1) expression rely heavily on biopsies of tumor tissue. These methods have limitations. Biopsies only offer a snapshot of the tumor at a single point in time and location, potentially missing important variations within the tumor (tumor heterogeneity) or changes due to prior treatments. The novel protein, FN3hPD-L1, offers a non-invasive way to visualize PD-L1 expression throughout the body using positron emission tomography (PET) imaging. This allows for repeated assessments, tracking changes over time, and improved lesion detection compared to biopsies. FN3hPD-L1 is also smaller than traditional antibodies, leading to faster clearance and clearer images.

What is the significance of using a fibronectin type-3 domain (FN3) scaffold in the design of FN3hPD-L1?

The fibronectin type-3 domain (FN3) scaffold is a key feature in the design of FN3hPD-L1. It is a small and stable protein structure. FN3 provides several advantages over traditional antibody-based imaging agents. One significant advantage is its size; FN3hPD-L1 is approximately one-tenth the size of a typical antibody, allowing it to clear from the body more quickly. This faster clearance can lead to clearer images in PET scans, which is crucial for accurately assessing Programmed Death Ligand-1 (PD-L1) expression in tumors. This, in turn, can improve the identification of patients likely to benefit from immunotherapy.

Describe the process of creating and validating FN3hPD-L1 for cancer imaging.

The creation and validation of FN3hPD-L1 involved several key steps. First, Protein Engineering was used to design the protein using a human fibronectin type-3 domain (FN3) scaffold. Next, Affinity Testing was conducted using CT26 mouse colon carcinoma cells that stably expressed hPD-L1 (CT26/hPD-L1) to ensure the protein binds specifically to Programmed Death Ligand-1 (PD-L1). Then, Radiolabeling involved labeling the protein with copper-64 (64Cu), a radioactive isotope for PET imaging. In Vivo Imaging was performed by injecting the radiolabeled protein into mice bearing different tumors, followed by PET scans to assess targeting of PD-L1. Finally, Immunohistochemistry compared the protein's ability to detect PD-L1 in human cancer tissue samples with established PD-L1 antibodies.

How could FN3hPD-L1 revolutionize cancer treatment, and what are the next steps?

FN3hPD-L1 has the potential to revolutionize cancer treatment by providing a non-invasive and repeatable method to assess Programmed Death Ligand-1 (PD-L1) expression. This could help clinicians identify patients most likely to benefit from immunotherapy, leading to more effective treatments, improved patient outcomes, and reduced healthcare costs. The next steps involve further research and clinical trials to fully realize its potential. Successful trials could lead to widespread use of FN3hPD-L1 in cancer imaging, personalizing treatment strategies and improving the fight against cancer by accurately identifying suitable patients for immunotherapy based on PD-L1 expression.