Novel Peptide Binder to Glypican-3 Shows High Specificity as a Theranostic Agent for Hepatocellular Carcinoma

A new study presented at the Society of Nuclear Medicine and Molecular Imaging Annual Meeting by lead author Chandrasekhar Bal, MD, of the Department of Nuclear Medicine, All India Institute of Medical Sciences, in New Delhi, India, highlights the development of a novel radiotracer, [⁶⁸Ga]Ga-RYZ-GPC3, which has shown remarkable specificity for detecting hepatocellular carcinoma (HCC). This radiotracer targets glypican-3 (GPC3), a protein commonly overexpressed in HCC, and offers promising potential as both a diagnostic and therapeutic agent.

HCC, the most prevalent primary liver cancer, remains challenging to diagnose and treat effectively, particularly in its early stages. Current imaging methods, such as abdominal ultrasound, triple-phase contrast computed tomography (CT), and magnetic resonance imaging, often fail to detect small lesions under 2 cm accurately. Furthermore, [¹⁸F]FDG positron emission tomography (PET) scans are limited by insufficient uptake in HCC lesions compared with the surrounding liver tissue. Thus, there is a critical need for advanced radiotracers that can provide more precise imaging for HCC.

The newly developed [⁶⁸Ga]Ga-RYZ-GPC3 radiotracer specifically targets GPC3, a cell surface protein largely found in HCC and minimally expressed in normal tissues. This makes it an ideal candidate for improved imaging and targeted therapy.

[⁶⁸Ga]Ga-RYZ-GPC3 is a small peptide-based radiotracer linked to a chelating agent that can bind various radioisotopes, including ⁶⁸Ga. The unlabeled peptide was synthesized and distributed to 3 imaging centers in India for investigator-led trials, each reviewed and approved by institutional review boards and ethics committees.

Patients with a high clinical suspicion or confirmed diagnosis of HCC received an injection of [⁶⁸Ga]Ga-RYZ-GPC3 (1.5-5.5 mCi) and underwent PET/CT scans at scheduled intervals. Some patients also had companion [¹⁸F]FDG PET/CT scans to compare the efficacy of the new radiotracer.

The study included 72 patients with HCC, with a median age of 60 years, and 22% were female. Most (69%) patients had liver cirrhosis, with hepatitis B, hepatitis C, or nonalcoholic steatohepatitis as the primary causes. Ninety percent of patients showed at least 1 positive lesion on [⁶⁸Ga]Ga-RYZ-GPC3 scans.

The median maximum standardized uptake value (SUVmax) for GPC3-positive liver lesions was 13.2, significantly higher than the median liver SUVmean of 1.6. Physiologic uptake was mostly seen in the kidneys, with a median SUVmean of 10.9.

Among the 19 patients who also underwent [¹⁸F]FDG PET/CT scans, the median SUVmax for liver lesions was 7.2 with [⁶⁸Ga]Ga-RYZ-GPC3, compared with 3.7 with [¹⁸F]FDG, indicating superior detection capability. Six patients with high [⁶⁸Ga]Ga-RYZ-GPC3 uptake were identified as potential candidates for GPC3-targeted therapy using [¹⁷⁷Lu]Lu-RYZ-GPC3.

The initial human imaging results demonstrate that [⁶⁸Ga]Ga-RYZ-GPC3 offers high specificity for HCC lesions, significantly outperforming conventional [¹⁸F]FDG PET/CT. Additionally, this radiotracer shows potential for therapeutic applications when labeled with therapeutic radioisotopes like ¹⁷⁷Lu or ²²⁵Ac.

These findings suggest that [⁶⁸Ga]Ga-RYZ-GPC3 could significantly enhance the detection and treatment of HCC, marking it as a promising theranostic agent.