A groundbreaking development in the treatment of HER2-positive breast cancer has emerged, heralding a new era in radioimmunotherapy that promises both efficacy and safety. Published in the November 2025 issue of The Journal of Nuclear Medicine, this novel therapeutic strategy leverages a pretargeted radioimmunotherapy (PRIT) system centered on the alpha-emitter Actinium-225 (^225Ac). The approach is designed to pre-treat tumors before delivering the lethal alpha radiation, thereby achieving durable tumor eradication while minimizing harm to healthy tissues. This research marks a significant stride towards precision oncology, especially for aggressive breast cancer subtypes that have historically presented formidable treatment challenges.
Human epidermal growth factor receptor 2 (HER2), a well-established oncogenic driver, is overexpressed in approximately 15 to 20 percent of breast cancers, correlating with high aggressiveness and poor clinical outcomes. Current HER2-targeted therapies have improved patient prognosis but often induce severe adverse effects and are prone to resistance mechanisms within tumor cells. To overcome these limitations, the team led by researchers from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center has innovated a highly sophisticated three-step HER2-targeted ^225Ac-PRIT regimen that maximizes tumor suppression while mitigating systemic toxicity.
Prior clinical attempts employing ^225Ac-labeled antibodies demonstrated promising antitumor activity but were hampered by the retention of alpha-particles in healthy organs, causing significant off-target toxicities. The current research circumvents this by implementing a sequential intravenous protocol starting with a bispecific antibody designed to bind HER2 on tumor cells and a radiometal chelator DOTA. This is followed by administration of a clearing agent that accelerates removal of unbound antibodies from circulation, consequently reducing nonspecific radiation. Finally, the ^225Ac-labeled radiotherapeutic agent is introduced, selectively binding the pretargeted tumor cells and delivering potent alpha radiation exactly where it is needed.
Extensive preclinical evaluation was carried out using the BT-474 human breast cancer xenograft model, which accurately recreates HER2-expressing tumor biology. Dose-finding studies assessed tumor-targeting efficiency, biodistribution, and toxicity profiles, especially nephrotoxicity, a major limiting factor in radionuclide therapy due to kidney accumulation. The researchers applied either one or two treatment cycles spaced by one week, carefully monitoring therapeutic responses and systemic side effects over an extended period.
Remarkably, all treated mice in the BT-474 xenograft model achieved complete tumor responses, with 85% evidencing histologic cures upon microscopic examination. This indicates not just tumor shrinkage but complete pathological eradication. Additionally, one-cycle interventions were as potent as two-cycle regimens, suggesting that treatment intensity can be optimized to reduce exposure without compromising outcomes. Throughout the study, no chronic radiation-induced toxicity was detected in vital organs, underscoring the regimen’s favorable safety profile.
In a compelling extension of the work, the therapy was tested on a patient-derived xenograft (PDX) model, which reproduces the heterogeneity and complexity of human tumors more faithfully. A single cycle of ^225Ac-PRIT elicited complete responses in 60% of PDX-bearing mice and significantly prolonged survival relative to untreated controls. Such translational findings hint at the modality’s potential applicability in clinical settings, offering hope for patients with refractory or advanced HER2-positive breast cancers who have limited therapeutic options.
A critical component of the study was the quantification of nephrotoxic absorbed doses, which delineated upper radiation thresholds to prevent irreversible kidney damage. Understanding these parameters is essential for guiding safe dose escalation in future clinical trials. The precise calibration of dosage and scheduling exemplifies the rational, methodical approach the investigators employed in balancing therapeutic benefit with toxicity risk.
The implications of this research are profound. By integrating molecular targeting with alpha-particle therapy via PRIT, the treatment achieves pinpoint accuracy, concentrating cytotoxic radiation to malignant cells while sparing normal tissues. Alpha-emitters such as ^225Ac deliver high linear energy transfer (LET) radiation that induces double-stranded DNA breaks, causing irreparable tumor cell kill even in radio-resistant cancer subpopulations.
According to Dr. Sarah Cheal from Weill Cornell Medicine, the incorporation of the clearing agent in this multi-step approach was pivotal to minimizing alpha-particle off-target effects, a notorious hurdle in traditional alpha-radioimmunotherapy. This innovation enhances the therapeutic index and opens new avenues for applying alpha emitters beyond hematologic malignancies to solid tumors—especially those driven by HER2.
Dr. Nai Kong Cheung of Memorial Sloan Kettering Cancer Center highlights this therapy’s promise not only in breast cancer but also in other HER2-expressing solid tumors, which include subsets of gastric, ovarian, and lung cancers. As HER2 remains a prominent oncogenic driver across multiple cancers, this PRIT platform could serve as a versatile and transformative treatment modality.
Future directions involve advancing this proof-of-concept into clinical trials with rigorously designed protocols to evaluate safety, dosing, and efficacy in human subjects. Given the favorable preclinical safety profile and high curative potential, ^225Ac-PRIT could redefine the therapeutic landscape for patients with HER2-positive malignancies, reducing reliance on chemotherapies and mitigating the pervasive problem of therapeutic resistance.
This study embodies the convergence of molecular biology, radiochemistry, immunology, and oncology to produce a next-generation therapeutic that exemplifies precision medicine’s core principles. The strategic sequencing of antibody targeting, clearing agent clearance, and alpha-radioisotope delivery lays the foundation for bespoke cancer treatments tailored to molecular tumor markers.
In summary, the advent of HER2-targeted ^225Ac-PRIT represents a paradigm shift in cancer radioimmunotherapy. It shows compelling preclinical evidence of durable tumor control and histologic cure with negligible chronic toxicity risks. Such a potent combination of efficacy and safety could soon translate into clinical breakthroughs that improve survival and quality of life for patients battling aggressive HER2-positive breast cancer.
Subject of Research: HER2-targeted alpha-emitter radioimmunotherapy for breast cancer
Article Title: 225Ac α-Pretargeted Radioimmunotherapy of Human Epidermal Growth Factor Receptor 2–Expressing Breast Cancer
News Publication Date: November 3, 2025
Web References:
https://doi.org/10.2967/jnumed.125.269601
JNM website
Image Credits: Image created by S. Rinne et al., Weill Cornell Medicine, New York, NY.
Keywords: Molecular imaging, Personalized medicine, Breast cancer
