Thorium-227 Pelgifatamab: Advancing Alpha-Particle Therapy for Prostate and Brain Cancers

Summary: Thorium-227 Pelgifatamab (²²⁷Th-PSMA-TTC, also referred to as ²²⁷Th-BAY2315497) is an emerging alpha-particle therapeutic designed to target prostate-specific membrane antigen (PSMA). By harnessing the power of a full IgG antibody, this therapeutic delivers Thorium-227 through the 3,2-HOPO chelating agent, ensuring a highly specific attack on cancer cells, especially in metastatic castration-resistant prostate cancer (mCRPC). Initial findings suggest that this targeted approach has the potential to enhance tumour cell eradication, reduce off-target effects, and improve patient outcomes.

Beyond prostate cancer, the cold antibody version of this agent has been investigated in the context of glioblastoma, underscoring its adaptability. With a Phase I clinical trial that started in October 2018 and is expected to conclude in November 2023, researchers aim to determine the safety, tolerability, and preliminary efficacy of Thorium-227 Pelgifatamab in human subjects. This article explores the scientific underpinnings of Pelgifatamab, its mechanism of action, the significance of PSMA targeting, its clinical development pathway, and the broader implications for treating both prostate and brain malignancies.

Keywords: Thorium-227; PSMA; Alpha-particle therapy; Metastatic castration-resistant prostate cancer (mCRPC); Glioblastoma; Targeted radiopharmaceutical.

Introduction to Thorium-227 Pelgifatamab

Radiopharmaceuticals have gained considerable attention over the past decade, especially for addressing tumours that either show resistance to conventional treatments or are located in challenging regions of the body. One of the most promising categories of these therapeutics involves alpha particles. Alpha particles, emitted by isotopes such as Thorium-227, possess a high linear energy transfer (LET), which translates into potent cell-killing power over a very short range. Such precision is particularly valuable in cancer therapy because it limits damage to surrounding healthy tissue.

Thorium-227 Pelgifatamab, commonly referred to as ²²⁷Th-PSMA-TTC or 227Th-BAY2315497, is a novel alpha-based agent designed to target prostate-specific membrane antigen (PSMA). PSMA is present in high levels on prostate cancer cells, making it an ideal molecular marker for delivering cytotoxic payloads precisely where they are most needed. The structure of Pelgifatamab includes a full IgG antibody backbone linked to the Thorium-227 radioisotope via the chelating agent 3,2-HOPO. Through this carefully engineered complex, the radiation from Thorium-227 can be delivered directly to malignant cells, thereby minimising the collateral damage often seen with broader therapies.

While the main indication for Thorium-227 Pelgifatamab is metastatic castration-resistant prostate cancer (mCRPC), researchers have also studied a cold antibody iteration in glioblastoma models. This highlights both the platform’s versatility and the potential to adapt the treatment for other types of solid tumours. The Phase I clinical trial, initiated in October 2018 and set to end in November 2023, aims to evaluate the agent’s safety, pharmacokinetics, and preliminary efficacy in humans.

PSMA and Its Significance

Prostate-specific membrane antigen (PSMA) has emerged as a focal point in prostate cancer research. This transmembrane glycoprotein is upregulated in prostate cancer cells, with its expression correlating to disease aggressiveness. Although it is also found in other tissues, such as the salivary glands and intestines, its overexpression in prostate cancer cells makes it an attractive target for therapeutic intervention.

PSMA is involved in various biochemical processes, including the metabolism of certain peptides, yet it is the receptor’s high density on cancer cells that garners the most interest in oncology. By targeting PSMA, researchers and clinicians can exploit a biological “flag” that signifies malignant tissue in order to deliver cytotoxic agents or visualise tumours more effectively through diagnostic imaging. This principle underpins the rationale for employing PSMA-targeting ligands in radioligand therapy.

Interestingly, PSMA has also been investigated in other cancers, including glioblastoma, because some tumour cells in the brain may exhibit PSMA-like expression in certain conditions. This revelation supports the utilisation of Pelgifatamab or its derivatives beyond prostate cancer. In the context of Thorium-227 Pelgifatamab, the emphasis on PSMA ensures a selective accumulation of the alpha-emitting isotope in prostate tumours, offering hope for better disease control with fewer side effects than conventional treatments.

Thorium-227 Labelling and Mechanism of Action

Central to the action of Thorium-227 Pelgifatamab is the careful incorporation of the Thorium-227 isotope into a full IgG antibody. Thorium-227 is an alpha emitter, producing high-energy but short-range alpha particles. When these alpha particles interact with cellular structures, they inflict extensive damage to the DNA of tumour cells, often leading to irreparable double-strand breaks. This induces apoptosis or necrosis, effectively eliminating cancer cells in close proximity.

However, achieving a stable bond between the antibody and Thorium-227 is crucial. To address this, Pelgifatamab employs 3,2-HOPO (3-hydroxy-2-pyridinone) as the chelating agent. Chelation ensures the isotope remains attached to the antibody and reaches its target instead of being released into the bloodstream prematurely. 3,2-HOPO is particularly adept at binding to Thorium-227, providing an optimised foundation for targeted delivery.

Once the chelated Thorium-227-laden antibody binds to PSMA on the tumour cell surface, it is often internalised. The alpha emissions from Thorium-227 cause localised DNA damage, but their limited path length (~50–100 micrometres) restricts the radius of destruction. Consequently, healthy cells in nearby tissues are better protected, reducing systemic side effects. This mechanism represents a significant leap forward for patients with advanced prostate cancer, who have sometimes exhausted conventional interventions such as hormone therapy, chemotherapy, or external beam radiotherapy.

Clinical Development and Phase I Trial

The journey from bench to bedside began with extensive preclinical work that investigated the safety and efficacy of Thorium-227 Pelgifatamab in various tumour models. Based on encouraging preclinical data, a Phase I trial was initiated in October 2018 to evaluate the drug in human subjects, particularly those with advanced prostate cancer. This trial, expected to end in November 2023, is designed to assess several key parameters:

• Safety and Tolerability: Researchers monitor the adverse events patients encounter while receiving increasing doses of Pelgifatamab. Common endpoints include haematological and organ toxicities, as well as any immunological reactions to the therapy.
• Dosimetry and Pharmacokinetics: By tracking how the radioisotope behaves in the body, scientists hope to establish the optimal dose that maximises tumour exposure while minimising healthy tissue irradiation. A precise understanding of drug distribution is vital for defining future dosage regimens.
• Preliminary Efficacy: Although Phase I trials primarily focus on safety, investigators also gather data on tumour response. Imaging studies, biochemical markers (including prostate-specific antigen levels), and clinical assessments help gauge whether patients are deriving any therapeutic benefit.
• Patient Selection and Eligibility: Typically, Phase I trials enrol individuals with limited treatment alternatives, especially those with progressing disease. In this study, men with metastatic castration-resistant prostate cancer, who may no longer respond to conventional treatments, constitute the priority population.

Gathering conclusive data from the Phase I trial will inform subsequent phases of clinical research. Should results demonstrate a favourable safety profile and encouraging efficacy signals, Pelgifatamab may advance to Phase II or III, ultimately guiding its path to regulatory approval.

Potential for Metastatic Castration-Resistant Prostate Cancer

Metastatic castration-resistant prostate cancer (mCRPC) is one of the most challenging phases of prostate cancer to manage, largely because tumours become unresponsive to hormonal therapy. Often, patients reach this stage after years of disease progression, and existing treatment options may offer only modest extensions in survival. As a result, developing new, innovative therapies that target cancer cells more effectively is paramount.

Thorium-227 Pelgifatamab holds promise in addressing this need. Harnessing the selectivity of PSMA and the potent alpha emissions of Thorium-227 offers a dual mechanism of specificity and cell lethality. The short range of alpha particles ensures that minimal radiation is delivered to non-target tissues, which is a crucial advantage compared to beta-emitting radiopharmaceuticals that can travel further and affect a larger volume of tissue.

In mCRPC, the tumour burden can be widespread, involving bones, lymph nodes, and other organ systems. Targeting PSMA in these metastatic lesions could improve local control and reduce tumour activity, potentially slowing disease progression. Although clinical trial data are still maturing, the strategy of employing alpha-emitters has captured the attention of oncologists and researchers, as it may circumvent some limitations of existing therapies, particularly in treatment-resistant cases.

Glioblastoma Indication and the Cold Antibody

Although Thorium-227 Pelgifatamab is primarily aimed at prostate cancer, the cold antibody analogue of Pelgifatamab has also been investigated for glioblastoma. Glioblastoma is notoriously difficult to treat, with a tendency to infiltrate surrounding brain tissue. Traditional therapies, including surgery, chemotherapy, and radiation, have had limited success in substantially prolonging patient survival. Consequently, novel approaches are urgently needed.

The investigation into the Pelgifatamab cold antibody for glioblastoma stems from observations that some glioblastoma cells may express markers akin to PSMA or share molecular pathways exploitable by anti-PSMA strategies. The tumour’s invasive nature means that targeted therapies could offer an advantage in identifying and eliminating cancerous cells while sparing healthy brain tissue.

However, the barrier known as the blood-brain barrier (BBB) poses a significant challenge. Large molecules, such as antibodies, often struggle to penetrate the BBB efficiently. Researchers are examining whether modifications or alternative delivery methods might enhance the antibody’s ability to reach intracranial tumour sites. Furthermore, the cold antibody approach, which does not carry a radioisotope, could be evaluated for diagnostic imaging or for delivering other therapeutic payloads. Overall, the exploration into glioblastoma underscores the adaptability of Pelgifatamab-based platforms and supports broader development for multiple indications.

Safety Considerations

Alpha emitters, including Thorium-227, must be handled with caution. Their potent cytotoxic effect is precisely what makes them promising in oncology, but it also raises concerns around unintended radiation dose to healthy tissues. Key safety considerations include:

• Radiation Handling: Medical facilities administering alpha-based therapies must follow stringent protocols to safeguard both patients and healthcare personnel from unnecessary exposure. This involves specialised shielding, waste disposal, and training.
• Off-Target Toxicity: Although PSMA targeting increases specificity, low-level expression in non-prostatic tissues like salivary glands and kidneys could lead to side effects. Continuous monitoring of patients for potential toxicities, including organ dysfunction, is integral.
• Bone Marrow Suppression: As with many systemic cancer therapies, the bone marrow is a vulnerable organ. Researchers will watch for reductions in blood cell counts, which can increase infection risk and cause fatigue or bleeding tendencies.
• Patient Selection: Identifying the right patient population for alpha-particle therapy can mitigate undue risk. Early clinical trials typically enrol individuals with limited choices, but as data accrues, investigators may refine eligibility criteria to maximise benefit and reduce harm.

Overall, the robust design of Phase I trials ensures that safety data are thoroughly collected and evaluated, guiding further modifications to dosage and administration protocols in the next phases of development.

Future Prospects

The potential of Thorium-227 Pelgifatamab extends beyond its immediate application in metastatic prostate cancer. As more is learned about its safety profile and efficacy, clinicians and researchers may explore the following:

• Combination Therapies: Pelgifatamab could be paired with immune checkpoint inhibitors, hormone therapies, or small molecule drugs to enhance treatment efficacy. Combining targeted alpha therapy with immuno-oncology agents might amplify tumour cell recognition and destruction while offering a more robust immune response.
• Broader Oncology Applications: Given the relatively general mechanism of alpha-particle–induced DNA damage, additional tumour types that express PSMA or could be engineered to express PSMA-ligands might become candidates for Thorium-227-based treatment. Brain malignancies, including glioblastoma, could see further development if the challenges of BBB penetration are addressed.
• Refined Delivery Methods: Innovations in drug-delivery systems, such as nanoparticles or carrier molecules that improve tumour penetration, might amplify Pelgifatamab’s impact. These approaches could help tackle cancers with challenging locations or poor vascularity.
• Extended Radiopharmaceutical Platforms: The experience and knowledge gained from Thorium-227 Pelgifatamab could inform the design of other alpha-emitting compounds targeting alternative cancer markers, paving the way for a broader class of alpha radiotherapies.
• Personalised Medicine Approaches: As genomic profiling becomes increasingly integrated into oncology practice, it may be possible to identify patients whose tumours express higher levels of PSMA or have molecular signatures that predict better responses to alpha therapy.

Advances in imaging, diagnostics, and patient selection will likely accelerate as Pelgifatamab moves through the clinical trial pipeline, shaping the drug’s ultimate role in future cancer treatment guidelines.

Conclusion

Thorium-227 Pelgifatamab (²²⁷Th-PSMA-TTC, ²²⁷Th-BAY2315497) represents an intriguing frontier in targeted alpha therapy for advanced cancers. By leveraging PSMA as a precise molecular target, Pelgifatamab is poised to deliver potent alpha emissions where they matter most—deep within the tumour cell. The agent’s design, featuring a full IgG antibody linked to Thorium-227 via 3,2-HOPO, underscores the careful engineering required to optimise stability, specificity, and safety.

The Phase I clinical trial that commenced in October 2018 is critical for illuminating the path ahead. As results become available in November 2023 and beyond, they will shape future phases of development and potential regulatory approval. If safety and efficacy thresholds are met or surpassed, Thorium-227 Pelgifatamab could redefine the treatment landscape for patients with metastatic castration-resistant prostate cancer, many of whom have few effective therapeutic alternatives. Additionally, research into its cold antibody variant opens the door to addressing glioblastoma and other challenging malignancies, illustrating the adaptability of this platform.

Alpha emitters offer the potential to combine remarkable precision with potent cytotoxic power. Through continued exploration of Thorium-227 Pelgifatamab’s capabilities, oncology may find a new class of therapies that move the field closer to achieving better clinical outcomes, prolonged survival, and an enhanced quality of life for individuals battling the most formidable forms of cancer.

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