Actinium-225 FPI-2059: Targeted Alpha Therapy in Oncology through NTSR1 Targeting

Actinium-225 FPI-2059, targeting NTSR1 with Actinium-225, promises breakthroughs in treating pancreatic cancer and other NTSR1-overexpressing tumours.


Actinium-225 FPI-2059: An Overview

Actinium-225 (225Ac) is a radioisotope gaining significant attention in the field of targeted alpha therapy (TAT). Among its numerous applications, the development of 225Ac-FPI-2059 stands out. This compound is an Actinium-225 labelled analogue of the previously developed 177Lu-IPN-1087, a neurotensin antagonist peptide targeting the Neurotensin Receptor Type 1 (NTSR1). This article delves into the characteristics, mechanisms, and potential applications of 225Ac-FPI-2059 in oncology, mainly focusing on its role in treating ductal pancreatic adenocarcinoma (DPAC) and other cancer types.

Actinium-225 FPI-2059, also known as 225Ac-3BP-227 and 225Ac-IPN-01087, is a radiopharmaceutical compound that harnesses the therapeutic properties of Actinium-225. It’s closely related to 177Lu-IPN-1087, both in structure and function, but differs significantly in the type of radiation it uses for therapeutic purposes. The primary target of this drug is NTSR1, a receptor frequently overexpressed in various cancer cells, including pancreatic adenocarcinoma.

Target/Mechanism: NTSR1

NTSR1 is a high-affinity receptor for neurotensin, a peptide involved in a wide range of biological processes. In the context of cancer, NTSR1 is often overexpressed, making it a viable target for targeted cancer therapies. Actinium-225 FPI-2059 binds to NTSR1, allowing for targeted delivery of Actinium-225 alpha particles directly to the cancer cells. This targeting minimises damage to surrounding healthy tissues, a significant advantage over traditional chemotherapy.

Carrier/Ligand: 3BP-227

3BP-227, the ligand component of 225Ac-FPI-2059, plays a crucial role in the drug’s targeting mechanism. It specifically binds to NTSR1 receptors on the surface of cancer cells. This specificity is key to ensuring that the alpha particles emitted by Actinium-225 are delivered directly to the tumour cells, maximising the therapeutic effect while reducing off-target damage.

Radiation Type: Alpha Particle (α)

The therapeutic efficacy of 225Ac-FPI-2059 lies in its use of alpha particles. Alpha radiation, due to its high linear energy transfer (LET), can induce substantial damage to cancer cells. The short range of alpha particles in biological tissues (~50-80 µm) allows for the targeted destruction of cancer cells with minimal impact on neighbouring healthy cells. This is particularly beneficial in treating solid tumours where precision is paramount.

Clinical Development and FDA Approval

In June 2022, the U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) applications for 225Ac-FPI-2059 and its imaging analogue, 111In-FPI-2058. This clearance marked a significant milestone in the clinical development of 225Ac-FPI-2059, allowing for human trials to assess its safety and efficacy in treating cancers, particularly ductal pancreatic adenocarcinoma (DPAC).

Ductal Pancreatic Adenocarcinoma (DPAC) and Other Oncology Indications

DPAC, known for its aggressive nature and poor prognosis, is a primary focus in the development of 225Ac-FPI-2059. The overexpression of NTSR1 in most DPAC cells provides an ideal target for the drug, aiming to deliver potent alpha particles directly to the tumour site. The rationale behind this approach is to maximise tumour cell death while sparing surrounding healthy tissues, a significant challenge in pancreatic cancer treatment.

Given its targeted mechanism of action, 225Ac-FPI-2059 also shows promise for other oncology indications where NTSR1 is overexpressed. These could include certain types of neuroendocrine tumours, prostate cancer, and potentially breast cancer. The versatility of this drug lies in its ability to be adapted for different cancer types by modifying the ligand or targeting molecule.

Comparative Analysis: 225Ac-FPI-2059 vs. 177Lu-IPN-1087

While both 225Ac-FPI-2059 and 177Lu-IPN-1087 target NTSR1, they differ in their radioactive components. Lutetium-177 (177Lu) emits beta particles, which have a more extended range in tissue but lower LET compared to alpha particles. This difference influences their respective therapeutic profiles. Due to their high LET, Alpha particles are more effective in inducing double-strand DNA breaks, leading to a higher probability of cell death. However, the short-range requires precise targeting, which is a strength of the NTSR1-targeted approach.

Future Perspectives and Challenges

The development of 225Ac-FPI-2059 opens new avenues in precision oncology. However, challenges remain in optimising the delivery, minimising off-target effects, and managing potential resistance mechanisms. Further clinical trials are essential to determine the optimal dosing, evaluate long-term efficacy, and identify potential side effects.

Additionally, the production and supply of Actinium-225 is a logistical challenge. As a rare isotope, ensuring a consistent and sufficient supply for widespread clinical use requires significant investment in nuclear technology and infrastructure.

Conclusion

Actinium-225 FPI-2059 represents a promising advancement in the field of targeted radionuclide therapy. Its specific targeting of NTSR1, combined with the potent cytotoxicity of alpha particles, offers a potential new treatment modality for DPAC and other NTSR1-expressing cancers. The clearance of its IND by the FDA is a critical step towards further clinical development and eventual clinical application. As research progresses, 225Ac-FPI-2059 could significantly impact cancer treatment, particularly for tumours that have been challenging to treat with conventional therapies.

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