Targeting Neurotensin Receptor-1: Lutetium-177 IPN-01087 in Oncology

Summary: Lutetium-177 IPN-01087 (¹⁷⁷Lu-3BP-227) is a promising neurotensin antagonist peptide targeting neurotensin receptor-1 (NTR-1), highly expressed in invasive cancers such as ductal pancreatic adenocarcinoma (DPAC). With its beta radiation capabilities, it has demonstrated potential in early-phase clinical trials, offering hope for tackling DPAC and other solid tumours. This article explores its mechanism, clinical progress, and future prospects.

Keywords: ¹⁷⁷Lu-IPN-01087; Neurotensin receptor-1 (NTR-1); Ductal pancreatic adenocarcinoma (DPAC); Radioligand therapy; Beta radiation; Oncology.

Introduction Ductal Pancreatic Adenocarcinoma

Ductal pancreatic adenocarcinoma (DPAC) is one of the most aggressive malignancies, with a high mortality rate and limited effective treatment options. Among recent innovations in oncology, targeted radioligand therapy has gained attention for its ability to selectively deliver therapeutic radiation to cancer cells. Lutetium-177 IPN-01087 (¹⁷⁷Lu-3BP-227) is an advanced therapeutic radiopharmaceutical targeting neurotensin receptor-1 (NTR-1), an important biomarker in cancers such as DPAC. This article looks into the structure, mechanism, clinical development, and future potential of ¹⁷⁷Lu-IPN-01087.

Mechanism of Action

Neurotensin receptor-1 (NTR-1) plays a key role in tumour growth and metastasis. This receptor is overexpressed in invasive cancers, including pancreatic intraepithelial neoplasia (PanIN), making it a valuable target for precision oncology.

• Targeting NTR-1: Lutetium-177 IPN-01087 binds specifically to NTR-1 using its carrier molecule, IPN-01087, a neurotensin antagonist peptide. By leveraging the overexpression of NTR-1 in malignant tissues, the molecule ensures high specificity and minimal off-target effects.
• Beta Radiation Therapy: ¹⁷⁷Lu emits beta electrons (β–), which induce lethal DNA damage in cancer cells within a localised radius. This mechanism minimises harm to surrounding healthy tissues, a significant advantage over conventional therapies.

Clinical Development

The development of Lutetium-177 IPN-01087 represents a milestone in the application of radioligand therapy for oncology. Its clinical progress underscores its potential as a treatment for DPAC and other solid tumours.

• Phase I Trial: Completed in 2018, the Phase I trial of Lutetium-177 IPN-01087 demonstrated its feasibility for treating DPAC. Importantly, the trial reported no significant adverse effects, showcasing the molecule’s safety profile. The trial findings marked the beginning of clinical evidence supporting the therapeutic potential of targeting NTR-1 in aggressive cancers.
• Phase I/II Trials: Following the promising results of the Phase I study, a combined Phase I/II clinical trial was initiated in May 2018. This trial aims to evaluate the efficacy and safety of ¹⁷⁷Lu-IPN-01087 in subjects with solid tumours expressing NTR-1, including pancreatic, colorectal, gastric, and head and neck cancers.

Dual Development with ²²⁵Ac-FPI-2059

In addition to its ¹⁷⁷Lu-labelled form, the molecule has been developed with the alpha-emitting radioisotope Actinium-225, under the name ²²⁵Ac-FPI-2059. This development explores the advantages of alpha radiation, which has a higher linear energy transfer (LET) and can deliver potent cytotoxicity to cancer cells over an even shorter range than beta radiation.

• Complementary Approaches: The ¹⁷⁷Lu and ²²⁵Ac versions of the molecule provide complementary therapeutic options, enabling tailored treatment strategies based on tumour characteristics and individual patient needs.
• Expanding Indications: The development of ²²⁵Ac-FPI-2059 broadens the clinical potential of the molecule, extending its utility to additional oncology indications.

Significance in Pancreatic Cancer

Pancreatic cancer remains a challenging disease to treat, with limited effective options. The introduction of Lutetium-177 IPN-01087 is a step forward in addressing this unmet need.

• Targeting PanIN and Metastases: Neurotensin receptor-1 is overexpressed not only in primary tumours but also in metastatic lesions, enhancing the molecule’s potential to control disease spread.
• Therapeutic Precision: Radioligand therapy with Lutetium-177 IPN-01087 offers a precision medicine approach, minimising off-target effects while delivering effective radiation doses directly to cancer cells.

Potential Applications Beyond DPAC

The high expression of NTR-1 in various solid tumours positions Lutetium-177 IPN-01087 as a versatile therapeutic option. Its potential applications include:

• Colorectal Cancer: NTR-1 overexpression has been observed in certain subtypes of colorectal cancer, where radioligand therapy could play a role in improving outcomes.
• Gastric Cancer: The molecule’s specificity for NTR-1 makes it a candidate for targeting gastric tumours that express this receptor.
• Head and Neck Cancer: NTR-1-targeted radiotherapy could provide a novel approach for treating head and neck malignancies, particularly those resistant to standard therapies.

Advantages of Radioligand Therapy

Radioligand therapy (RLT) offers several advantages over conventional cancer treatments, making it an attractive option for patients with advanced malignancies.

• High Specificity: RLT delivers radiation directly to tumour cells expressing the target receptor, sparing healthy tissues.
• Minimised Side Effects: The targeted nature of the therapy reduces the systemic side effects commonly associated with chemotherapy and traditional radiotherapy.
• Potential for Combination Therapy: RLT can be combined with other treatment modalities, such as immunotherapy or chemotherapy, to enhance efficacy.

Future Directions

The development of ¹⁷⁷Lu-IPN-01087 and its ²²⁵Ac-labelled analogue represents the beginning of a new era in targeted radiopharmaceuticals. Future directions include:

• Expanded Clinical Trials: Larger Phase II and III trials will be critical to validate the efficacy of ¹⁷⁷Lu-IPN-01087 in a broader patient population and across multiple tumour types.
• Combination Strategies: Integrating radioligand therapy with other modalities, such as checkpoint inhibitors, could offer synergistic benefits.
• Personalised Treatment: Advances in imaging techniques, such as PET scans using NTR-1-targeted tracers, could enable better patient selection and therapy monitoring.

Conclusion

Lutetium-177 IPN-01087 represents a significant innovation in the treatment of ductal pancreatic adenocarcinoma and other NTR-1 expressing tumours. With its high specificity, favourable safety profile, and promising clinical trial results, it is poised to make a meaningful impact in oncology. As research progresses, this molecule—and its alpha-emitting analogue—may redefine the therapeutic landscape for aggressive cancers, offering new hope to patients and clinicians alike.

You are here: home » Lutetium-177 IPN-01087