Lutetium-177 Debio 1124: A Second-Generation Theranostic Agent Targeting CCK2R-Expressing Tumours

Summary: Lutetium-177 Debio 1124 is a second-generation radiolabelled peptide analogue of minigastrin, designed for targeted radiotherapy of tumours expressing the Cholecystokinin B Receptor (CCK2R). Developed as a theranostic agent, it facilitates both patient selection and therapy. Primarily being investigated in advanced Medullary Thyroid Cancer (MTC), it shows promise in treating other CCK2R-expressing tumour types. Phase 0/I studies have demonstrated its safety and efficacy, with pivotal data published in 2018 and 2020. With its novel targeting mechanism, this agent represents a significant advancement in personalised oncology care.

Introduction to Theranostic Agents

The advent of theranostic agents has revolutionised oncology, enabling simultaneous diagnosis and treatment while improving patient outcomes. Among these agents, Lutetium-177 Debio 1124 is a standout innovation targeting tumours expressing the Cholecystokinin B Receptor (CCK2R). This radiolabelled peptide analogue of minigastrin is engineered to selectively deliver beta-emitting radiotherapy to cancer cells, making it particularly promising for advanced Medullary Thyroid Cancer (MTC) and other malignancies expressing CCK2R.

CCK2R as a Target in Oncology

The Cholecystokinin B Receptor (CCK2R) plays a pivotal role in the pathophysiology of several malignancies, particularly medullary thyroid carcinoma. Approximately 92% of MTC cases exhibit CCK2R expression, making it an attractive therapeutic target. CCK2R, a G-protein-coupled receptor, binds to endogenous peptides such as gastrin and cholecystokinin, which regulate various physiological processes including cell proliferation.

Therapeutic Implications

By leveraging the high expression of CCK2R in tumour cells, radiolabeled agents like ¹⁷⁷Lu-Debio 1124 can deliver targeted beta-emitting radiation, reducing off-target toxicity and enhancing therapeutic efficacy. This receptor’s expression in other tumours, including some neuroendocrine and gastrointestinal cancers, widens the scope of its therapeutic potential.

Mechanism of Action and Molecular Design

Lutetium-177 Debio 1124 employs a theranostic approach by combining diagnostic imaging with targeted therapy. Its mechanism involves:

• Ligand Specificity:
  The minigastrin-based carrier ligand PSIG-2 demonstrates high specificity for CCK2R, ensuring targeted delivery to tumour cells.
• Radiolabelled Component:
  Lutetium-177 emits beta particles (β–), which cause DNA damage in tumour cells, leading to apoptosis. Additionally, the gamma emission from ¹⁷⁷Lu facilitates imaging, enabling patient selection and treatment monitoring.
• Therapeutic Delivery:
  Upon binding to CCK2R on the tumour cell surface, the complex is internalised, concentrating radiation within cancer cells and sparing normal tissues.

Theranostics: Combining Diagnosis and Treatment

Theranostics bridges the gap between diagnostics and therapy by integrating radiopharmaceuticals for patient stratification and personalised treatment. For ¹⁷⁷Lu-Debio 1124, this involves:

• Patient Selection:
  Diagnostic imaging using gamma emission from ¹⁷⁷Lu or other paired imaging isotopes (e.g., ⁶⁸Ga) confirms CCK2R expression in tumours.
• Therapy Monitoring:
  Imaging tracks the biodistribution and efficacy of the radiolabeled agent during and after therapy.

This dual functionality enhances clinical decision-making and optimises therapeutic outcomes.

Clinical Development and Results

Phase 0/I Studies

The clinical journey of ¹⁷⁷Lu-Debio 1124 began with Phase 0/I studies initiated in 2015. These trials aimed to assess safety, dosimetry, and preliminary efficacy.

• Safety Profile:
  The agent demonstrated an acceptable safety profile, with manageable side effects predominantly limited to mild haematological toxicities.
• Dosimetry and Biodistribution:
  Imaging studies revealed selective accumulation in CCK2R-positive tumours, confirming its targeted mechanism.
• Efficacy:
  Preliminary evidence of tumour control and stabilisation of disease in advanced MTC patients was reported.

Publication Highlights:

• Initial findings were published in 2018, showcasing the safety and dosimetry data.
• Additional Phase 0 data in 2020 further validated its potential, emphasising its role in advanced and metastatic MTC.

Applications in Medullary Thyroid Cancer (MTC)

MTC, a rare neuroendocrine tumour arising from parafollicular C cells, is challenging to treat in advanced stages. Surgical resection is the primary curative option, but metastases often necessitate systemic therapies. Targeting CCK2R with ¹⁷⁷Lu-Debio 1124 offers a novel approach for:

• Metastatic Disease:
  The agent shows potential in controlling metastases by selectively targeting tumour deposits expressing CCK2R.
• Personalised Therapy:
  As a theranostic agent, it allows for tailored treatment based on receptor expression.

Potential in Other Tumour Types

Beyond MTC, the widespread expression of CCK2R in various malignancies positions ¹⁷⁷Lu-Debio 1124 for broader applications. These include:

• Neuroendocrine Tumours:
  Some neuroendocrine tumours express CCK2R, presenting an opportunity for targeted therapy.
• Gastrointestinal Cancers:
  Gastrin-sensitive tumours, such as certain gastric cancers, may benefit from this approach.

Future clinical trials are expected to explore these indications.

Advantages of ¹⁷⁷Lu-Debio 1124

• Enhanced Targeting:
  High specificity for CCK2R ensures precise delivery of radiation, minimising collateral damage.
• Theranostic Capability:
  The combination of imaging and therapy simplifies patient management and improves outcomes.
• Improved Safety Profile:
  Radiotherapy’s localisation reduces systemic side effects compared to traditional chemotherapies.

Challenges and Future Directions

• Heterogeneity of Receptor Expression:
  Variable CCK2R expression among patients and within tumour sites may affect treatment efficacy.
• Radiation Safety:
  Handling and administering radiolabeled agents require stringent safety protocols.
• Cost and Accessibility:
  Theranostic treatments are often expensive, limiting widespread access.

Future Directions

• Expanding Indications:
  Clinical trials should explore its utility in other CCK2R-expressing tumours.
• Optimising Dosimetry:
  Personalised dosimetry could further enhance safety and efficacy.
• Combination Therapies:
  Combining ¹⁷⁷Lu-Debio 1124 with immune checkpoint inhibitors or targeted agents may improve outcomes.

Conclusion

Lutetium-177 Debio 1124 exemplifies the promise of theranostic approaches in modern oncology. By targeting CCK2R, it offers a highly specific, effective treatment option for advanced MTC and other malignancies. With encouraging results from early clinical trials and ongoing investigations, this agent is poised to transform the therapeutic landscape, heralding a new era of personalised cancer care. Future research will undoubtedly refine its applications, solidifying its role in targeted radiopharmaceutical therapy.

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