Yttrium-90 DOTA-FF-21101: A Novel Chimeric Monoclonal Antibody Therapy Targeting P-Cadherin in Solid Tumours

Summary: Yttrium-90 DOTA-FF-21101 has emerged as a promising therapeutic agent in the field of targeted radionuclide therapy for various solid tumours, including lung, pancreatic, colon, ovarian, biliary tract and head-and-neck cancers. Built upon the foundation of chimeric monoclonal anti-P-Cadherin (CDH3) technology, Yttrium-90 DOTA-FF-21101 uses the chelator DOTA to bind the radioactive isotope Yttrium-90, which delivers potent beta-emitting radiation directly to tumour cells. P-Cadherin, a subtype of cadherin proteins overexpressed in an array of malignancies, serves as the crucial molecular target of this therapy, guiding the radioactive agent to cells that display tumour-promoting features such as increased motility, adhesion and invasive behaviour. The therapeutic mechanism is complemented by its modulation of the insulin-like growth factor 1 receptor (IGF-1R) pathway, which is often implicated in tumour growth and resistance. Early-phase clinical trials have already been initiated in multiple regions, with key focuses on dosage, safety and tolerability, paving the way for more extensive research into efficacy and future applications.

Keywords: P-Cadherin; Chimeric Monoclonal Antibody; Yttrium-90; Radionuclide Therapy; IGF-1R; Solid Tumours.

Introduction to Yttrium-90 DOTA-FF-21101

In the rapidly evolving landscape of oncological treatments, targeted therapies have become a cornerstone for improving patient outcomes, minimising adverse effects and overcoming resistance mechanisms. One particularly noteworthy advancement is the development of Yttrium-90 DOTA-FF-21101, a chimeric monoclonal antibody designed to bind P-Cadherin (CDH3), a molecule that plays a pivotal role in tumour progression. Through its utilisation of a radionuclide — in this case, the beta-emitting Yttrium-90 — this treatment seeks to deliver cytotoxic radiation specifically to tumour cells. There has been a rising interest in harnessing these targeted radioimmunotherapies for a spectrum of solid tumours, ranging from lung and pancreatic cancers to less common malignancies such as biliary tract cancers.

Moreover, this antibody therapy’s effectiveness is potentially enhanced by its crosstalk with the IGF-1R signalling pathway, further contributing to the inhibition of tumour cell proliferation. The objective of this article is to probe into the unique features of Yttrium-90 DOTA-FF-21101, highlight the molecular underpinnings of P-Cadherin, describe the role of IGF-1R in cancer, explore the existing clinical data from Phase I studies, and discuss potential future directions in the application of this novel therapy.

P-Cadherin: A Key Player in Tumour Biology

Cadherins are a group of transmembrane proteins predominantly involved in calcium-dependent cell-to-cell adhesion, helping maintain the structural integrity of epithelial tissues. Within this family, P-Cadherin (CDH3) has garnered particular interest in oncology because it is found to be overexpressed in a variety of tumours, including those of the lung, colon, pancreas, ovary and biliary tract. Its overexpression is commonly linked to increased tumour aggressiveness, metastasis and poor prognosis.

• Cell Adhesion and Motility: P-Cadherin fosters cell-to-cell adhesion in normal epithelial cells. However, in cancer, the aberrant expression of P-Cadherin can disrupt normal cellular architecture, amplifying invasive properties. This aberrant expression may allow clusters of malignant cells to invade surrounding tissues more readily.
• Invasion and Metastasis: The transition from a localised tumour to metastatic disease marks a critical juncture in cancer progression. Malignant cells often gain the ability to degrade basement membranes, infiltrate blood vessels and circulate to distant sites. P-Cadherin overexpression contributes to these capabilities by altering normal cell adhesion and helping malignant cells detach.
• Tumour Proliferation: Elevated levels of P-Cadherin can also promote cell division, partly due to the interplay with growth factor signalling pathways. This synergy can potentiate tumour proliferation, offering a mechanistic rationale for targeting P-Cadherin in therapeutic interventions.
• Therapeutic Vulnerability: Since P-Cadherin is not ubiquitously overexpressed in healthy tissue, therapies designed to target it can yield high specificity towards tumour cells. This specificity is precisely why chimeric monoclonal antibodies like FF-21101 hold so much promise, as they can discriminate between malignant and normal cells.

Mechanism of Action: IGF-1R Crosstalk and Beta Radiation

While P-Cadherin serves as the primary target of Yttrium-90 DOTA-FF-21101, another significant aspect of its mechanism is modulating the insulin-like growth factor 1 receptor (IGF-1R) pathway. IGF-1R is well-documented to support cancer cell proliferation, survival and resistance to chemotherapy. Dysregulated IGF-1R signalling can lead to aggressive phenotypes in solid tumours, rendering it an important therapeutic target.

• IGF-1R in Cancer: IGF-1R is a tyrosine kinase receptor that, when bound to its ligands (IGF-1 and IGF-2), triggers a cascade of downstream signalling pathways, including the PI3K/AKT and MAPK pathways. These pathways enhance cell growth, inhibit apoptosis and can enable tumour cells to evade standard treatments.
• Enhanced Radio-sensitisation: By binding to P-Cadherin on tumour cells, Yttrium-90 DOTA-FF-21101 may deliver cytotoxic radiation that damages DNA and disrupts cellular functions. The crosstalk with IGF-1R signalling can amplify this effect, as tumour cells heavily reliant on IGF-1R pathways for survival may be less able to repair the radiation-induced damage.
• Beta Radiation and Therapeutic Efficacy: The choice of Yttrium-90 is central to this therapy’s potential efficacy. Yttrium-90 decays by emitting beta particles (β-), which have a tissue penetration range of a few millimetres. This penetration range is optimal for targeting tumour cells while limiting damage to neighbouring healthy tissues. A key benefit is the capacity to eradicate microscopic disease or tumour cells on the periphery of the main lesion, thus reducing the likelihood of recurrence.

Yttrium-90 Labelling with DOTA Chelator

A pivotal aspect of Yttrium-90 DOTA-FF-21101 lies in its labelling strategy. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is one of the most widely used chelators in radiopharmaceutical development, renowned for its ability to form stable complexes with various radionuclides, including Yttrium-90. This stability is crucial to minimise radioactive leakage into normal tissues and reduce off-target toxicity. When bound to the FF-21101 antibody, DOTA effectively holds the Yttrium-90 isotope in place as it targets P-Cadherin-expressing cells, ensuring that the radiation is largely delivered to the tumour environment.

Advantages of DOTA as a Chelator

• High Thermodynamic Stability: DOTA forms highly stable complexes that are resistant to dissociation, thus lowering the risk of free radionuclide release in the bloodstream.
• Versatility for Multiple Radionuclides: DOTA is also used for other therapeutic or diagnostic isotopes, such as Lutetium-177 or Gallium-68, enabling a flexible platform for diverse imaging and treatment modalities.
• Biocompatibility: The neutral charge and aqueous solubility of DOTA complexes improve their circulatory residence time and reduce immunogenic responses compared to older-generation chelators.

Clinical Trials and Safety Evaluation

Clinical trials for Yttrium-90 DOTA-FF-21101 have primarily concentrated on establishing safe dosage ranges, tolerability, pharmacokinetics and initial efficacy signals.

Phase I Studies

• Multi-Centre Phase I Trial (Initiated 2016): A clinical safety and tolerability study was launched in 2016 in patients with advanced solid tumours. This trial also includes using Indium-111 (¹¹¹In-FF-21101) for dosimetry to precisely estimate radiation distribution and accumulation in tumours, followed by Yttrium-90 FF-21101 for therapeutic administration. By the end of 2021, the study was expected to conclude the primary data-gathering phase, offering insights into safe dosing and early efficacy.
• Japan Phase I Trial (Initiated April 2020): A separate Phase I study commenced in Japan in April 2020. This trial focuses on several solid tumours, including ovarian, biliary tract and head-and-neck cancers. The aim is to further delineate the safety profile across a different patient population and explore potential differences in tumour response rates.

Key Objectives of Phase I

1. Safety and Tolerability: A primary concern in early-phase trials is identifying adverse events associated with the therapy. So far, no unexpected or severe toxicities have halted trials, though final data is still pending.
2. Optimal Dosage and Dose-Limiting Toxicity (DLT): Investigators seek to define the maximum tolerated dose (MTD) that can achieve tumour-targeting efficacy while minimising damage to healthy tissues.
3. Biodistribution and Pharmacokinetics: Using ¹¹¹In-FF-21101 for imaging allows clinicians to understand how the antibody-radionuclide complex disperses throughout the body, which is crucial for refining treatment protocols.
4. Preliminary Efficacy: Although Phase I trials are not primarily focused on efficacy, any observed tumour reduction or stabilisation of disease can bolster support for larger Phase II or III trials.

Potential Indications and Broader Clinical Relevance

One of the standout qualities of Yttrium-90 DOTA-FF-21101 is its ability to target P-Cadherin, which is implicated in a wide range of malignancies. Consequently, the therapy’s indications of interest are extensive:

• Lung Cancer: Particularly in non-small cell lung cancer (NSCLC), P-Cadherin expression has been correlated with aggressive behaviour and poor survival rates. Targeting P-Cadherin could potentially offer a new avenue for patients who have exhausted conventional chemotherapy and immunotherapy options.
• Pancreatic Cancer: Often characterised by advanced stage at diagnosis and limited therapeutic options, pancreatic cancer presents an enormous clinical challenge. Therapies that inhibit key drivers of tumour growth could disrupt pancreatic tumours’ notoriously robust stroma and invasive characteristics.
• Colon Cancer: High P-Cadherin expression in colon adenocarcinomas has been associated with increased tumour aggressiveness. Combining radioimmunotherapy with standard treatments like surgery, chemotherapy, or immunotherapy might lead to better disease control.
• Ovarian Cancer: This malignancy typically presents at a late stage and has a high rate of recurrence. By directly targeting P-Cadherin in ovarian tumour cells, Yttrium-90 DOTA-FF-21101 can potentially be integrated into frontline or salvage therapy regimens.
• Biliary Tract Cancer: A rare yet aggressive cancer type with limited therapies, biliary tract cancer could benefit significantly from a targeted approach that exploits P-Cadherin overexpression.
• Head-and-Neck Cancers: These malignancies can exhibit significant morbidity and mortality. By harnessing the specificity of P-Cadherin-targeted radioimmunotherapy, treatment could be more localised, reducing the side effects commonly associated with broad-spectrum chemotherapy and radiation fields.

Challenges and Considerations

While the promise of Yttrium-90 DOTA-FF-21101 is substantial, there remain challenges to be addressed as development continues:

• Patient Selection: Not all tumours overexpress P-Cadherin to the same extent. A clear biomarker strategy is crucial to identify patients most likely to respond. Molecular imaging techniques and tissue biopsies could be used to establish P-Cadherin expression levels as a prerequisite for therapy.
• Treatment Resistance: Tumours frequently develop resistance mechanisms, including alterations in the targeted molecules or activation of alternative survival pathways. It is, therefore, critical to study combination strategies with other targeted drugs, chemotherapy agents or immunotherapies.
• Toxicity Profile: Beta radiation delivered by Yttrium-90 can cause damage to nearby normal tissues if not properly localised. DOTA chelation and thorough dosimetric assessments can mitigate this risk, but careful monitoring and dose optimisation remain essential.
• Manufacturing and Scalability: Chimeric monoclonal antibodies require complex production processes, and integrating a radiolabelling step adds another layer of logistical complexity. Consistent and cost-effective manufacturing of Yttrium-90 DOTA-FF-21101 on a global scale will be key for its widespread adoption.
• Long-Term Outcomes: As with many new oncological interventions, long-term data on survival, quality of life and late toxicities remain incomplete. Ongoing and future trials must keep gathering extensive follow-up information to provide a full picture of therapeutic benefit versus risk.

Future Outlook and Conclusion

The field of radioimmunotherapy is steadily gaining momentum as researchers and clinicians seek targeted approaches that spare healthy tissues while eradicating malignancies. Yttrium-90 DOTA-FF-21101 exemplifies this paradigm by combining:

• A specific chimeric monoclonal antibody (anti-P-Cadherin) binds cancer cells overexpressing CDH3.
• A robust chelation strategy (DOTA) that ensures the stable attachment of Yttrium-90.
• A potent radionuclide (Yttrium-90) emitting beta particles that can destroy tumour cells at close range.
• Mechanistic synergy with IGF-1R pathways that augments the efficacy of radiation.

Results from Phase I studies suggest that the therapy is generally well-tolerated, with the potential for meaningful anti-tumour activity. Further clinical trials, especially Phase II and III, will be necessary to establish efficacy in specific cancer types, optimal dosage regimens and survival benefits. Additionally, combination strategies with other emerging treatments — such as immune checkpoint inhibitors, targeted drugs blocking complementary pathways or advanced surgical techniques — could open new therapeutic frontiers.

In addition, robust biomarker development is paramount for identifying patients who are most likely to benefit and those who may be at heightened risk for adverse effects. Personalised medicine approaches that stratify patients based on P-Cadherin expression levels or IGF-1R pathway activity could significantly enhance clinical outcomes.

Another important area for future research lies in refining dosimetry and imaging. Innovations in nuclear medicine imaging could allow clinicians to visualise the precise localisation of the radioimmunoconjugate in real time, allowing for more accurate predictions of treatment response. Such an approach would not only optimise individual patient outcomes but also reduce off-target toxicity.

Equally vital is ongoing surveillance for rare toxicities and long-term effects that may not become apparent during early-phase trials. Success will hinge on a collaborative approach among oncologists, nuclear medicine physicians, radiopharmacists, and researchers specialising in tumour biology and immunology.

Conclusion

Yttrium-90 DOTA-FF-21101 stands at the forefront of next-generation cancer therapies by capitalising on a powerful synergy between molecular targeting and radionuclide delivery. It showcases a pathway forward for tackling a wide range of solid tumours characterised by overexpression of P-Cadherin, offering renewed hope for patients facing challenging diagnoses. As the international oncology community awaits more definitive evidence from ongoing and upcoming clinical trials, the promise of improved survival rates and better quality of life through a targeted, mechanism-based approach becomes increasingly clear. With well-coordinated efforts and continued scientific innovation, Yttrium-90 DOTA-FF-21101 could ultimately transform the standard of care across multiple tumour types.

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