Unleashing a New Era in Neuroblastoma Treatment: The Promise of Lutetium-177 DTPA-Omburtamab

Summary: Neuroblastoma remains one of the most challenging paediatric cancers to treat, driving researchers and clinicians to explore highly targeted therapies. One promising newcomer is Lutetium-177 DTPA-Omburtamab (¹⁷⁷Lu-Burtomab), a novel radiopharmaceutical designed to selectively target the B7-H3/CD276 antigen found on neuroblastoma cells. By coupling a murine-derived monoclonal antibody (Omburtamab) with the beta-emitting radioisotope Lutetium-177, this therapy aims to deliver potent radiation directly to malignant cells while minimising damage to healthy tissue. Currently under clinical investigation—initial patient dosing commenced in June 2021, with study completion anticipated by the end of 2024— Lutetium-177 DTPA-Omburtamab represents the next generation of targeted radiotherapeutics. If successful, it could herald a transformative shift in how these aggressive tumours are approached, forging a pathway to better long-term outcomes and improved quality of life for children and their families.

Keywords: Neuroblastoma; B7-H3/CD276; Radiopharmaceutical; Lutetium-177; Monoclonal Antibody Therapy; Targeted Radiation.

Introduction to Neuroblastoma

Neuroblastoma, a malignancy originating in neural crest cells, predominantly affects infants and young children. This type of solid tumour often presents in the adrenal glands or along the sympathetic nervous system chain, and its biological complexity poses significant treatment challenges. Conventional approaches—surgery, chemotherapy, radiation therapy, and immunotherapy—have steadily improved survival rates over the past few decades. However, resistant disease, high relapse rates, and significant long-term side effects underscore the need for more refined interventions that directly target tumour cells while preserving healthy tissues.

One innovative approach is the development of radiopharmaceutical therapies that combine the tumour-targeting specificity of monoclonal antibodies with the tumouricidal power of radionuclides. By engineering antibodies to recognise tumour-specific antigens, researchers can deliver radiation directly to cancer cells. Lutetium-177 DTPA-Omburtamab, also referred to as ¹⁷⁷Lu-Burtomab, emerges from such a paradigm. Engineered at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York and licensed exclusively to Y-mAbs Therapeutics, Inc., this agent serves as a next-generation alternative to the earlier ¹³¹I-Omburtamab. With its first patient injection recorded in June 2021 and the clinical study projected to conclude by late 2024, ¹⁷⁷Lu-DTPA-Omburtamab is poised to reshape the therapeutic landscape for children with neuroblastoma.

Understanding the Target: B7-H3/CD276

At the heart of Lutetium-177 DTPA-Omburtamab is its targeted action is its specificity for the B7-H3 (CD276) antigen. B7-H3 is a surface glycoprotein belonging to the B7 family of immunomodulatory molecules. Although its exact physiological role remains under investigation, it is widely expressed on the surface of many solid tumours, including neuroblastoma, and correlates with more aggressive disease characteristics. This pronounced expression on malignant cells, combined with relatively limited expression in normal tissues, makes B7-H3 a compelling therapeutic target.

By directing a monoclonal murine antibody against B7-H3, researchers aim to exploit the tumour’s unique biology. Omburtamab—a specially engineered monoclonal antibody—binds tightly to B7-H3, ensuring that the subsequent payload of radiation is delivered straight to the tumour. In doing so, this approach limits off-target effects and spares healthy tissues from excessive radiation, a critical factor in paediatric oncology where long-term side effects and quality of life are paramount concerns.

Carrier and Ligand: Omburtamab and DTPA

Omburtamab’s role is not merely to latch onto B7-H3, but to serve as a robust ‘carrier’ guiding the radioactive payload to the tumour site. Originally known for its role in targeting B7-H3 in the context of central nervous system (CNS) metastases and leptomeningeal metastases of neuroblastoma, Omburtamab has evolved into a versatile delivery vehicle.

Attaching the radioactive isotope Lutetium-177 to Omburtamab requires a chelating agent to ensure stable binding and prevent radionuclide leakage. The chelator chosen is diethylenetriamine pentaacetic acid (DTPA), a molecule adept at forming stable complexes with metal ions. The resultant Lutetium-177 DTPA-Omburtamab complex ensures that the ¹⁷⁷Lu remains firmly bound throughout circulation and upon tumour binding, reducing systemic toxicity and enhancing delivery efficiency. Integrating these components results in a powerful radiotherapeutic tool designed to seek out, bind to, and irradiate neuroblastoma cells.

The Radiopharmaceutical: Lutetium-177

Central to the potency of Lutetium-177 DTPA-Omburtamab is Lutetium-177, a radionuclide that emits low-energy beta particles (β–). Selected for its favourable half-life (approximately 6.7 days) and emission properties, ¹⁷⁷Lu offers a balanced approach to tumour control. Its relatively short path length in tissue ensures that the radiation predominantly affects cells within a limited radius, sparing distant healthy cells from collateral damage.

By using a beta emitter like ¹⁷⁷Lu, the therapy capitalises on the capacity to deliver focused radiation over an extended period, in contrast to a single high-dose exposure. This methodical, localised radiation can lead to more effective tumour control, potential tumour shrinkage, and eventually, improved patient outcomes. In addition, the gamma emissions of ¹⁷⁷Lu can facilitate imaging, enabling clinicians to track the distribution and localisation of the radiopharmaceutical in real-time, and make informed adjustments to therapy if needed.

Advancing from ¹³¹I-Omburtamab to ¹⁷⁷Lu-DTPA-Omburtamab

Lutetium-177 DTPA-Omburtamab is considered the next generation of targeted radiopharmaceutical therapy following in the footsteps of ¹³¹I-Omburtamab. Although the earlier iteration harnessed the power of Iodine-131 to deliver radiation, questions remained regarding optimal dosing, radiation safety, and the balance between efficacy and toxicity. By substituting ¹³¹I with ¹⁷⁷Lu, researchers aimed to refine the therapy, improving its targeting precision, toxicity profile, and overall therapeutic index.

Another benefit is that Lutetium-177 radiolabelling often demonstrates better stability and a more predictable dosimetric profile. While Iodine-131 is effective, its relatively high-energy beta emissions and gamma emissions can require more extensive radiation safety measures. ¹⁷⁷Lu as lower-energy beta emissions reduce the radius of radiation damage, potentially improving tolerability and enabling outpatient treatment in some instances. Such refinements in the radiopharmaceutical design signify an evolution in the precision medicine paradigm, striving to elevate the standard of care for neuroblastoma patients.

Clinical Development and Trials

The clinical journey of Lutetium-177 DTPA-Omburtamab began in earnest when the first patient was administered the radiopharmaceutical in June 2021. This event marked a crucial milestone, representing the translation of years of preclinical research into a tangible therapeutic approach for patients. As part of an ongoing clinical trial, children with recurrent or resistant neuroblastoma—those often facing limited treatment options—are receiving this experimental therapy under carefully controlled conditions.

Researchers and clinicians will systematically evaluate various facets of Lutetium-177 DTPA-Omburtamab during the trial:

• Safety and Tolerability: Establishing a favourable safety profile is paramount. Clinicians will monitor acute and long-term side effects, focusing on haematological toxicity, organ function, and any unexpected adverse events.
• Dosimetry and Pharmacokinetics: By examining how the radiopharmaceutical distributes within the body, the optimal dosing regimen can be refined. Understanding how ¹⁷⁷Lu-DTPA-Omburtamab clears from normal organs, how it accumulates in tumours, and how long it remains in circulation will inform dosage adjustments and improve therapeutic windows.
• Efficacy Measures: The ultimate measure of success is whether the drug can shrink tumours, halt disease progression, or improve survival outcomes. Response assessments using imaging, tumour markers, and clinical evaluations will guide the optimisation of treatment schedules and dosage levels.
• Quality of Life Assessments: In paediatric oncology, treatment is about more than prolonging life; it is about preserving the quality of life. The trial will likely include quality-of-life metrics to ensure that improved tumour control does not come at the expense of significant long-term harm.

As the trial proceeds towards its completion date at the end of 2024, the collected data will offer invaluable insights into how ¹⁷⁷Lu-DTPA-Omburtamab performs as a viable addition to the neuroblastoma treatment arsenal.

Potential Advantages in the Neuroblastoma Landscape

Neuroblastoma is a heterogeneous disease with a complex biological makeup. Treatment outcomes vary widely, and current regimens can be both aggressive and burdensome for young patients and their families. The introduction of a radiopharmaceutical like Lutetium-177 DTPA-Omburtamab can potentially refine the treatment approach in several ways:

• Enhanced Specificity: By zeroing in on B7-H3, the drug ensures that radiation is concentrated where it is needed most—within the tumour. This approach minimises collateral damage, reducing both short-term toxicity and long-term treatment-related complications.
• Overcoming Resistance: Neuroblastoma cells that have developed resistance to conventional chemotherapy or immunotherapy may still be susceptible to radiation damage. Radiopharmaceutical therapy offers a novel mechanism of action, complementing and enhancing existing treatments.
• Integration into Multimodal Therapy: As with many malignancies, neuroblastoma therapy is rarely a single-step process. ¹⁷⁷Lu-DTPA-Omburtamab could be integrated into a broader treatment regime, perhaps combined with immunotherapy, surgery, or chemotherapy. The synergy between these modalities could offer improved outcomes.
• Personalised Medicine Approach: The ability to image the distribution of Lutetium-177 DTPA-Omburtamab in real-time could enable clinicians to personalise treatment. By adjusting doses based on individual patient uptake, doctors could maximise efficacy while minimising toxicity.

Safety Considerations and Toxicity Management

Radiopharmaceuticals must be administered with meticulous attention to safety. Although ¹⁷⁷Lu, as relatively low-energy beta emissions, is more contained than those of certain other isotopes, radiation safety protocols remain essential. Medical staff will be trained in handling these agents, and patients’ families will be counselled on safety guidelines during and after treatment.

Toxicity management involves monitoring for common radiotherapy-related side effects, such as bone marrow suppression, which can lead to reduced blood cell counts and increased infection risk. Regular blood tests and supportive care measures, including growth factor support or blood transfusions, may be required to help children cope. Early detection and management of toxicity is key, ensuring that patients maintain the best possible health status during therapy.

Regulatory and Manufacturing Considerations

Transforming a promising compound into an approved medication is a complex process that involves stringent regulatory oversight. Regulatory bodies such as the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) will review the data from clinical trials, focusing on safety, efficacy, and manufacturing consistency.

Manufacturing a radiopharmaceutical like Lutetium-177 DTPA-Omburtamabinvolves balancing multiple factors. The production must be scalable, meet quality standards, and be reliably delivered to treatment centres worldwide. Y-mAbs Therapeutics, Inc., as the exclusive licensee, will coordinate with manufacturing partners to streamline production. Scaling up manufacturing to support wider patient access, if the product proves successful, will be a critical phase of commercialisation and implementation.

The Road to Approval and Integration into Practice

If ¹⁷⁷Lu-DTPA-Omburtamab meets its clinical endpoints—demonstrating robust safety and significant efficacy—it could proceed towards regulatory approval. Once approved, the drug could become available as part of standard clinical practice for children with neuroblastoma, potentially altering the current treatment guidelines.

Integration into established treatment algorithms will require close collaboration between oncologists, nuclear medicine physicians, radiopharmacists, and other healthcare professionals. This team-based approach can ensure that patients receive the therapy at the most advantageous time in their treatment journey. For instance, ¹⁷⁷Lu-DTPA-Omburtamab might be administered after initial chemotherapy has reduced tumour burden, or it might be used to tackle residual disease post-surgery. Tailoring its use based on individual patient factors, such as disease stage, tumour markers, and previous treatment responses, will be essential.

Future Directions and Research Potential

As experience with Lutetium-177 DTPA-Omburtamab grows, researchers may explore its utility beyond neuroblastoma. The B7-H3 antigen is expressed in other solid tumours, and successful results in neuroblastoma could encourage trials in osteosarcoma, glioblastoma, or other hard-to-treat cancers. Moreover, continued technological advances may allow for improved chelators, enhanced conjugation techniques, or the combination of multiple radionuclides within a single treatment regimen.

Clinical investigations may also explore combining Lutetium-177 DTPA-Omburtamab with emerging immunotherapies. In some cases, targeted radiation can modulate the tumour microenvironment, making cancer cells more susceptible to T-cell mediated killing. This interplay between radiation and the immune system could usher in a new era of combined modality treatments that leverage the body’s own defences to eradicate cancer more effectively.

Additionally, ongoing research into biomarkers and molecular signatures could guide the use of Lutetium-177 DTPA-Omburtamab. Identifying patients who are most likely to benefit from this therapy would improve treatment outcomes and resource allocation. Biomarker-driven patient selection could result in personalised therapy plans that maximise the benefits and minimise unnecessary exposure to radiation.

Conclusion

Neuroblastoma remains a formidable challenge in paediatric oncology, both in terms of the aggressive nature of the disease and the complexity of its treatment. The emergence of Lutetium-177 DTPA-Omburtamab, targeting the B7-H3 antigen, stands as a testament to how far the field has evolved. By fusing the specificity of monoclonal antibody therapy with the directed intensity of radionuclide irradiation, this approach represents a carefully engineered weapon against a relentless adversary.

From its origins at MSKCC to its ongoing clinical trial, this radiopharmaceutical marks a bold step forward. By the end of 2024, the data gathered will illuminate whether Lutetium-177 DTPA-Omburtamab can deliver on its promise. If successful, it could integrate seamlessly into a complex therapeutic tapestry, providing new hope for children and families facing neuroblastoma. In the broader landscape of oncology, it underscores the power of precision medicine, showing that targeted strategies hold the key to more effective, personalised, and compassionate cancer care.

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