Summary: Iodine-131 Naxitamab (¹³¹I-3F8) is a murine monoclonal antibody targeting the GD2 disialoganglioside, labelled with radioactive iodine-131. It has been explored as a therapeutic agent for neuroblastoma, melanoma, and small cell carcinoma of the lung (SCLC). Since its inception in the 1980s, 3F8 has undergone significant developments, including humanisation to form hu3F8 (naxitamab) and trials with alternative radioisotopes like iodine-124. This article reviews the historical background, mechanism of action, clinical trials, and future directions of ¹³¹I-Naxitamab, highlighting its potential in radioimmunotherapy.
Overview of Radioimmunotherapy
Radioimmunotherapy (RIT) represents a fusion of radiation therapy and immunotherapy, aiming to deliver targeted radiation doses to malignant cells while minimising exposure to healthy tissues. By coupling a radioactive isotope to a monoclonal antibody that specifically binds to antigens expressed on cancer cells, RIT offers a precision approach to cancer treatment. Over the past few decades, significant strides have been made in this field, leading to the development of novel agents such as ¹³¹I-Naxitamab (¹³¹I-3F8).
Introduction to Iodine-131 Naxitamab
Iodine-131 Naxitamab, also known as ¹³¹I-3F8, is a murine-derived monoclonal antibody specifically targeting GD2, a disialoganglioside highly expressed on the surface of certain cancer cells. When labelled with iodine-131 (¹³¹I), the antibody delivers cytotoxic beta radiation directly to tumour sites. This agent has been investigated for its therapeutic potential in treating neuroblastoma, melanoma, and small cell carcinoma of the lung (SCLC), among other malignancies.
Historical Background
Early Development of 3F8 Antibody
The concept of targeting GD2 with monoclonal antibodies emerged in the 1980s. The murine antibody 3F8 was developed to exploit the overexpression of GD2 on neuroblastoma cells. Early preclinical studies demonstrated the antibody’s ability to localise to tumour sites, paving the way for its use in clinical settings.
Initial Human Trials with ¹³¹I-3F8
In the 1990s, the first human trials with ¹³¹I-3F8 were conducted. These studies aimed to assess the safety, biodistribution, and therapeutic efficacy of the radiolabelled antibody in patients with neuroblastoma and other GD2-expressing tumours. The results provided valuable insights into the potential of ¹³¹I-3F8 as a targeted radiotherapeutic agent.
Mechanism of Action
Targeting GD2 (Disialoganglioside)
GD2 is a disialoganglioside expressed abundantly on the surface of neuroblastoma cells and other tumours such as melanoma and SCLC, but with limited expression on normal tissues. This differential expression makes GD2 an ideal target for antibody-based therapies. Naxitamab binds specifically to GD2, enabling selective targeting of tumour cells.
Beta Emission of ¹³¹I
Iodine-131 is a radioactive isotope that emits beta particles (β–) and gamma rays. The beta particles have a tissue penetration range suitable for damaging tumour cells while sparing surrounding healthy tissues. When ¹³¹I is conjugated to naxitamab, it delivers lethal doses of radiation directly to GD2-expressing cells, inducing DNA damage and cell death.
Clinical Trials and Developments
Transition to ¹²⁴I Labelling
While iodine-131 has been instrumental in therapeutic applications, its gamma emission can contribute to unnecessary radiation exposure and suboptimal imaging quality. Labelling naxitamab with iodine-124 (¹²⁴I) was explored as an alternative, improving image quality due to the positron emission suitable for positron emission tomography (PET) imaging. Additionally, ¹²⁴I reduces dosimetry to the patient, potentially lowering the risk of radiation-induced side effects.
Development of Humanised 3F8 (hu3F8)
The murine origin of 3F8 posed challenges related to immunogenicity, as patients could develop human anti-mouse antibodies (HAMA) that diminish therapeutic efficacy and increase adverse reactions. To address this, a humanised version of the antibody, hu3F8 (naxitamab), was developed. Humanisation reduces the immunogenic potential, allowing for repeated dosing and improved patient tolerance.
Ongoing and Completed Clinical Trials
Phase II Trial in CNS and Leptomeningeal Cancer
Since 2006, a Phase II trial has been underway to evaluate the efficacy and safety of ¹³¹I-3F8 in patients with central nervous system (CNS) cancers or leptomeningeal metastases. These malignancies are challenging to treat due to the blood-brain barrier limiting the delivery of therapeutic agents. The radiolabelled antibody’s ability to penetrate and deliver targeted radiation offers a promising therapeutic strategy.
Trials in Relapsed or Refractory Neuroblastoma
Another study was completed focusing on patients with relapsed or refractory neuroblastoma. The trial assessed the therapeutic impact of ¹³¹I-3F8, providing evidence of its potential to improve outcomes in this difficult-to-treat population.
Multiple Parallel Trials with Naxitamab
Presently, at least nine clinical trials are running in parallel involving either the murine 3F8 or the humanised hu3F8 (naxitamab). These trials encompass Phase I and II studies, investigating the antibody’s efficacy across various cancer types and stages.
Phase II Pivotal Trial with Cold Antibody
A Phase II pivotal trial is underway with the cold (non-radiolabelled) antibody hu3F8 (naxitamab), expected to be completed by 2027. This trial aims to solidify the therapeutic role of naxitamab in oncology, potentially leading to broader regulatory approvals and clinical adoption.
Dosimetry and Imaging Considerations
Accurate dosimetry is essential in RIT to maximise therapeutic efficacy while minimising toxicity. The use of ¹²⁴I-labelled naxitamab has improved the ability to perform precise dosimetry calculations through PET imaging. This allows clinicians to tailor dosing regimens based on individual patient pharmacokinetics and tumour uptake.
Imaging plays a crucial role in monitoring treatment response and disease progression. PET imaging with ¹²⁴I-naxitamab provides high-resolution images of tumour sites, aiding in the assessment of therapeutic effectiveness and planning of subsequent treatment cycles.
Patient Outcomes and Efficacy Results
Clinical trials have demonstrated that ¹³¹I-Naxitamab can lead to significant tumour reduction in patients with GD2-positive cancers. In neuroblastoma patients, responses have included partial and complete remissions, with some patients achieving long-term disease-free survival.
Adverse effects are generally manageable, with myelosuppression being the most common toxicity due to the bone marrow’s sensitivity to radiation. Pain at tumour sites, known as neuropathic pain, can occur due to GD2 expression on nerve fibres but is typically transient and responsive to analgesics.
Future Directions
Expected Completion of Pivotal Trials by 2027
The anticipated completion of pivotal trials by 2027 may mark a significant milestone in the clinical application of naxitamab. Positive outcomes could lead to new standards of care for patients with neuroblastoma and other GD2-expressing tumours.
Potential Applications in Melanoma and SCLC
Beyond neuroblastoma, the expression of GD2 in melanoma and small cell lung carcinoma opens avenues for the application of ¹³¹I-Naxitamab in these cancers. Ongoing research is exploring the efficacy of GD2-targeted therapies in these malignancies, potentially expanding the therapeutic arsenal available to oncologists.
Challenges and Considerations
While promising, the use of ¹³¹I-Naxitamab presents challenges, including managing radiation exposure, optimising dosing regimens, and overcoming potential resistance mechanisms. Continued research is essential to address these issues and enhance the therapeutic index of the antibody.
Conclusion
Iodine-131 Naxitamab (¹³¹I-3F8) represents a significant advancement in the field of radioimmunotherapy. By targeting GD2, it offers a precision approach to treating cancers that overexpress this antigen. The evolution from murine 3F8 to humanised naxitamab has improved the antibody’s clinical utility, reducing immunogenicity and enhancing patient outcomes. Ongoing clinical trials and future research will determine the ultimate role of ¹³¹I-Naxitamab in oncology, with the potential to improve survival and quality of life for patients with neuroblastoma, melanoma, SCLC, and other GD2-positive cancers.
You are here: home »