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Advancing next-generation radioconjugates to redefine radiotherapy in oncology
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Radioconjugates are a novel drug modality that delivers radiation directly to cancer cells. Here we explain their mechanism of action and implications for targeted radiotherapy in cancer.
What are radioconjugates and how do they work?
Radioconjugates are targeted medicines that combine a potent medical radioisotope, known as the payload, with a targeting molecule such as an antibody, peptide or small molecule via a chemical linker.1
Traditional radiotherapy, such as external beam radiation therapy, can kill surrounding healthy cells in the process of cancer treatment. In contrast, radioconjugates’ targeting molecule is designed to bind specifically to tumour associated antigens on the surface of cancer cells. This allows for more stable and prolonged tumour uptake of the therapeutic agent.1
For example, by attaching a radioactive payload, such as actinium-225, which is an alpha-emitting particle that holds the promise of being a next-generation radioisotope in cancer treatment, radioconjugates can deliver a greater radiation dose over shorter distance, with potential for more targeted delivery to reduce damage to surrounding healthy tissue.
Learn more about radioconjugate therapies’ mechanism of action:
Radioconjugates exert their cancer killing effect with a radioactive isotope which emits ionising radiation that affects the DNA structure directly by inducing double stranded breaks to the DNA helix.1 The extent of cell death depends on the absorbed dose of the radioactive isotope, the rate at which the dose is delivered, and the ability of the tumour to repair DNA damage.
Unlike antibody-drug conjugates, radioconjugates are not dependent on inhibition of a specific cellular process, which means cancer cells are less likely to develop resistance to treatment. Instead, once bound to a protein that’s highly expressed in cancer cells, the radioconjugate exerts DNA damage that results in a cancer killing effect.1
Since radioconjugates are administered via systemic delivery, they can reach tumour types not accessible to external beam radiotherapy and target cancer cells that have spread from the main tumour to other sites in the body.1
They also have potential value as a diagnostic, and can be used as an imaging agent to first investigate tumour retention, before they are used to deliver radioactive components intended for cancer killing.1
Radioconjugate binding to a cancer cell to deliver radiation cancer treatment:
Establishing a portfolio of differentiated radioconjugates
30–50% of patients receive radiotherapy at some point during their cancer treatment.2 Radioconjugates are an emerging modality which has the potential to bring transformative outcomes for many patients with cancer. Our vision is for radioconjugates to redefine radiotherapy regimens and to become the backbone for novel cancer therapies, including combination approaches.
Radioconjugates are an important part of the Oncology R&D strategy and a key part of our diverse portfolio, designed to attack cancer from multiple angles.
Building on an ongoing collaboration, the acquisition of Fusion Pharmaceuticals in 2024, a clinical stage biopharmaceutical company developing next generation radioconjugates, marked a major step forward in AstraZeneca delivering on our aim to transform cancer treatment and outcomes for patients by replacing traditional radiotherapy regimens with more targeted treatments.3
The next step for the field is to redefine the boundaries of radiation treatment by evaluating tumour types beyond those currently treated with traditional radiotherapy, and in patients whose tumours cannot be treated with available therapies.
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References:
1. National Institute of Cancer. Radiopharmaceuticals: Radiation Therapy Enters the Molecular Age [Last Accessed 23 July 2024]. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2020/radiopharmaceuticals-cancer-radiation-therapy
2. Majeed H, Gupta V. Adverse Effects of Radiation Therapy. 2023. In: StatPearls [Internet].
3. AstraZeneca to acquire Fusion to accelerate the development of next-generation radioconjugates to treat cancer.
Veeva ID: Z4-65988
Date of preparation: September 2024