Radioconjugates: Targeting for Precision

Radiation therapy has been explored as a treatment for cancer right back to the turn of the 20th century, only a few years after the discovery of X-rays. [1] A lot of research has gone into making radiation therapy safer and more effective, including the development of radioconjugates – targeted molecules designed to carry radionuclides directly to cancerous cells, lowering systemic exposure and increasing the precision of treatment.

Targeted conjugates: an introduction

Targeted drug conjugates were a step forward in cancer treatment by improving efficacy and safety compared with conventional chemotherapeutics. These combine a tumour-targeting ligand (an antibody, peptide or small molecule) with a cytotoxic molecule, connected by a chemical linker. By taking the chemotherapeutic to the cell, the conjugates reduce off target effects, lower the risk of resistance and allow the precision use of higher toxicity drugs. [2] The concept of targeted drug conjugates has been extended to create radioconjugates (also known as radionuclide-drug conjugates or RDCs) that carry radioisotopes directly to cancer cells, for diagnostic imaging, and to deliver radiotherapy. Radioconjugates have a similar make-up to the targeted drug conjugates: a tumour-targeting ligand, a linker/chelator and a radioisotope payload.

The role of the targeting ligand is to guide the radioconjugate to its desired location, where it can bind to the target on the cell. The ligand can be an antibody (creating a radionuclide antibody conjugate or RAC) or a peptide or small molecule chosen for its high affinity to the antigens on the surface of the target cell. [3-5]

Examples of targeting ligands for radioconjugates: [5]

· Antibodies

    o CD20, CD37, CA 19-9

· Peptides

    o Octreotide acetate targeting somatostatin receptor type 2

· Small molecules

    o Fibroblast activation protein inhibitors

The linker and chelator connect the targeting ligand and the payload. Non-metallic isotopes, such as I-131 and I-123, can be connected directly to a ligand using a linker alone, whereas metallic isotopes need a chelator (such as DOTA and DTPA) as well as a linker. The linker and chelator must be designed to not affect the binding ability or the targeting ligand or the activity of the isotope. The linkers are generally non-cleavable to reduce cross-linking, improve the stability and increase the safety of the conjugate. [3-6]

The choice of radioisotope payload will depend on whether the conjugate is designed to be a therapeutic or an imaging agent. Diagnostic isotopes are β+- or γ-emitting and can be detected using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). The chosen radionuclide should have a short half-life and the conjugate should be eliminated from the body rapidly to limit radiation exposure to the patient. Examples include Tc-99m, I-123, I-124, F-18, Cu-64, Zr-89, Ga-67 and Ga-68.

Therapeutic isotopes generally emit short-range particles such as α or β particles that kill target cells, and examples include Ac-225, I-131, Lu-177, Y-90, and Ra-223. Alpha emitters can be more effective for faster growing cancers, and the longer paths of β radiation emitted by Y-90 and Lu-177 can also trigger a bystander effect, which can kill nearby cells that don’t carry the target antigen. The isotope half-life should be long enough for therapeutic efficacy. [3, 5, 6]

The challenges and benefits of radioconjugates

Radioconjugates need to be manufactured and shipped to patients within hours or days, especially when they are being used as a last line of treatment in seriously ill patients. However, the logistics can be challenging as the radionuclides have a specific half-life, their availability may be limited and there are regulations around their handling and shipping. The manufacturing process for the radioconjugates is also complex. [4, 6]

By targeting a radionuclide directly to the cancer site, therapeutic radioconjugates reduce overall system exposure to radiation, while allowing a higher local dose of a radionuclide, reducing damage to healthy tissues. As therapeutic radionuclides act by directly damaging cells, there is a lower risk of resistance developing compared with conventional chemotherapeutics. The irradiated cells may also emit signalling chemicals that affect the immune activity of cells close by, and in the microenvironment. [4, 6]

Radioconjugates: Now and the future

The two therapeutics approved by the FDA are Lutathera and Pluvicto, both β-emitters from Novartis. Lutathera (lutetium Lu-177 oxodotreotide), developed for somatostatin-positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs), was approved in 2017 in Europe and 2018 in the US. It was the first peptide receptor radionuclide therapy (PRRT) approved by the FDA. [5, 6] 

In 2022, Novartis' Pluvicto (lutetium Lu-177 vipivotide tetraxetan) was approved in the US and described as the first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. The FDA also approved the company's complementary diagnostic imaging agent, Locametz, which is radiolabelled with Ga-68 for the identification of PSMA-positive lesions. [7]

The future of radioconjugates

A number of major pharmaceutical companies are moving into radioconjugate therapies following acquisition of smaller specialist companies.

AstraZeneca, following the acquisition of Fusion Pharmaceuticals, is developing a number of radioconjugates in clinical trials: [8]

· FPI-2265 – an Ac-225-based PSMA-targeting radionuclide in Phase 2 in metastatic castration-resistant prostate cancer

· An EGFR-targeted molecule in Phase I

RayzeBio, now a wholly-owned subsidiary of Bristol Myers Squibb, has an actinium-based radiopharmaceutical platform and a pipeline of radiopharmaceutical therapeutics: [9, 10]

· RYZ101 – an Ac-225-DOTATATE-based SSTR2-targeting radionuclide in Phase 3 in second-line and later treatment of SSTR2+ gastroenteropancreatic neuroendocrine tumours and Phase I in extensive stage small cell lung cancer and HR+/HER2- unresectable metastatic breast cancer

Eli Lilly’s acquisition of POINT Biopharma brought the big pharma a pipeline of clinical and preclinical stage radioligand therapies for cancer. Lilly has expanded a deal with AdvanCell for Pb-212-based radiotherapeutics and gained rights to Radionetics’ pipeline of small molecule radiopharmaceuticals that target G protein-coupled receptors. [11-13]

The use of combination therapies is commonplace in cancer treatment, and there is potential for the use of radioconjugate therapeutics in combination with chemotherapy, external radiotherapy and immunotherapy. [6]

Cancer survivorship rates have improved enormously. In the EU, between 2011 and 2021, cancer mortality decreased by 12%. [14] Despite this, cancer remains the leading cause of death worldwide, causing nearly one in six deaths, according to the World Health Organization. [15] Early and accurate diagnosis, along with appropriate and effective therapy, have potential to improve outcomes for cancer patients, increasing both survival rates and patient quality of life. The targeting element of radioconjugates allows the drugs to target disease cells accurately, offering precision treatment and diagnosis. [4]

References

1. History of Cancer Treatments: Radiation Therapy. American Cancer Society. Last accessed: 12 June 2014. Available from: https://www.cancer.org/cancer/understanding-cancer/history-of-cancer/cancer-treatment-radiation.html.

2. Jia, G., Y. Jiang, and X. Li, Targeted drug conjugates in cancer therapy: Challenges and opportunities. Pharmaceutical Science Advances, 2024. 2: p. 100048.

3. Brown, A., What are Radionuclide Drug Conjugates (RDCs)? Molecular Cloud, 25 April 2024. Available from: https://www.molecularcloud.org/p/what-are-radionuclide-drug-conjugates-rdcs.

4. Cheng, Q., Beyond chemotherapy: The rise of precision medicine with radionuclide drug conjugates. Drug Discovery and Development, 14 May 2024. Available from: https://www.drugdiscoverytrends.com/beyond-chemotherapy-the-rise-of-precision-medicine-with-radionuclide-drug-conjugates/.

5. Radionuclide Drug Conjugates (RDCs): Current Status. Biopharma PEG. Last accessed: 8 August 2024. Available from: https://www.biochempeg.com/article/407.html.

6. Challener, C.A., Rising Interest in Radioconjugate Therapies. Pharma's Almanac, 25 February 2025. Available from: https://www.pharmasalmanac.com/articles/rising-interest-in-radioconjugate-therapies.

7. Novartis Pluvicto™ approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. Novartis. Last accessed: 23 March 2022. Available from: https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant-prostate-cancer.

8. Waldron, J., From ADCs to radiopharma: How AstraZeneca is trying to 'redefine oncology care'. Fierce Biotech, 9 April 2025. Available from: https://www.fiercebiotech.com/biotech/adcs-radiopharma-how-astrazeneca-aims-redefine-oncology-care.

9. Bristol Myers Squibb Completes Acquisition of RayzeBio, Adding Differentiated Actinium-Based Radiopharmaceutical Platform. Bristol Myers Squibb. Last accessed: 26 February 2024. Available from: https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Completes-Acquisition-of-RayzeBio-Adding-Differentiated-Actinium-Based-Radiopharmaceutical-Platform/default.aspx.

10. In the pipeline. Bristol Myers Squibb. Last accessed: 2 May 2025 2025. Available from: https://www.bms.com/researchers-and-partners/in-the-pipeline.html.

11. Lilly Completes Acquisition of POINT Biopharma. Lilly Investors. Last accessed: 27 December 2023. Available from: Lilly Completes Acquisition of POINT Biopharma.

12. Taylor, N.P., Eli Lilly inks duo of deals, teaming with AdvanCell, OliX to push deeper into radiopharma, MASH. Fierce Biotech, 10 February 2025. Available from: https://www.fiercebiotech.com/biotech/eli-lilly-inks-duo-deals-teaming-advancell-olix-push-deeper-radiopharma-mash.

13. Alvarado, D., Eli Lilly inks another radiopharma deal, gaining option to buy startup. Biopharma Dive, 1 July 2024. Available from: https://www.biopharmadive.com/news/eli-lilly-radionetics-radiopharmaceuticals-option-gpcr/720342/.

14. Commission publishes Country Cancer Profiles ahead of World Cancer Day. European Commission. Last accessed: 3 February 2025. Available from: https://ec.europa.eu/commission/presscorner/detail/en/ip_25_393.

15. Cancer. World Health Organization. Last accessed: 3 February 2025. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer.