Conceptual illustration of radio drug conjugate (RDC) technology for oncology, demonstrating the targeted delivery of radioactive isotopes to cancer cells to enhance therapeutic efficacy. Credit: WuXi AppTec.
Radionuclide Drug Conjugates (RDCs) hold the potential to transform cancer treatment by offering effective, precise treatment and diagnosis with minimal side effects. Regulators have already approved several RDCs around the world, and more are in the pipeline as researchers seek to further improve their efficacy, safety, and personalization. RDCs have evolved from other branches of cancer treatments over time, and now look set to bring hope to patients who face the devastation of cancer.
What are RDCs?
Traditional radiotherapy delivers radiation from outside of the body without differentiating between normal cells and cancerous tumor cells. RDCs can deliver radiation much more effectively and target tumors in a manner that greatly reduces side effects, attacking only the cancerous cells. By taking a targeted approach, RDCs avoid damaging healthy tissue and deliver much more damage to cancerous cells.
RDCs are made up of four major components:
- Radionuclide: This is the radioactive atom that emits radiation capable of killing a cancerous cell. They can emit particles or rays and release energy to both diagnose and provide therapy to a patient.
- Targeting molecule: Like a homing beacon, this molecule locates and binds to disease cells. Targeting molecules can be a peptide, an antibody, or another substance that has a high affinity to a receptor in a disease cell.
- Chelator: The chelator binds the radionuclide, ensuring it’s securely in place and can be delivered to the diseased cells without affecting healthy tissue.
- Linker: The linker connects the targeting molecule to the chelator, binding it to the radionuclide as well. This component plays a crucial role in the safety and stability of the RDC. Non-cleavable linkers are normally used by RDCs for safety considerations.
How were RDCs developed over time?
Radium was first used to treat disease in 1913, marking the beginning of radiotherapy. This showed the potential for radioactive materials to treat cancer, but the therapy was untargeted and often damaged healthy tissue. In 1946, iodine was deployed to treat thyroid cancer, enabling a minimally invasive therapy for the disease. This showed researchers that radionuclides could be used in a targeted manner in specific types of cancer. Five years later, Abbot Laboratories created the Iodine human serum protein, a landmark event in the development of radiopharmaceuticals.
Progress advanced rapidly over decades until 2013, when the first targeting radiopharmaceutical, Xofigo® (developed by Bayer) was approved for advanced bone metastatic castration-resistant prostate cancer. Three years later, the first RDC was approved, and the technology has developed significantly since, with many new therapies in the pipeline.
Notably, nine RDCs have been approved by American regulators since 2016, including seven for cancer diagnoses and two for cancer therapy.
Major advantages of RDCs over other therapies
RDCs offer several advantages over other therapies targeting similar diseases. These advantages include:
Drug resistance
Traditional therapies, including small molecules and biologics, are prone to inducing drug resistance because the mechanism of action (MOA) can rely on single pathways and targets. Cancer cells are highly adaptable, so they can mutate to find a new pathway and continue growing. In contrast, RDCs mainly rely on direct irradiation from the radionuclides, which break DNA and trigger the death of cells. So RDCs are more tolerate to drug resistance comparing to other therapies.
Locating tumors
RDCs can locate a tumor quickly and reliably. Traditional methods of diagnosing tumors include imaging such as CT, MRI, and biopsy, but they take a long time. The biopsy process is risky, and the result can depend heavily on the doctor’s skill. Some sites are impossible to sample, such as bone metastasis. RDCs can reach these sites and identify tumor metastasis through molecular images.
Integrating diagnostics and therapy
Some radionuclides emit positrons, which can be used for diagnostic imaging to help measure the location of tumors. After the imaging is completed, RDCs equipped with alpha or beta-particle-emitting nuclides can be used for treatment. By integrating diagnosis and therapy, doctors can more effectively treat patients. RDCs can provide more precise information about a tumor, including its size, location, and the specific antigens it expresses. This means therapies can be tailored to the patient, enabling personalized medicine.
Challenges of developing RDCs
RDCs have enormous potential but developing them can be challenging. As the nuclides are radioactive, their supply is limited and firmly supervised. Qualifications and environmental protections are stringently scrutinized, much more so than other drugs. Also, because of their short half-life, logistics can be tricky. RDCs cannot be used after a period of time, which can be hours or days. This means they must be produced and transported from a site close to a hospital and distribution must be immediate and based on the needs of medical staff.
There are also regulatory challenges to overcome. Because RDCs are novel, navigating regulatory requirements can be challenging. Regulators expect a wealth of data to understand the benefits and risks fully. The long-term effects of radiation make the whole process more difficult. As a result, drug developers lacking the expertise required in-house are encouraged to work with a trusted and experienced lab partner.
A final word
RDCs have come a long way in a relatively short timeframe, but there is still a lot of progress to be made. Researchers are working hard to optimize the DMPK characteristics—i.e., absorption, distribution, metabolism, and excretion (ADME)—and targeting capabilities, thereby improving tumor penetration while maintaining a suitable half-life. Progress is also being made to combine the effects of RDCs with inhibitors of DNA repair factors to stop tumors from reversing the damage done by therapies. Combining RDCs with immune checkpoint inhibitors is yet another strategy being explored to improve patient outcomes.
RDCs are an exciting area of medicine, which could give hope to millions of patients suffering from cancer in the future. Researchers developing new RDCs face challenges as they bring therapies to market, but through efficient and safe testing, they can introduce new treatments to patients desperately seeking hope in their fight against cancer.
About Dr. Qigan Cheng
Dr. Qigan Cheng is a senior Study Director in the DMPK Service Department at WuXi AppTec. He has more than 10 years of research experience in drug discovery and development and more than four years of research experience in preclinical pharmacokinetics. He has successfully supported more than 20 new drug IND applications globally.
Filed Under: Drug Discovery, Drug Discovery and Development, Oncology
