Harnessing the power of copper isotopes 64Cu and 67Cu for pretargeted radioimmunotherapy that could change how we fight cancer
Imagine a cancer treatment so precise that it can first identify enemy cells with reconnaissance, then deploy a specialized weapon that attacks only those cells, leaving healthy tissue virtually untouched. This isn't science fiction—it's the promise of pretargeted radioimmunotherapy (PRIT) using a pair of remarkable copper isotopes. For decades, cancer treatment has struggled to balance effectiveness with safety, but now, harnessing the power of copper-64 (64Cu) and copper-67 (67Cu), scientists are developing a revolutionary approach that could change how we fight cancer.
Traditional treatments like chemotherapy and radiation cause significant collateral damage to healthy tissues.
PRIT separates tumor identification from radiation delivery, minimizing harm to healthy cells.
The problem with traditional cancer treatments is their collateral damage. Chemotherapy attacks rapidly dividing cells throughout the body, causing devastating side effects. Radiation therapy can damage healthy tissue surrounding tumors. Even conventional radioimmunotherapy (RIT), which uses antibodies to deliver radiation directly to cancer cells, has a critical flaw: antibodies circulate in the bloodstream for days, potentially delivering harmful radiation to healthy organs 1 2 .
Enter pretargeted radioimmunotherapy—a clever two-step system that separates tumor identification from radiation delivery. This approach, combined with the ideal nuclear properties of copper-64 and copper-67, creates a theranostic platform that allows doctors to see exactly where treatment will be delivered before administering therapy 1 2 . The term "theranostic" describes this powerful combination of therapy and diagnostics—using the same targeting molecule with different isotopes to both identify and treat cancer.
Traditional radioimmunotherapy faces a fundamental timing problem. Antibodies—the precision guidance systems that seek out cancer cells—can take several days to accumulate at tumor sites and clear from the bloodstream. To remain active throughout this process, they must be paired with radioactive atoms that have similarly long half-lives. This combination means that while the antibody is circulating throughout the body, it continues to deliver radiation to healthy tissues, particularly the bone marrow, which is especially sensitive to radiation damage 2 .
This limitation has hampered the widespread clinical use of an otherwise promising treatment approach. Doctors have had to choose between effective tumor dosing and dangerous toxicity to healthy cells—an unacceptable compromise when treating cancer patients.
Pretargeted radioimmunotherapy elegantly solves this problem by decoupling the antibody from the radiation source. Instead of directly attaching radiation to antibodies, the system uses two separate components that combine only at the tumor site:
An antibody specially designed to recognize cancer cells is administered first, but instead of carrying radiation, it carries a unique "docking station" called trans-cyclooctene (TCO).
Antibody accumulates at tumor, clears from blood (typically about 72 hours).
These two components rapidly connect at the tumor through what chemists call a bioorthogonal reaction—meaning it occurs quickly and specifically inside the human body without interfering with normal biological processes. This specific reaction is known as the inverse electron-demand Diels-Alder reaction 2 .
| Step | Component | Function | Timing |
|---|---|---|---|
| 1 | Antibody-TCO conjugate | Binds to cancer cells and provides docking stations | Day 0 |
| Waiting Period | - | Antibody accumulates at tumor, clears from blood | 72 hours |
| 2 | Radiolabeled Tz molecule | Delivers radiation precisely to pre-targeted cells | Day 3 |
| In Vivo | Click chemistry | Rapidly connects components at tumor site | Minutes after Step 2 |
This innovative approach fundamentally changes the radiation delivery paradigm. The small Tz molecule circulates briefly—long enough to find its docking station at the tumor site but not long enough to cause significant damage to healthy tissues. Any unused Tz is rapidly eliminated from the body, dramatically reducing overall radiation exposure 1 2 .
The success of pretargeted radioimmunotherapy depends on having the right pair of radioactive isotopes, and copper-64 and copper-67 form what scientists consider an nearly perfect matched theranostic pair 3 4 . These two isotopes have identical chemical behavior—the body processes them exactly the same way—but different radioactive properties that make them ideal for their respective roles:
With a half-life of 12.7 hours, this isotope emits positrons, which are used in positron emission tomography (PET) scanning. This allows doctors to precisely visualize where the radioactive compound has accumulated in the body, verifying that it has successfully reached the tumor before proceeding with treatment 1 4 .
With a longer half-life of 61.8 hours, this isotope emits beta particles that are ideal for therapy. These beta particles have just the right energy to destroy cancer cells while penetrating only about 2-3 millimeters into surrounding tissue—enough to cover a small tumor without excessive damage to healthy cells 1 4 7 .
| Isotope | Half-Life | Emission | Role | Key Properties |
|---|---|---|---|---|
| Copper-64 | 12.7 hours | Positrons (17.5%), Beta particles (38.5%), Electron capture (44%) | Diagnosis | Enables PET imaging, ideal for antibody kinetics |
| Copper-67 | 61.8 hours | Beta particles (100%), Gamma rays | Therapy | Medium-energy β- particles, imageable γ rays |
One significant hurdle in using copper for medical applications has been finding a way to securely attach it to targeting molecules without the copper breaking free and traveling to other parts of the body, particularly the liver. Early copper radiopharmaceuticals struggled with this issue, limiting their effectiveness 4 .
The breakthrough came with the development of a remarkable chelator called sarcophagine (Sar)—from the Greek for "flesh-eater," though in this case, it simply describes its cage-like structure that securely encapsulates copper atoms. Specifically, scientists created a version called MeCOSar (methyl-carboxylate sarcophagine) that can be easily attached to antibodies and radiolabeled with copper in minutes at room temperature—crucial for working with temperature-sensitive antibodies 4 .
This advancement means that copper stays firmly bound to its targeting molecule until it reaches the tumor, then delivers its radiation payload exactly where needed.
Cage-like structure that securely encapsulates copper atoms
For decades, the limited availability of copper-67, particularly in the quantities and purity needed for clinical applications, hindered research. However, recent advances in production methods have dramatically improved availability 3 7 . Scientists have developed new techniques using accelerator-generated neutrons to produce both isotopes, with efficient separation methods that allow for high purity and sufficient quantities for both research and clinical use 3 7 .
In a groundbreaking 2020 study published in Proceedings of the National Academy of Sciences, researchers demonstrated the remarkable potential of this approach in fighting colorectal cancer 1 2 . The team used:
A humanized antibody called huA33 that specifically targets the A33 antigen present on most colorectal cancer cells.
The antibody was modified with TCO docking stations, creating huA33-TCO.
The experimental design was both meticulous and insightful. Mice with human colorectal tumors received the huA33-TCO antibody first, followed 72 hours later by one of three different doses of the therapeutic [67Cu]Cu-MeCOSar-Tz (18.5, 37.0, or 55.5 MBq). To validate the theranostic approach, some mice received the imaging version [64Cu]Cu-MeCOSar-Tz first, allowing researchers to predict the therapeutic outcome before actual treatment 1 .
The findings were striking. The treatment produced a clear dose-dependent therapeutic response 1 :
Perhaps most impressively, the researchers observed a direct correlation between the tumor uptake of the diagnostic [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz—exactly what is needed for a reliable theranostic approach 1 .
| Dose (MBq) | Median Survival | Tumor Growth Inhibition | Key Findings |
|---|---|---|---|
| 18.5 | 68 days | Significant inhibition | Demonstrated baseline efficacy |
| 37.0 | Increased | Strong inhibition | Dose-dependent response confirmed |
| 55.5 | >200 days | Complete regression or sustained inhibition | Highest efficacy with fractionated dosing improving hematological values |
The successful implementation of copper-based pretargeted radioimmunotherapy depends on a carefully designed toolkit of specialized reagents and materials. Each component plays a critical role in ensuring precise tumor targeting and effective radiation delivery.
| Reagent | Function | Role in PRIT |
|---|---|---|
| huA33-TCO antibody | Binds to A33 antigen on colorectal cancer cells, provides TCO docking stations | Targeting moiety that localizes to tumor cells |
| MeCOSar chelator | Bifunctional sarcophagine ligand that securely encapsulates copper ions | Prevents copper release, ensures radiation delivered only to tumor |
| Tetrazine (Tz) ligand | Rapidly reacts with TCO via bioorthogonal chemistry | Connects radiation payload to pre-targeted antibody |
| Copper-64 (64Cu) | Positron-emitting radionuclide (t1/2 = 12.7 h) | Enables PET imaging, dosimetry calculations, treatment planning |
| Copper-67 (67Cu) | Beta-emitting radionuclide (t1/2 = 61.8 h) | Delivers therapeutic radiation to tumor cells |
| AG1-X8 resin | Anion exchange chromatography medium | Purifies copper isotopes from irradiated targets |
These reagents work together as an integrated system, each playing an essential role in the sophisticated dance of pretargeted therapy. The beauty of this toolkit is its adaptability—while the original research focused on colorectal cancer, the same basic components can be redirected against different cancers by simply changing the targeting antibody 1 4 .
The potential of copper pretargeted therapy extends far beyond colorectal cancer. Recent research has demonstrated impressive results in targeting HER2-positive breast cancer using the same fundamental approach but with a different antibody.
In a 2025 study published in Chemical Science, researchers created Sar-trastuzumab—a conjugate of the sarcophagine chelator with trastuzumab (Herceptin), an antibody that targets HER2-positive cancer cells 4 . When radiolabeled with copper-64, this conjugate showed exceptional tumor uptake in mice with HER2-positive tumors, with PET imaging revealing mean SUVmax values of 21.0 ± 2.5 at 48 hours after administration—indicating very high concentration at the tumor site 4 5 .
The therapeutic version, [67Cu]CuSar-trastuzumab, produced dramatic results even at relatively low doses 4 5 :
| Cancer Type | Target | Targeting Molecule | Research Status |
|---|---|---|---|
| Colorectal | A33 antigen | huA33 antibody | Established preclinical proof-of-concept 1 |
| HER2+ Breast | HER2 receptor | Trastuzumab antibody | High efficacy in preclinical models 4 |
| Neuroendocrine | Somatostatin receptor | SarTATE peptide | Clinical trials underway 4 |
| Prostate | PSMA | PSMA-targeting molecules | Early investigation |
These exciting findings across multiple cancer types suggest that the copper pretargeting platform represents a versatile approach that can be adapted to many different cancers by selecting the appropriate targeting antibody.
As research progresses, several key developments are shaping the future of copper-based pretargeted radioimmunotherapy:
Significant efforts are underway to increase the availability and purity of both copper-64 and copper-67. Recent research from Japanese scientists demonstrates novel production routes using accelerator-generated neutrons, potentially making these isotopes more accessible and economically sustainable for widespread clinical use 3 7 .
The promising preclinical results have set the stage for clinical trials in humans. The stability of the sarcophagine-copper complex, proven in human trials with other copper-based radiopharmaceuticals, provides confidence that the pretargeting approach will perform well in patients 4 .
The theranostic nature of the copper-64/copper-67 pair enables truly personalized treatment. Physicians can use copper-64 PET imaging to confirm tumor targeting, calculate precise radiation doses for individual patients, and predict treatment response before administering therapy 1 4 .
The development of pretargeted radioimmunotherapy using copper-64 and copper-67 represents a paradigm shift in how we approach cancer treatment. By separating targeting from treatment and leveraging the unique properties of these copper isotopes, scientists have created a system that offers unprecedented precision in fighting cancer while minimizing damage to healthy tissues.
The research journey—from understanding the limitations of conventional radioimmunotherapy to developing sophisticated bioorthogonal chemistry and stable chelators—showcases how creative problem-solving in science can overcome seemingly intractable challenges. As we stand on the brink of clinical translation, this technology promises to deliver on the long-held dream of cancer treatments that are both highly effective and gentle on the body.
While more research is needed to fully realize the potential of this approach across different cancer types, the remarkable results in colorectal and breast cancer models offer hope that we may soon have a powerful new weapon in our arsenal against cancer—one that delivers precisely targeted radiation using these remarkable copper "bullets" to strike at the heart of tumors while leaving healthy tissue unscathed.