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The search for radiopharmaceuticals has opened up a new avenue in oncology, promising targeted therapies with fewer side effects.

By Elie Dolgin

Translation | Snow

On a Wednesday morning in late January 1896, in a small lightbulb factory in Chicago, a middle-aged woman named Rose Lee was the beginning of a groundbreaking medical career. She placed an X-ray tube over a lump in her left breast and treated it by sending a beam of high-energy particles through the malignancy.

“Thus,” her doctor later wrote, “without trumpets or drumbeats, X-ray therapy was born.”

Radiation therapy has come a long way since those early days. The discovery of radium and other radioactive metals opened the door to targeting higher doses of radiation to cancer lesions deeper in the body. Later, the introduction of proton therapy made it possible to precisely guide particle beams to irradiate tumors, reducing damage to surrounding healthy tissue—a precision that was further enhanced by advances in medical physics, computer technology, and advanced imaging techniques.

But it wasn't until the new millennium that targeted radiopharmaceuticals became available.(Also called "nuclear medicine")These agents are like infrared-guided missiles designed to hunt cancer, delivering their nuclear warheads directly to the tumor through the bloodstream.

Using radiation to kill cancer cells has a long history. In this 1915 photo, a woman undergoes "X-ray therapy" - using X-rays to treat epithelial cell cancer on her face. Image source: WIKIMEDIA COMMONS

Currently, only a few drugs of this type are commercially available, especially for the treatment of prostate cancer, cancers originating in the pancreas and gastrointestinal tract.hormoneBut that number is expected to grow as the biopharmaceutical industry begins investing heavily in the technology.

On June 4, 2024, AstraZeneca completed its acquisition of next-generation radiopharmaceutical company Fusion Pharmaceuticals for $2.4 billion, becoming the latest heavyweight to join this field. This move follows Bristol-Myers Squibb（Bristol Myers Squibb，BMS）and Eli Lilly（Eli Lilly）Since then, the two companies have made similar transactions in recent months, involving amounts exceeding $1 billion; Novartis（Novartis）It also acquired several innovative radiopharmaceutical companies earlier, continuing its serial acquisition plan that began in 2018. According to news in May, Novartis plans to spend another $1 billion in upfront payment to acquire a radiopharmaceutical startup.(Translator's note: referring to Mariana Oncology)。

“It’s incredible, and all of a sudden it’s all the rage,” says George Sgouros, a radiation physicist at the Johns Hopkins University School of Medicine and founder of Rapid, a Baltimore-based company that provides software and imaging services to support radiopharmaceutical development. The surge in interest reflects a greater recognition that radiopharmaceuticals offer “a fundamentally different way to treat cancer,” he says.

However, treating cancer differently means overcoming a unique set of challenges, such as manufacturing and precisely timed delivery of these new therapeutics before their radioactivity decays. Expanding the treatment to treat a wider range of cancers will also require new types of tumor-killing particles and finding more suitable targets.

"There's a lot of potential here," said Wedbush Securities in San Francisco.（Wedbush Securities）said David Nierengarten, an analyst covering the radiopharmaceutical sector, adding, “There is still a lot of room for improvement.”

Advances in atomic technology

For decades, radioactive iodine was the only radiopharmaceutical on the market. Once ingested, the iodine is taken up by the thyroid gland, helping to destroy cancer cells in the gland in the neck — a treatment technique invented in the 1940s that is still commonly used today.

However, this targeting strategy does not apply to other tumor types.

The thyroid gland instinctively absorbs iodine from the blood. This mineral is present in a non-radioactive form in many foods and is necessary for the thyroid gland to synthesize certain hormones.

Other cancers have an incomparable affinity for radioactive elements. Therefore, researchers have to design drugs that can recognize and target specific proteins produced by tumor cells, rather than manipulate natural physiological pathways. These drugs are then further designed as targeted carriers to deliver radioisotopes—unstable atoms that emit nuclear energy—directly to the site of the malignancy.

The figure above describes the basic principles of radiopharmaceuticals.

The first drugs of this type to come to market were designed only to obtain images of tissues in the body. Using relatively mild, short-lived isotopes, these products can precisely illuminate tumor tissue in PET scans, helping doctors more accurately map the location of malignant cells and make diagnoses. This innovative approach paved the way for more powerful, but also more lethal, radiation therapies that now aim not just to image tumor cells, but to destroy them.

However, it will take time for this strategy to prove itself in routine cancer treatment.

The first marketed therapy combining a radioisotope with a cell-targeting molecule was a drug called Quadramet, which was approved by U.S. regulators in 1997. It was used to relieve bone pain caused by cancer, not to shrink tumors, and few clinicians were willing to prescribe it.

In the early 2000s, two new drugs for treating lymphoma were introduced. Both drugs carry radioactive particles designed to target a protein on malignant blood cells called CD20.(Tumor Markers)Although these two drugs areClinical TrialsAlthough both drugs were very effective, shrinking the tumors of the vast majority of participants, they have struggled to gain widespread acceptance in clinical practice. Neither drug was able to compete with rituximab, a non-radioactive blockbuster drug that also targets CD20, and they were eventually discontinued. Today, neither drug is available to patients.

After these commercial setbacks, interest in radiopharmaceuticals waned and investment in them stagnated. “In those days, drug companies wouldn’t touch radiopharmaceuticals with a 10-foot pole, even if that pole was made of lead,” said Neil H. Bander, founder and chief scientific officer of Convergent Therapeutics, a startup focused on radiopharmaceuticals. “They hated the concept of radiopharmaceuticals.”

But efforts are continuing at universities, including at Weill Cornell Medical College in New York, where Neil H. Bander, a professor emeritus after 40 years of service, began working in 2000 on using radioactive markers to identify the cause of death.AntibodyDrugs to treat prostate cancer.

These drugs are designed to bind to a receptor protein on the surface of prostate cancer cells, the prostate-specific membraneantigen（PSMA）Once bound, they are internalized by these cells and deliver the radioactive material directly to the genetic core of the tumor cell.(Bander in 2024Annual Review of MedicineThis and other PSMA-based therapies are discussed in this article.)。

Nuclide selection

Around the same time, clinicians in Europe were making progress in developing radiolabeled drugs for another target, the somatostatin receptor.（somatostatin receptor）These proteins are found in rare neuroendocrine tumors, where they mediate hormonal signals that drive tumor growth. The researchers found that hormone-mimicking molecules containing radioactive isotopes can bind to these receptors and effectively shrink tumors.

Clinicians experimented with different radioactive loads under compassionate-use protocols, which allow seriously ill patients to receive experimental treatments. Researchers experimented with unstable isotopes of elements such as yttrium and indium, then focused on isotopes of lutetium. This rare earth metal is favored because it is gentler on the kidneys and has a longer half-life, which facilitates manufacturing and logistics. At a clinic in Bad Berka, Germany, more than a thousand patients were treated over a decade and had improved survival rates compared with typical conventional treatments.

Meanwhile, several fledgling pharmaceutical companies are beginning to build the regulatory foundation for broader approval. One company, Advanced Accelerator Applications, is working on a new approach to developing a drug that can be used to treat cancer.（AAA）A lutetium-labeled drug led by a French company passed a randomized trial and reported in 2017 that it significantly slowed the progression of intestinal tumors compared with the existing standard of care. The drug, marketed as Lutathera, was quickly approved by regulators in Europe and the United States.

Novartis took notice. The Swiss pharmaceutical giant had dabbled in radiopharmaceuticals in the past, but now it was going all in. Within weeks of Lutathera’s European approval, Novartis struck a deal to buy AAA for nearly $4 billion. A year later, it bought a small Indiana company called Endocyte for more than $2 billion.

“It was like someone flipped a switch,” Bander says. The industry’s interest in radiopharmaceuticals was rekindled and put directly on the fast track.

Radiotherapy drugs need to be specially packaged in lead containers and lined boxes and delivered to the treatment site quickly and accurately. Image source: NOVARTIS

With its acquisition of Endocyte, Novartis has introduced a PSMA-targeted drug that will be a real game changer—both for patients with certain hard-to-treat advanced prostate cancers and for Novartis.

In a randomized clinical trial, adding this drug to standard treatment reduced disease progression.（disease progression）The average time before the disease was detected more than doubled - from less than four months to more than eight months, and the subjects' lifespans were also extended by several months.

It’s worth noting that despite Lutathera’s impressive clinical results, neuroendocrine tumors are extremely rare, and this scarcity means that Lutathera may never reach the coveted $1 billion annual sales threshold that such drugs are known as “blockbuster” drugs in the industry.（blockbuster）By contrast, the PSMA-targeted prostate drug, approved in 2022 under the brand name Pluvicto, treats a very common disease—about one in seven men will be diagnosed with it in their lifetime. As a result, it is just $20 million away from blockbuster sales in less than two years.

"Beta version"

Both Pluvicto and Lutathera are built around small protein sequences – peptides – that bind specifically to target receptors on cancer cells – PSMA in the case of prostate cancer and the somatostatin receptor in the case of Lutathera – and release radiation through the decay of an unstable lutetium isotope.

These drugs are injected into the bloodstream and circulate throughout the body until they firmly attach to the surface of tumor cells they encounter. Once fixed on these targets, the lutetium isotopes emit two types of radiation that help treat cancer. The main radiation is beta particles, which are high-energy electrons that can penetrate tumors and surrounding cells, tearing and damaging DNA, and ultimately triggering cell death.

A small amount of gamma rays are also produced during the process, which does not cause much tissue damage, but allows medical personnel to track the distribution of drugs in the body in real time, so as to monitor the progress of treatment and adjust strategies accordingly. "You can actually imagine where the drug is going and learn more about it," said Thomas Hope, a nuclear medicine expert at the University of California, San Francisco. Hope has worked for RayzeBio.(Before being acquired by BMS earlier this year)and other radiopharmaceutical manufacturers not mentioned in this article.

Many other therapies currently in clinical trials also use radiolutium and other beta radioisotopes, but current research efforts and significant industry investment are increasingly moving toward drugs with alpha radioisotopes.

Compared to beta particles, alpha particles are larger and more energetic. This property allows them to simultaneously disrupt the double helix, destroy DNA, and cause local cell destruction. "It's basically like a bomb exploding inside the cell," said John Valliant, founder and CEO of Canadian Fusion Pharmaceuticals.

Another key advantage of alpha particles is their limited penetration distance. They typically only penetrate about 50 to 100 micrometers — roughly the thickness of a human hair. This is in stark contrast to beta particles, which can penetrate several millimeters of tissue before running out of energy. As a result, therapies using alpha particles can achieve a highly localized effect: They destroy tumor tissue while avoiding harm to nearby healthy cells.

There is growing interest in radiopharmaceuticals using alpha particles because they can be targeted more precisely to cancer tissue and have enhanced local cell-killing properties.

"Alpha version released"

Some of the first alpha radiopharmaceuticals to come to market may target prostate-specific membrane antigen（PSMA）Developers are optimistic that the drugs will eventually outperform Pluvicto, and they are adding extra features to improve efficacy.

At Convergent, for example, Bander and his team are developing a large drug based on an antibody linked to an alpha radioactive isotope. Because of its size and complexity, the drug stays in the body much longer than peptide drugs, which tend to be excreted quickly by the kidneys. This means the drug has more time to find its target and kill tumor cells. In addition, alpha radioactive antibodies against PSMA appear to be less damaging to the salivary glands than peptide drugs, offering a potential additional safety advantage.

However, Telix Pharmaceuticals(Located in North Melbourne, Australia)Chris Behrenbruch, CEO of , argues that precise cell destruction with alpha radioactivity is not always advantageous. He says the choice of radioactive payload should be influenced by the disease state and other combination drug therapies the patient is receiving, which are becoming the standard of care for cancer.

As clinicians begin to explore the potential of pairing radiopharmaceuticals with other drugs that stimulate anti-tumor immune responses, Behrenbruch notes that causing some damage to surrounding tissue may actually be beneficial, because that damage helps attract anti-tumor T cells. “Nothing irritates your immune system more than healthy tissue being irradiated,” he says.

Telix is ​​currently exploring this hypothesis by conducting a clinical trial to label a lutetium-labeled antibody(The antibody targets an enzyme produced by kidney cancer cells)It is used in combination with an immunotherapy drug designed to activate T cells in the body. Because the radiopharmaceutical is directed at a new target, Telix's drug also has the potential to cause collateral damage, as not only kidney cancer cells but also healthy stomach, pancreatic and gallbladder cells produce the target enzyme. Behrenbruch noted that preliminary trial data showed that the treatment was generally tolerable. However, continued research is still needed to fully evaluate its safety.

The challenge of specificity—targeting only cancer cells without affecting healthy tissue—is not limited to this case. Beyond PSMA and somatostatin receptors, there are very few proteins that are expressed exclusively or predominantly by tumor cells, notes Ken Herrmann, a nuclear medicine specialist at the University Hospital Essen in Germany. This limited selection complicates the development of treatments that can effectively target tumors without inadvertently causing unnecessary harm to surrounding healthy tissue, says Herrmann, who consults for most major pharmaceutical companies as well as several smaller biotechs.

“Everyone is working on new targets,” he said, “but which new targets are going to win? We don’t know yet.”

In the race to find the next breakthrough target, Novartis is at the forefront. The company is developing a new generation of radiolabeled drugs that target several promising cancer-selective proteins, some of which are already in clinical evaluation and others in early discovery and validation stages. At the same time, the company is expanding its production capabilities with new dedicated facilities around the world for large-scale production of radiopharmaceuticals.

Unlike the production of other types of cancer drugs, supply chain issues are common for radiopharmaceuticals. As Bristol-Myers Squibb discovered, a shortage of isotopes forced the company to halt enrollment in a Phase III trial of a drug led by Rayzebio, which Bristol-Myers Squibb acquired. Moreover, even if the necessary isotopes are available, the rapid decay of radioactive raw materials requires a unique logistics system that requires careful coordination between clinicians and manufacturers to ensure that the drug reaches the hospital within a strictly defined time window to ensure efficacy.

Companies typically have a two-week planning window during which to manufacture the radioisotope, attach it to a targeted drug carrier, and then ship the drug for use. It’s not exactly a customized, made-to-order model; it’s not an off-the-shelf product, either. It’s somewhere in between, says Jeevan Virk, who oversees radiation therapy development at Novartis, where each dose is typically “made for a specific patient at a specific time, in a specific place.”

Earlier this year, Novartis opened a $100 million dedicated manufacturing facility in Indianapolis, where it plans to produce hundreds, if not thousands, of doses of Pluvicto every day. It’s a far cry from the humble facilities in the lightbulb factory in Chicago, where Rose Lee became the first cancer patient to be treated with X-rays a few hours away. In these Midwestern innovation hotspots, history is radiating forward, connecting past discoveries to future possibilities.

This article is translated with permission from Elie Dolgin, Radioactive drugs strike cancer with precision,

Knowable Magazine.

Original link:
https://knowablemagazine.org/content/article/health-disease/2024/cancer-fighting-radiopharmaceuticals-are-taking-off