External radiation therapy is known to cause damage to cancer cells, but without the ability to target delivery of the radiation, damage is caused to many healthy cells as well. By linking radionuclides to bioactive molecules capable of targeting cancer/tumor cells, it is possible to deliver high doses of radiation with much greater specificity. As a result, radioconjugates / radioligands remain a promising class of therapeutics. Limited radionuclide supply, complex manufacturing, and difficulties with distribution and drug administration, patient referrals, and reimbursement must be overcome if the full potential of radioconjugates is to be realized.
Radioconjugate Design
Radioconjugates (also radionuclide–drug conjugates or radioligands), are molecules in which a radioisotope is attached to an antibody or other molecule with the ability to bind to a specific type of cancer cell. They are similar to antibody–drug conjugates (ADCs), except, instead of a cytotoxic agent, the payload is a radioactive substance.
Typically, radioconjugates consist of four components: the radionuclide, which is attached to one end of linker via a complexing agent, and the targeting molecule (often an antibody, but can be a small molecule or peptide), which is attached to the other end of the linker.1–4 The antibody is capable of binding to the desired cancer cells via tumor-associated antigens on the surfaces of the cells. Once binding occurs, the radioisotope is delivered into the cell where it causes cell death.
Advantages of Radioconjugates
External radiation therapy can be effective for treating cancer, but often, owing to the inability to target the radiation only to cancer/tumor cells, significant negative side effects result from collateral damage to healthy cells. Radioconjugates offer an alternative, more targeted approach to radiotherapy. Bringing the radioisotope to the cancer cell allows the use of higher doses while reducing the risk of healthy tissue damage. Given that as many as half of cancer patients receive traditional radiotherapy, radioconjugates have the potential to dramatically improve both treatment regimens and outcomes.1
Although radioconjugates are similar to ADCs in their design, because they kill cancer cells with radiation rather than by interfering with a particular disease mechanism, development of resistance to these therapies is not a concern like it can be for ADCs.2–4 In addition, there is evidence to suggest that signaling chemicals emitted by radiated cells may impact immune activity of nearby cells and in the tumor microenvironment.4 Furthermore, depending on the isotope, radioconjugates can be used as diagnostic agents and therapeutics.
The Four Key Components
Design of radioconjugates must be carefully achieved to ensure the radioisotope is not release in the bloodstream before the molecule reaches and binds to the target tumor cells. The common approach, therefore, is to use a complexing or chelating agent to attach the radioisotope to a linker that is then attached to the targeting agent. A chelating agent is required because most radioisotopes are metals (e.g., actinium (Acc), lutetium (Lu)). The chelating agent binds to the metal and also contains functional groups (e.g., amines, carboxylic acids) that enable connection to the linker. It must do its job without impairing the activity of the radioisotope and without impeding the binding ability of the targeting moiety, which can be challenging, given that often large chelating molecules are needed for the large radionucleids.2
The linker chemistry must also be chosen carefully.2 It must be sufficiently stable to maintain the entire radioconjugate structure as the molecule is traveling through the bloodstream, including the attachments to the targeting molecule and the chelating agent surrounding the radioisotope. However, once the radioconjugate reaches the target cells, the linker must degrade in some manner to release the radioactive payload.
It is also worth noting that nanoparticle-based radioconjugates are also attracting attention.5 In this case, the targeting agent is attached to a nanoparticle, with many different types of nanoparticles being explored, including silica, gold, liposomal, polymeric, micellar, zeolite, quantum dot, and many others. Common ligands include small molecules, antibodies, antibody fragments, aptamers, and diabodies targeting prostate-specific membrane antigen (PSMA) on prostate cancer cells and an integrin αvβ3 receptor present in many solid tumors.
A Choice of Emitters
Several different radionuclides are being invested for use in radioconjugates. In general, the radioactive elements fall into two categories: alpha (α) emitters and beta (β) emitters.2,5 Alpha emitters, including 225Ac, 223Ra, and 131I, emit α particles, which comprise two protons and two neutrons. These particles have higher energy but are heavier and travel shorter distances (50–100 μm) than β particles, and thus are less likely to damage nearby cells while allowing delivery of high radiation doses. They kill cells by causing double-strand breaks in DNA.6
Beta emitters, including 177Lu and 90Y, emit electrons, which have lower energy but travel much further than α particles. Many also emit gamma (γ) rays. Radionuclides that emit Auger electrons (161Tb, 125I) are also under investigation as radioconjugate payloads.
The choice of emitter depends on the type of cancer and the specific tumor cell target.2 Particular attributes that should be considered are the range of the particles in biological tissues, their relative biological effectiveness (RBE), their physical half-life, and their linear energy transfer (LET).4 For instance, radioconjugates containing radionuclides with shorter half-lives must be prepared close to the time and place of administration.6 Isotope availability is another crucial issue, as medical-grade radioactive nuclides can be difficult to source. 225Ac has many attractive properties but very limited availability currently.
While emitters are best suited for slower growing cancer cells, alpha emitters are more appropriate for treating aggressive tumors. The two U.S. Food and Drug Adminstration (FDA)-approved radioconjugates on the market (Lutathera and Pluvicto) leverage β emitters. Another important factor to consider is the half-life, which should be sufficiently long to allow maintenance of therapeutic efficacy.5 In addition, the half-life of the radionucleotide should match the clearance behavior of the targeting molecule.
For diagnostic applications, radioisotopes that emit positrons (β+) or γ rays are used.5 They include 64Cu, 68Ga, 67Ga, 18F, 89Zr, and 124I and 111In, 99Tc, respectively. Ideally, radionuclides for use in diagnostics should have short half-lives for limited radiation doses and rapid elimination from the body.
Estimating Dosages
In addition to limited supply of important radionuclides, determining the optimal dosages of radioligand or radioconjugate therapies is an important challenge. One of the main approaches is to compare the RBEs of targeted medicines to those of comparable external beam radiation therapy (ERBT) treatments.7 It is also important to optimize the dose according to the specific attributes of the tumor being treated, as variable responses have been observed even for patients with similar clinical characteristics.8 Typically empirical activity administration is pursued, although there is a growing desired to develop patient-specific dosimetry solutions.
Managing Time
Proper time management is another issue for radioconjugate therapies. Since these novel treatments are often used as a last line of defense, there is a need to manage the window of time in which patients can receive treatments. In addition, because by their nature radionuclides decay over time, it is essential to carefully schedule the production of radioconjugates to ensure they reach the patient and are administered with a high level of radioactivity remaining.
With most radionuclides, manufacturing of radioconjugates and their delivery to patients must be achieved in days if not hours. To this challenge is added the need for and precise organization of logistics to ensure delivery of the right therapy to the right patient at the right time.9 Fortunately, because the risk of radiation exposure is minimal, these drug products can be shipped using commercial airlines and cargo planes.10 While currently manufacturing of the two approved radioconjugates is centralized, some researchers have proposed that patients would be better served with the establishment of several manufacturing sites distributed in various regions to reduce logistics issues and costs and ensure more rapid and reliable delivery to patients.6
Interest in Combination Therapies
As is the case in many other areas of oncology, there is growing interest in the use of radioconjugate therapies in combination with other advanced treatments to support a multi-mechanistic approach. In addition to the use of a mix of external and internal radiotherapy,11 radioligands have been used in combination with chemotherapeutic agents12 and immunotherapies, such as checkpoint inhibitors.4
Notable Acquisition Activity
Both large and small pharmaceutical companies are pursuing the development of radioconjugate therapies, although the number of smaller players is shrinking owing to a rise in acquisition activity. The two approved drugs are marketed by Novartis, which announced the purchase of Mariana Oncology in May 202413 following FDA approval in January 2024 of its second U.S. radioligand therapy manufacturing facility, giving the company four worldwide production sites.14
AstraZeneca, meanwhile, announced the purchase of Fusion Pharmaceuticals in March 2024.15 Fusion has a pipeline of radioconjugate therapies, including its lead candidate FPI-2265 based on 225Ac for treatment of metastatic castration-resistant prostate cancer (mCRPC), which is undergoing a phase II clinical study. FPI-2068 is a separate candidate that is being investigated in a phase I trial.
A few months earlier (December 2023), Bristol-Myers Squibb (BMS) announced that it is acquiring RayzeBio, which is developing its own pipeline of 225Ac radioconjugate therapies targeting solid tumors, including its lead candidate RYZ101, which is in phase III development for treatment of gastroenteropancreatic neuroendocrine tumors.16 RayzeBio recently constructed a new in-house manufacturing facility for GMP drug production.
In the fall of 2023, Eli Lilly acquired Point Biopharma and PNT2002, its 177Lu -based lead radioligand therapy against prostate cancer.
Smaller firms involved in this market include Isotope Technologies Munich, Endocyte, Curie, Aktis Oncology, Actinium Pharmaceuticals, Progenics Pharmaceuticals, AdvanCell Isotopes, and Precirix.18
Challenges to Overcome — but High Expectations
Companies developing radioconjugate therapies face a wide range of challenges related to raw material procurement, manufacturing, distribution, and adoption.6 While some investments are being made to increase capacity and thus availability of medical-grade isotopes for the production of radioconjugate therapies, many radionuclides remain in short supply, with no easy solutions for increasing production on the horizon. Manufacturing challenges also exist, including the need for appropriate facilities and equipment, highly skilled and trainer operators, and expertise in both large and small molecule manufacturing under high-containment conditions. Regulatory uncertainty also contributes to greater risk.3
With respect to clinical development, identification of a greater number of target receptors is needed, as is improved understanding of biological mechanisms to support enhanced targeting and better efficacy.17 In addition, larger trials involving more patients must be completed to generate data confirming results received in smaller, early-phase trials. Greater understanding of biological mechanisms.
Many other issues related to the difficulties in getting radioconjugate therapies to patient in the short timelines required and issues with adoption, which include complicated prescribing and referral processes, the need for specialized infrastructure and processes that allow incorporation of radioligand therapy in cancer treatment plans, difficulties with administration and monitoring due to complex dosing, high cost, and reimbursement challenges.6,9
Despite these challenges, the global radioconjugate/radioligand therapy market is predicated to be expanding at a compound annual growth rate of approximately 5% to reach $13 billion by 2030.19 Much of the focus is on neuroendocrine neoplasms and prostate cancer, although a few companies are investigating treatments for non-cancerous conditions such as arthritis and others involving inflammation.
References
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11.”Combination of Internal (Particles) and External (Photons, Particles) Radiotherapy.“ Helmholtz Zentrum Dresden Rossendorf Preclinical Radioconjugates Institute. Accessed 14 Dec. 2024.
12. Nair, Rajiv Ranjit et al. “Glioblastoma Treatment by Systemic Actinium-225 α-particle Dendrimer-radioconjugates is Improved by Chemotherapy.” bioRXiv. 17 Oct. 2024.
13. Novartis enters agreement to acquire Mariana Oncology, strengthening radioligand therapy pipeline. Novartis. 2 May 2024.
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