The success of Pluvicto has sparked a new wave of radiopharmaceutical (RLT) research and development. Globally, biotech companies focused on radioligand therapy (RLT, targeted radiopharmaceuticals) are emerging like mushrooms after rain, while large pharmaceutical companies are building deeper RLT pipelines. With Pluvicto officially entering the “blockbuster drug” club in 2024 (annual sales reaching $1.392 billion), the momentum in the radiopharmaceutical field is rising to a new level.
On June 3, Nature Reviews Drug Discovery published an analytical report titled "The landscape for radioligand therapies in oncology", dissecting the current opportunities and challenges in the radiopharmaceutical field. Below is an excerpt of key points:
The global RLT pipeline is rapidly expanding. Besides the already marketed Pluvicto and Lutathera, there are over 60 pipelines in clinical development (see figure at the end).
RLT generally consists of four components: a radioactive isotope, a chelator (responsible for stabilizing or “caging” the radionuclide to prevent it from harming innocent tissue before reaching its target), a targeting ligand (responsible for precise recognition and binding to tumor targets), and a linker (connecting the targeting ligand and the chelator). Current RLT innovation mainly focuses on isotopes and targeting ligands, aiming to expand RLT to broader targets and tumor types.
The clinical performance of RLT is closely related to the physical characteristics of radioactive isotopes, including their half-life and the particles emitted during decay, which have different radiation energy levels and tissue penetration distances. The currently approved Pluvicto and Lutathera both use lutetium-177 (Lu-177, emits β particles) as the payload. In clinical-stage RLT pipelines, Lu-177 usage accounts for 45%.
Next-generation RLTs are investigating new radioactive isotopes, including α-particle emitters. Compared to β particles, α particles have higher energy and shorter penetration distance, which could translate into greater efficacy while minimizing off-target toxicity. Actinium-225 (Ac-225) is the primary α-emitter used for RLT development, accounting for 28% of clinical pipelines, with several late-stage candidates such as FPI-2265 (Phase II/III), RYZ101 (Phase III). However, Ac-225’s complex decay chain may cause daughter isotopes to “escape” from the chelator, leading to off-target activity. Lead-212 (Pb-212) is an emerging α-emitter, accounting for 9% of clinical pipelines. Compared to Ac-225, it has a shorter half-life and simpler decay chain, potentially supporting better safety and allowing dose optimization to improve efficacy.
Copper-67 (Cu-67) is another radioactive isotope under development. Unlike Lu-177-based RLTs, which require pairing with other isotopes like gallium-68 for imaging, Cu-67 can be paired with isotopes of the same element such as Cu-61 or Cu-64, providing consistent biodistribution and pharmacokinetics between imaging and therapy. Terbium-161 has similar half-life and β-particle emission characteristics as Lu-177 but also emits numerous low-energy Auger and conversion electrons. These electrons have short tissue penetration distances and produce highly localized radiation, potentially enhancing efficacy especially against micrometastases.
RLT targeting ligands must balance size and binding affinity to achieve favorable pharmacokinetics, ensure tumor uptake and distribution, and minimize off-target exposure. Currently approved RLTs use “peptides” and “non-peptide small molecules” to target SSTR2 and PSMA, respectively. These two classes dominate the RLT pipeline, with peptide ligands accounting for 33% and non-peptide small molecules 29% of clinical pipelines. Next-generation RLTs based on peptides and small molecules are also in development.
Besides these modalities, traditional antibodies remain an option (17% of clinical-stage pipelines). Although antibodies increase the range of usable targets through high specificity, their larger size and longer circulation times may pose challenges for tumor uptake and toxicity. Accordingly, next-generation RLTs are leveraging engineered proteins and antibody derivatives such as minibodies, antibody fragments, and nanobodies (e.g., AKY-1189, CAM-h3, RAD204) to enhance delivery and reduce toxicity risks.
Currently, nearly half of clinical-stage RLT pipelines focus on two validated targets: 32% target PSMA and 17% target SSTR2.
However, RLT research and indications are diversifying, involving over 20 tumor types and more than 25 unique targets, including those validated by other drug classes (e.g., HER2, FRα) as well as exploratory new targets without approved products (e.g., FAP, GRPR, and MC1R).
RLT combines the potency of external radiotherapy with the precision of targeted therapy, providing opportunities to address unmet needs across various cancer types. With more pipelines entering clinical stages and ongoing innovations in radioactive isotopes and targeting ligands, RLT is expected to bring new breakthroughs in cancer treatment.
Currently, from biotech startups to multinational corporations, investments in targeted radiopharmaceutical development are increasing. These substantial financial commitments reflect the players’ expectations and confidence in developing more transformative radiopharmaceutical products.
Reference:
https://www.nature.com/articles/d41573-025-00096-w
