Radiopharmaceuticals – also referred to as targeted radiotherapeutics – have gained an important place in precision oncology, but their potential remains largely untapped. To date, two validated targets, namely PSMA and SSTR, have yielded most mature clinical data with two radiopharmaceuticals on the market. Over the last few years, however, the field has shifted markedly with exciting data emerging: a broader range of targets is now being pursued across a similarly broad range of vectors – antibodies, miniproteins, peptides and small molecules, which is key to extending the reach of radiopharmaceutical therapy and delivering benefit to more cancer patients.
The radiopharmaceutical concept is compelling: pair a vector capable of selectively recognizing a tumor-associated antigen with a radioactive isotope, thereby delivering radiation directly to cancer cells while limiting exposure and side-effects on healthy tissue.
Two prominent successes, Lutathera® ([¹⁷⁷Lu]Lu-DOTA-TATE, targeting SSTR) and Pluvicto® ([¹⁷⁷Lu]Lu-vipivotide tetraxetan, targeting PSMA), have demonstrated the clinical benefit of this approach in patients with gastroenteropancreatic neuroendocrine tumors and prostate cancer, respectively. Many subsequent programs have built on these successes, either through next-generation vectors targeting SSTR and PSMA or through approaches exploring other therapeutic isotopes.
This raises the question: If targeted radiotherapy can work so well for selected targets and tumor types, how do we extend its potential to many more indications?
Part of the answer may lie not only in identifying new targets or radionuclides, but also in paying closer attention to the molecule connecting the two: the targeting vector.
At first sight, the requirements for an ideal radiopharmaceutical vector seem straightforward. It should rapidly reach the tumor, bind its target with high specificity, remain there long enough to efficiently deposit its radiation energy, and clear quickly from blood and healthy organs. In practice, achieving all these properties simultaneously against a broad range of targets is far from straightforward. Molecular composition and size influence biodistribution, residence time and clearance, while target expression, internalization and the physical properties of the radionuclide also influence the efficacy and safety of a radiopharmaceutical.
Today there is a growing landscape of scaffolds being evaluated as targeting vectors for next-generation radiopharmaceuticals, which bring different strengths and trade-offs.
Small molecules and peptides offer rapid tissue penetration and clearance, and have already provided important clinical proof of concept; however, neither can readily be developed against every tumor-associated antigen. Miniproteins combine relatively small size with the potential for high-affinity binding. At the other end of the spectrum, antibodies can access a broad range of targets with high affinity, but their long systemic residence time raises concerns with radioactive payloads. In addition, several approaches to tune pharmacokinetic properties of radiopharmaceuticals are starting to be explored across all vector classes.
Rather than seeking a universal winner, the more useful question is: which vector has the right molecular and pharmacokinetic properties to optimally match the biology of a tumor and associated antigen, combined with the properties of the selected radionuclide?
The isotope itself is another critical part of this equation.
Radionuclides differ in physical half-life and type of emitted radiation, which determine how their energy is deposited in tissue. The selection of an isotope must therefore remain driven by target and disease biology and the properties of the targeting vector.
Different radionuclides require different chelators, and chelators, like radiometals, can alter the properties of the targeting vector.
The targeting vector, meanwhile, determines how quickly the drug reaches the tumor, how long it remains there and how rapidly it leaves healthy tissues.
As such, successful radiopharmaceutical design requires a careful alignment between the pharmacokinetics of the vector and the physical properties of the isotope.
Development decisions are initially based on preclinical data, but human biology may tell a different story. Tumor uptake, residence time or normal-organ exposure may not translate as expected.
Imagine developing a radiopharmaceutical against a given tumor target. Preclinical studies demonstrate high tumor uptake and encouraging tumor-to-normal-tissue ratios with one radionuclide. The program advances, only for human imaging to reveal that its kinetics are not ideally matched to the chosen therapeutic isotope.
This is where the concept of an isotope-agnostic vector becomes interesting.
If changing the isotope requires rebuilding and re-optimizing the targeting molecule, the development program may need to loop back substantially. If, however, the targeting vector tolerates changes in the chelator-isotope combination while maintaining its underlying biodistribution profile, developers have more options – essentially, radionuclide selection can be an evidence-driven decision taken later in development, rather than the initial isotope choice defining the entire trajectory.
“Isotope agnostic” can therefore be understood as the ability of a targeting vector to accommodate different pairs of radionuclide-chelator while preserving the biodistribution characteristics that made it attractive in the first place.
That flexibility could have significant implications for drug development – in terms of time, cost, and competitiveness.
Among the various targeting scaffolds being explored, DARPins (Designed Ankyrin Repeat Proteins) are one example of suitable vectors for radioligand therapies. DARPins are small engineered binding proteins with high affinity and specificity to targets. In addition, their pharmacokinetic profiles can be tuned through half-life engineering to increase tumor uptake.
Recent data illustrate Radio-DARPins as isotope-agnostic vectors. Two Radio-DARPin candidates, each specific for a distinct tumor target, showed highly similar biodistribution preclinically when conjugated with the respective chelators and labelled with either ¹⁷⁷Lu or ²⁰³Pb. First-in-human dosimetry data with ²⁰³Pb-labelled MP0712, Molecular Partners’ DLL3-targeting Radio-DARPin therapeutic, indicate that both therapeutic isotopes ²¹²Pb and ²²⁵Ac could be suited for the DLL3 Radio-DARPin. A US multicenter Phase 1 study is evaluating ²¹²Pb-MP0712 and additional compassionate care work utilizing the DLL3 Radio-DARPin loaded with ²²⁵Ac has recently been initiated in South Africa, highlighting the isotope flexibility of the Radio-DARPin platform.
In addition to DARPins, a broad range of vectors are in principle amenable to different radionuclides and chelators, including small molecules, cyclic peptides, miniproteins, antibody fragments, and full antibodies. However, swapping the chelator and radionuclide has frequently been shown to alter the biodistribution profile, making isotope flexibility far from trivial. Dedicated engineering principles and approaches are therefore needed to enable such swaps while preserving the desired pharmacokinetic properties.
The future is unlikely to be defined by peptides versus miniproteins versus antibodies, or alpha versus beta emitting isotopes. Each may suit different biological problems.
Radiopharmaceutical oncology is entering a phase in which we are learning simultaneously about targets, vectors, isotopes and tumor and healthy-tissue radiobiology. In such an environment, flexibility has value.
The next generation of radiopharmaceuticals may be defined not by finding a single ideal isotope or a universally superior vector, but by matching the right target, the right vector and the right radionuclide for each unmet medical need.
Platforms that preserve optionality, while those decisions are being made, could give developers more room to learn from clinical data, refine dosimetry and adapt their therapeutic strategy.
Ultimately, “isotope-agnostic” is less about being indifferent to the isotope than about not being unnecessarily constrained by the first one chosen.
And as radiopharmaceutical therapy expands beyond its first successful targets and indications, the ability to adapt may become a very valuable property a targeting vector can offer.
