Terbium-161: new radionuclide therapy hits the clinic

If you can get rid of circulating tumour cells and tumour cell clusters that detach from a tumour, spreading the disease in the body, cancer is less likely to return. This is the hope behind a radioactive molecule for targeted radionuclide therapy that has been developed at PSI and is now being tested in the clinic. “With our new radionuclide, we hope to be able to better eliminate ultra-small cancer lesions and thus improve patient outcomes,” says Roger Schibli, head of the Center for Radiopharmaceutical Sciences at PSI and associate professor at ETH Zurich.

This new radionuclide is terbium-161. Linked to a ligand that recognises proteins on tumour cells, the radioactive molecule is guided to exactly where the radiation dose is needed. These drugs – known as radiopharmaceuticals – thus enable a highly targeted and effective cancer treatment of disseminated disease when other therapy modalities are no longer applicable.

Radiopharmaceuticals based on terbium-161 will be tested in two Phase 1 clinical trials. In the first of these, which is already underway, six patients are receiving treatment for metastasised neuroendocrine tumours – a type of cancer that affects cells found in glands and organs that produce hormones. The study, funded by the Swiss National Science Foundation, is a collaboration with Damian Wild, head of Nuclear Medicine at the University Hospital Basel, and his team.

The second trial, scheduled to start in early 2024, will see terbium-161 treating patients with metastatic prostate cancer. In a dose-escalation study, the safety and efficacy of the new radiopharmaceutical will be investigated in approximately thirty patients at University Hospital Basel. The study, a collaboration with the groups of Nicola Aceto at ETH Zurich and Wild at University Hospital Basel, has been awarded funding from the ETH Domain Personalized Health and Related Technologies (PHRT) strategic focus programme.

“The reason for our research is to help cancer patients. It is deeply rewarding, after over ten years of radionuclide development and five years of preclinical development, to see this happening,” says Schibli.

It’s all about how terbium-161 emits its electrons

Over these last five years of preclinical studies, Schibli’s laboratory at PSI has consistently demonstrated that terbium-161 is more effective at treating cancer than a similar radionuclide that is currently on the market: lutetium-177. Radiopharmaceuticals using lutetium-177 were approved for use against neuroendocrine tumours in 2018 and prostate cancer in 2022. “For over 30% of cancer patients treated with lutetium-177, either tumours recur or patients don’t respond,” says Schibli. The reason for this, Schibli and colleagues believe, is that lutetium-177 misses ultra-small lesions that are not visible on positron emission tomography scans but are responsible for relapse of the disease at a later stage. And this is where terbium-161 can help.

It’s all about how terbium emits its electrons, he explains. Both terbium-161 and lutetium-177 are beta-emitters. What’s more, they both possess a similar half-life of just under seven days. But terbium-161 emits in addition abundant low-energy so-called conversion and Auger electrons. These deliver a punch of radiation over a short distance - within the cancer cell. 

Schibli and colleagues believe this will allow them to catch the circulating tumour cells and cell clusters missed by lutetium-177. “As we’ve demonstrated in preclinical in vitro studies, terbium-161 is effective at eliminating even single cancer cells,” explains Schibli.

Not just a new radionuclide, but a new compound to treat cancer

Making the most of terbium-161’s attractive decay properties requires strategically guiding it to the right location in the body. Designing the ligand that guides it and optimising its properties is the work of Cristina Müller and her team in the group of Nuclide Chemistry.

The ligand to which terbium-161 is bound, and the receptor that it targets, significantly influences the efficacy and specificity of the treatment. In the case of the prostate cancer clinical study, patients will benefit from not only a new radionuclide, but also from an optimised ligand to deliver it: the small molecular-weight molecule SibuDAB. This targets the prostate specific membrane antigen (PSMA) – a protein that is overexpressed in prostate cancer cells.  In preclinical studies in mice, the team found that this new ligand allows a three-fold improved uptake compared to the ligand currently on the market in conjunction with lutetium-177.

For the study in neuroendocrine tumour patients, the team are using a ligand known from the literature: the peptide DOTA-LM3. This targets somatostatin receptors, found abundantly in neuroendocrine tumours. But this too is a change from the ligand used in the lutetium-177 conjugate on the market for treatment of neuroendocrine tumours. In preclinical studies both in vivo and in vitro using several ligands, the team found the tumour uptake of terbium-161 conjugated to DOTA-LM3 to be greatly increased.

“For both studies, we hope that the combination of improved tumour uptake of our optimised ligands with the benefits of the terbium-161 decay profile will give a major therapeutic advantage,” says Müller.

From bench to bedside: A PSI product through and through

Seeing terbium-161 entering clinical trials is a proud moment for Müller and colleagues. “What is so satisfying is that this is a project that combines all that the Center for Radiopharmaceutical Sciences can provide. We could perform the whole process here, from radionuclide development to ligand optimisation, all the way to preparation of radiopharmaceuticals in a cleanroom for the clinic,” she says. “This is a triumph for us.”

Terbium-161 was developed in the Laboratory for Radiochemistry at Paul Scherrer Institute. In fact - as Nick van der Meulen, who leads the Radionuclide Development group, proudly points out - terbium-161 is the first new radionuclide developed in Switzerland to be specified for use in the clinic - ever.  

Since the first irradiations of gadolinium-160 targets to produce terbium-161, van der Meulen’s team have optimised production and separation of the radionuclide from its target material - a process considered the gold-standard for preparation of terbium-161. They have also perfected the synthesis and preparation of the radiopharmaceuticals at high purity. With the new Swissmedic-accredited laboratories, which opened at PSI in 2021, the terbium-161-ligand conjugates can even be manufactured at PSI ready for use in the clinic.

“We began with the first irradiations and took terbium-161 all the way to the clinic. That an academic partner can bring the product from bench to bedside is something unique,” says Schibli.

Future clinical studies will need larger quantities of terbium-161. For this, an agreement has been signed with industrial partners in Munich to scale-up production. The road to bringing a pharmaceutical to market is long, and it will likely be several years before terbium-161 is routinely available – if trials succeed. Yet the latest developments mark a turning point in translating scientific discovery into improved patient care.

Text: Paul Scherrer Institute / Miriam Arrell