Pioneering with a radioactive medicine

One thing is clear after speaking with Dr Erik de Blois, clinical radiochemist and head of quality control at Erasmus MC: his team had to invent virtually everything themselves for the development of their new drug against prostate cancer, based on a radioactive actinium isotope. ‘We started from almost nothing,’ he says.

De Blois outlines the challenges he and his team faced. From the availability and purification of actinium and its conjugation to a biologically active molecule, to the strict legislation governing work with α-emitters and the thin-layer chromatography and HPLC techniques he had to develop in order to say anything meaningful about yield and purity. And for a phase 1 study, everything also had to be conducted under GMP conditions. ‘I’d wanted to do this for a long time but had no idea where to begin — there were so many technical challenges,’ he says with a laugh.

Nuclear waste and nuclear weapons

How does one go about obtaining Ac-225? That turns out to be quite a story in itself. ‘Actinium only exists as a radioactive isotope and is extraordinarily toxic,’ De Blois explains. ‘It is barely used anywhere yet, there are virtually no suppliers, and no GMP protocols for its production currently exist.’

The most common sources turn out to be nuclear waste and decommissioned nuclear weapons, from which the precursor thorium-229 is extracted. This is radioactive with a half-life of 7,430 years. You bind it to a column, elute it, and radium-225 is released, which in turn decays to Ac-225. De Blois refers to this setup as a ‘milking cow’ for the production of Ac-225; this particular milking cow is located at JRC Karlsruhe (Germany), part of the Joint Research Centre and the Directorate for Nuclear Safety and Security of the European Commission.

‘It is quite possible that many colleagues also saw the potential of this method, but were not prepared to burn their fingers on the technical challenges’

Actinium emits α-particles: two protons and two neutrons. ‘These α-particles are ideal for this type of therapy,’ says De Blois. ‘The high energy causes relatively considerable damage, but over a very short range.’ It is therefore of the utmost importance that the drug reaches the tumour cells precisely and dissipates rapidly when it is elsewhere. The unbound Ac-225-PSMA is excreted in the urine — around 70% within twelve hours — where it causes little to no damage. Furthermore, the PSMA bound to the prostate tumour cells has a biological half-life of approximately two days, meaning that the body has eliminated half of the Ac-225-PSMA after two days.

A few femtomoles

According to De Blois, the quality control steps took a few years to master: purification, demonstrating that the product is bound to the chelator, that the production protocol is sufficiently consistent, and that it also reaches the prostate cancer cells in a sufficiently active concentration — and that this holds true every time it is administered. De Blois: ‘It was enormously difficult. We are talking about a few femtomoles of a material that is already very hard to measure, because it is easily attenuated — even by a sheet of paper. However, francium-221 is a decay product of Ac-225, and it emits γ-radiation (a photon, ed.) at an energy of 218 keV, well within a conventional measurement range. And that is representative of the quantity of Ac-225 present.’

‘Very little is yet known about Ac-225 in a pharmacological setting’

A further complication is the high energy released during the first decay of Ac-225. ‘That process is called recoil and means that the actinium atom is knocked out of the chelator, changing its chemical properties,’ says De Blois. ‘We therefore first have to perform thin-layer chromatography to separate the bound actinium fraction from the recoil-released fraction and from any free Ac-225 fraction, so that we can make a statement about the quantity of actually active drug.’

The damage that the α-particles inflict on the DOTA chelator and on PSMA means the product has a shelf life of only three hours, even in the presence of quenchers and radical scavengers such as vitamin C, gentisic acid, and ethanol.

Pioneering

‘We have received approval to begin a phase 1 study, supported by a KWF grant,’ De Blois explains. ‘An important component of that is a dose-escalation study, in which we start low and gradually increase the dose. We have already selected the first patients, who will receive their treatment in mid-February.’ Those patients form a fairly well-defined group: end-stage prostate cancer patients whose prostate has been removed but who have developed metastases. In Germany, several case studies — not regulated according to phases 1 and 2 — are known involving a comparable technique, and according to De Blois these have yielded ‘very promising results’. ‘Some patients were completely clear after three months.’

The GMP treatment technique was published last year in Pharmaceutics, with De Blois’s doctoral student Eline Hooijman as first author. Their work has attracted considerable attention worldwide, even from the International Atomic Energy Agency, because it is ‘genuine pioneering work,’ he says. ‘I’ve now been in this field for 22 years and I know most colleagues reasonably well, as radiochemistry is not a particularly large field. It is quite possible that many colleagues also saw the potential of this method, but were not prepared to burn their fingers on the technical challenges.’

‘We are now working on several compounds that we are labelling with Ac-225’

He, for his part, relished precisely that aspect, and was aided in doing so by his background. De Blois began his career at MLO level and worked his way up through evening classes at HLO to a university master’s in drug innovation and ultimately a doctorate as a radiochemist. ‘I’m a practical person by nature, and that is enormously helpful when it comes to implementing this kind of technical problem-solving. But of course I don’t do it alone — the team has done remarkable work. Pioneering is something we do together.’

And the future looks bright, De Blois believes. ‘We are now working on several compounds that we are labelling with Ac-225, and a second KWF grant has been awarded. So things are really gathering momentum.’