Highlights from ISMERAD 2024

The 9th international symposium on medical radioisotopes (ISMERAD) on alpha therapy radionuclides. Ghent, April 16th, 2024.

I often attend conferences, scribble down some notes and never look at them again. Anyone else guilty of this? This time, I thought I would put in marginally more effort to make notes that are useful to myself – and others – in the future. I believe it was worth the effort. My hope is that others will do the same, to help interesting and useful ideas spread, and to effectively allow us to "attend" more conferences without the time and travel burden.

Please view this article as my notes of what the speakers said. I take no credit for these ideas. I am simply doing my best to accurately summarise what they have said. I have occasionally added some small remarks in square brackets [like this] for elaboration. If you feel the presentations have been misrepresented, please let me know! For any data mentioned, I encourage you to search peer-reviewed sources.

Lu-177 | Zena Wimana , H?pital Universitaire de Bruxelles (H.U.B) - Academisch Ziekenhuis Brussel (H.U.B)

Why has Lu-177 been so successful? … because it meets the five A’s:

• Achievable – Can (Lu-177) targeted radiopharmaceuticals be made?
• Appropriate – Are they safe and efficacious?
• Applicable – Can (Lu-177) be easily applied to other applications and indications? (Copy paste model)
• Adoptable – Are oncologists using it?
• Available – Is there actually (Lu-177) supply?

Naturally, they next question was which alphas meet the 5 A’s?

• Bi-213 – Maybe not as the half-life (45 min) presents difficulties.
• Ra-223 – Already in the clinic as a radionuclide without a targeting vector; however, difficult chemistry presents challenges for incorporating into targeting vectors. Therefore, it is not so applicable.
• Ac-225, At-211, Pb-212, Tb-149, Th-227 – you can make up your own mind.

To alpha or not to alpha? / Beta vs alpha?

Doesn’t see these as a binary choices. Will depend on indication and (geographic) location.

What does the future look like?

Combinations of treatments possible/likely. Both combinations of radionuclides and combinations of radionuclide therapy and non-radionuclide therapies.

What alpha emitter will be the “best”?

Most appropriate alpha will depend on where you want to use it, since logistics play such a large role in feasibility.

Comment from Sven Van den Berghe – reiterated the importance of cost as investors reluctant to invest in infrastructure that will be redundant/superseded in a few years.

Ac-225 | Sven Van den Berghe, PANTERA

What is the challenge of making Ac-225 accessible?

Ac-225 is a challenge to make since it uses scarce and expensive starting materials and requires processing in high radiation fields. Thankfully only small amounts of starting material are required, allowing economically feasible Ac-225 production.

Radionuclide suppliers cannot allow themselves to only capture small fractions of the value chain. Radionuclides are incredibly valuable starting materials that should be command prices reflective of their value. (Implication here that radionuclides historically have not. Typically the radiopharmaceutical manufacturer captures the majority of the profit)

In the next decade we will see a quantum leap in Ac-225 demand from 10 Ci to 500 Ci. Industry needs to be prepared for that.

How is Ac-225 made? And how does Pantera make Ac-225?

1. Thorium generator: Thorium-229 decay to Ac-225. Challenge is Th-229 supply is finite (legacy material). Pantera will use this method for early supply up to 60-70 Ci/yr.
2. Th-232 spallation: Proton bombardment of (natural) Th-232. An issue here is Ac-227 contamination.
3. Radium-226 proton irradiation. A downside is high radium loses [Ra-226 supply is expensive but possible]. Ra-226 difficult to work with (1600 yr half-life and emits radioactive gas). Heat accumulation during irradiation (difficulty to upscale).
4. Radium-226 gamma irradiation. Downside is that you need a lot more Ra-226 (which Pantera have). [Ra-226 supply is expensive but possible, especially when recycling is efficient]. Pantera will use this method for commercial supply, coming online in ~ 5 years.

Pantera’s 8 key technologies

1. Rhodotron HE. High performance, energy and reliability electron accelerator.
2. Electron-gamma converter. Technology with well-known thermohydraulics.
3. Irradiation station. Hybrid technology allowing low activation and flexible access.
4. Radium source. >100g pure RaCl2 crystals. More Ra recoverable from waste materials.
5. Radium target. Enhanced loading 3-6 Ci per irradiation run with >99.9% target recovery.
6. Radiochemical extraction. High performance separation chemistry. >99.9% radium recycling.
7. High efficiency radon trap.
8. Radium waste route available. Low losses.

Pantera initially did not plan to supply for clinical trial. However, due to demand, they have partnered with Terrapower Isotopes to supply Ac-225 for clinical trails. Note: that early supply source is different to commercial supply.

Th-Ra-Ac separation has done before by SCK CEN for (Ac-227 production for space race).

Note: that Pantera's early supply is different to commercial supply.

Ra-226 conversion to Ac-225 is so infinitesimally small that it does not measurably affect Ra-226 stockpile. Losses do however come from the Ra-226 recycling. There

Ways to get radium:

-????????? You have it (legacy)

-????????? Recover (E.g., brachytherapy needles)

-????????? Mine (Th/Uranium ore, but quantities so small, and safety concern).

At-211 | Matthijs Sevenois, MITH Brussel

Benefits of At-211:

• 7.2 h half-life [for compounds with fast kinetics, i.e., small molecules to nanobodies]
• No toxic daughters
• No high energy photons (that require extensive radiation protection)

Availability is the biggest challenge of At-211.

Who can make At-211 in Europe?

• Rigshospitalet (Copenhagen) - Scanditronix Magnet AB MC32 cyclotron. Production capacity 1.5 GBq (up to 6 GBq in the future).
• Arronax Nantes - IBA C70 XP cyclotron. Production capacity: 1-1.5 GBq (new target in future to increase capacity).
• Shortly: Julich, IBA cyclone C30XP), Birmingham (Scanditronix MC32), Warsaw/Polatom (IBA cyclone C30XP).

Methods of producing At-11

• Rn-211/At-211 generator

Acceleration of Li-7 beam on Bi-209 (natural)

Challenge: co-production of at least 1% At-210 which cannot be separated

Japan has large network of cyclotons that can make At-211.

Different radiochemical separation methods.

• Dry distillation

Pros: fast, astatine in desired form, commercialised Atley Solutions , 80 % d.c.

Cons: radioactive gas, contamination from scraping process, variations in yield.

• Liquid-liquid separation

Pros: no radioactive gases, reproducible yield 78% dc.

Cons: >1h, several steps, not automated.

• Solid phase extraction

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Takeaway points

Trapping and recovery conditions must be optimised for subsequent chemistry.

Challenge: higher energy At-211 productions to increase At-211 yield causes subsequent increase in Po-210.

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Pb-212 | ? Philippe Dasse ? ?, ARTBIO

4 pillars of ARTBIO

• Ideal isotope
• Distributed manufacturing
• Pb-212 generators: reliability, scalability and 99.99& purity
• Differentiated pipeline

Distributed manufacturing

Distribution network to model imaging agent distribution - Radionuclide and radiopharmaceutical production at each site (requires GMP).

• USA – SpectronRx , Eckert & Ziegler SE , PharmaLogic Holdings Corp. [Collaboration with Nucleus RadioPharma accounced May 7th, 2024]. Long-term vision for 10-15 production sites.
• Europe – Partnership signed by not announced. Two others in discussion. Long-term vision for 10-15 production sites.
• China – AlphaGen Therapeutics . Long-term vision for a development and go-to market partnership.

Pb-212 [radiopharmaceutical] production steps

1. Precursor supply: Th-228.
2. Th-228 source holder: load with 1 GBq of Th-228.
3. Pb-212 isolation: Daily elution of Pb-212 from AlphaDirect (housed in hot cell).
4. CMC drug product: GMP process development for radiolabelling, formation and dispensing.
5. Distributed network: Drug product manufacturing and automated radiolabelling of ligand with Pb-212, formulation and dispensing.
6. Drug product shipping: Shipping ideally via road (up to 1 half-life for logistics).
7. Patient injection: AB001 phase 1 doses are 100, 150 or 200 MBq.

Th-228 supply is foundation of ARTBIO operations

• 85 MW high flux isotope reactors at ORNL.
• 10-day neutron irradiation of Ra-226 (200 mg). Produces Th-228 (and Th-229) which is separated from parent materials via ion exchange chromatography.

Simple Pb-212 isolation mechanism

• Gas-gased, no separation needed. Implied that collection bottle is orientated horizontally.
• Pb-212 deposited in vial in >99.99% purity.
• US patent granted. Trademarks pending.

Production process with AlphaDirect

• AlphaDirect will be placed in CDMOs to enable daily clinical dose production in simple, scalable format.
• CDMO partner provides up to 3 hot cells in a cleanroom for Pb-212 collection, radiolabelling and dispensing [Note: labelling done at the Pb-212 production site, no mention of autoclaving].
• Following dispensing, quality control (QC) is performed to authorise for shipment. Further QC required to release for injection by QP/QA @ end of production (EOP) + 5 hours.

Logistics

• ~8 hours for pick and and shipping (road preferred).

• ~8-hour dosing window. Last dosing finished by EOP +14 h.

Considerations for scale-up

• Th-228 quality: Yield variation and purity.
• Rn-220 management: radioactive authorization and leak testing.
• Generator Pb-212 yield: source holder and product shelf-life.
• Radiolysis: Pb-212 dedicated formulation and variability per ligand.
• Shipment: quality control.

Introduction to various non-profit organisations

ICPO Foundation-International Centers for Precision Oncology

Online education, target towards medical staff, covering: oncology, radiochemistry, medical physics, and nursing and patient management.? Free for academics(?).

www.theranostics.academy

ICPO theranostics summit November 14th and 15th (virtual)

Oncidium foundation

Built around 3 pillars:

• Access
• Education: patient-focused
• Hope

The RLT-CONNECT project: Connecting healthcare professionals with radioisotope companies and local radiopharmacies. Hopes to help deliver 2000 patient doses in the next 5 years.

Rad4Med.be, Radiation for Medicine

Belgian foundation consisting of 100 partner organisations that make the complete circle of nuclear medicine expertise available.

List of partners available online

Alpha Therapy Clinical Potential | Mike Sathekge , University of Pretoria

Need to consider the microenvironment when treating cancers with radiopharmaceuticals.

Ra-223 still has potential for it to be useful by combination with other therapies and radionuclide therapies.

Many examples provided of alpha therapy in clinical trials.

Challenges in Dosimetry | Michel Koole , KU Leuven

TAT overcomes resistance to B- as alpha radiosensitivity independent of oxygen in the microenvironment.

Ac-225 difficult to image due to low dose and minimal gamma emission.

SPECT optimised for lower energies

Redistribution of Ac-225 daughters

• Free Bi-213 and Fr-221 redistribute
• Francium primarily to the kidneys, Bismuth 35% to urine, 35% kidney, 7% GI, 5% liver

AlphaMET - European project to better understand the metrology (dosimetry), to support the implementation of end-to-end traceabilty for TAT before wide routine adoption/ 2.3 M EUR, 3 year project.