Combination Radioligand Therapy Methods of Treating Cancer Combining Lutetium-177 and Actinium-225 PSMA-Targeted Radioligand Therapies for Prostate Cancer

This patent covers combination radioligand therapy for prostate cancer using PSMA-targeting compounds loaded with two different radioactive isotopes – the beta emitter Lutetium-177 and the alpha emitter Actinium-225 – to deliver lethal radiation directly and selectively to cancer cells expressing prostate-specific membrane antigen.

The Problem

Prostate-specific membrane antigen (PSMA) is a cell surface protein expressed at extremely high levels on prostate cancer cells – typically 100 to 1,000 times the levels found in normal tissues. Its restricted expression pattern and the fact that it is rapidly internalised by the cancer cell after binding make it an ideal target for delivering cytotoxic payloads directly into tumour cells.

Radioligand therapy (RLT) exploits this by attaching a radioactive isotope to a small molecule that binds PSMA, allowing the compound to seek out cancer cells throughout the body – including metastases – and irradiate them from within.

Lutetium-177 (Lu-177), a beta emitter with a half-life of 6.7 days and tissue path lengths of several millimetres, is effective against well-vascularised tumour deposits. However, larger tumour deposits, hypoxic areas, and micrometastases may be less responsive to beta radiation: the longer path length can miss small clusters of cells, and hypoxic conditions allow cells to repair sub-lethal DNA damage.

Actinium-225 (Ac-225), an alpha emitter, delivers densely ionising radiation with a much shorter path length of two to four cells, a relative biological effectiveness at least five times that of beta radiation, and an action that does not depend on the presence of oxygen, making it effective in hypoxic microenvironments where Lu-177 may fall short. Using either isotope alone leaves gaps. A combination approach is the logical next step.

What This Invention Does

The invention provides methods of treating PSMA-expressing cancers – primarily prostate cancer – using a combination of a Lu-177-labelled PSMA ligand (Compound I-Lu or Ia-Lu) and an Ac-225-labelled PSMA ligand (Compound I-Ac or Ia-Ac).

Compound I and its analogue Ia are small molecules that bind specifically to PSMA and are internalised by the cancer cell via clathrin-coated endocytosis, concentrating the radioactive payload within the cell and retaining it there.

By combining a beta emitter for broad tumour volume coverage with an alpha emitter for high-LET, hypoxia-independent, short-range destruction, the therapy addresses the complementary weaknesses of each modality alone. The patent also covers methods of treating patients in whom stable disease results after combination treatment, supporting a maintenance or sequential therapy strategy.

Key Features

• Dual isotope PSMA targeting. The combination of Lu-177, a beta emitter with a longer path and oxygen-dependent effect, with Ac-225, an alpha emitter with a short path, oxygen-independent effect, and high relative biological effectiveness, is designed to be more effective across the spectrum of metastatic prostate cancer presentations than either alone.
• PSMA ligand internalisation. Both conjugates bind PSMA and are internalised by the cancer cell, trapping the radioactive isotope inside the target cell and prolonging irradiation of the tumour relative to agents that bind but are not internalised.
• Applicability beyond prostate cancer. PSMA is also expressed on the neovasculature of numerous other cancers including renal clear cell carcinoma, thyroid cancer, glioblastoma, non-small cell lung carcinoma, and breast carcinoma, extending the potential scope of the therapy beyond prostate cancer.
• Stable disease indication. The patent specifically covers use of the combination in patients who achieve stable disease following treatment, addressing a real clinical management scenario and potentially supporting an extended treatment or maintenance approval pathway.

Who Is Behind It?

The applicants are Endocyte, Inc., an Indiana-based clinical-stage biopharmaceutical company that was acquired by Novartis in 2018 for approximately 2.1 billion US dollars, and Dr Mike Sathekge, a nuclear medicine physician at the University of Pretoria whose clinical research has been central to the clinical evaluation of PSMA radioligand therapy in South Africa and internationally.

The named inventors are Richard Messmann, Mike Sathekge, and Alison A. Armour. The application is a divisional of AU 2019345320, the national phase of PCT/US2019/052161, with priority from US Provisional Application 62/734,649 filed 21 September 2018. The Australian patent attorney is Spruson and Ferguson in Sydney.

Why It Matters

Lu-177 PSMA-617, marketed as Pluvicto by Novartis, received regulatory approval for metastatic castration-resistant prostate cancer in the United States in 2022 and has since been evaluated for regulatory approval in multiple other jurisdictions.

Prostate cancer is the most commonly diagnosed cancer in Australian men, with AIHW cancer data estimating it as Australia’s most commonly diagnosed cancer overall in 2025.

The availability of PSMA-targeted radioligand therapy – and the prospect of combination Lu-177 and Ac-225 approaches for patients whose disease progresses on Lu-177 alone – represents one of the most significant therapeutic advances in advanced prostate cancer in recent years.

Australia has active nuclear medicine infrastructure, including cyclotron facilities and hospital-based radiopharmacy units, that supports the delivery of these therapies. ANSTO has also noted that lutetium-177 used in Lu-PSMA therapy has been produced locally in Sydney using the OPAL multi-purpose reactor.

Patents in this family, controlled now by Novartis through its acquisition of Endocyte, are commercially central to the global rollout of PSMA radioligand therapy and have direct relevance to reimbursement, licensing, and clinical access discussions in Australia.

AU 2026201845 was published in the Australian Official Journal of Patents on 2 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.

Related Concepts

This application sits within the broader field of radionuclide therapy, where radioactive compounds are designed to bind to specific biological targets.

In prostate cancer, PSMA-targeted imaging and therapy have become especially important because PSMA is commonly overexpressed on prostate cancer cells. Lutetium-177 PSMA therapies such as Pluvicto use beta radiation, while Actinium-225 PSMA approaches use alpha radiation with a shorter tissue range and higher energy transfer.

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AU 2026201845 was published in the Australian Official Journal of Patents on 2 April 2026 and is open for public inspection. Patent applications represent inventions that are sought to be protected and do not necessarily reflect commercially available products.