Isotopes are atoms of the same element that have a different number of neutrons (but the same number of electrons and protons). Every isotope has its own unique chemical and physical properties which determine the best application in radiopharmaceutical medicines. These properties include half-life (the amount of time radioactivity is emitted), the type of radiation emitted (such as alpha particles, beta particles, or Auger particles), the energy of the emitted radiation, and the decay path (the other radioisotopes the isotope turns into before becoming a stable isotope). Other important considerations for making radiopharmaceuticals include how readily available and accessible the isotope is.
As industry-leading groups continue to create new and cost-effective ways to produce large amounts of medically useful radioisotopes, POINT is establishing partnerships with these leaders to be able to evaluate and harness emerging medical isotopes for the treatment of cancer. We are positioned at the forefront of radiopharmaceuticals by focusing on using the right isotope to create the most effective treatment options available.
The role of alpha and beta particle-emitting radioisotopes in targeted radioligand therapy
One of the key differences between radioisotopes is the method in which energy is released during decay from the unstable radioactive form to a stable, non-radioactive isotope. Some radioisotopes decay by releasing beta particles, which are very small electrons that can travel relatively far distances. Others decay by releasing alpha particles, which are much larger and heavier, and are higher in energy compared to beta particles, but travel much shorter distances. Both alpha and beta particles have been shown to cause damage to the DNA of tumour cells, resulting in tumour cell death, however there are distinct advantages to each type of decay.
Alpha-emitting radioisotopes can deposit 2-3 orders of magnitude more energy to tumour cells than beta-emitters, which can lead to greater efficacy of the treatment. Beta-emitters in turn, may be better suited to the tumour environment, which is often non-uniform, as beta particles can travel to more distant tumour cells that may not be in direct contact with the radioisotope. With the option of several different alpha and beta-emitting isotopes for radiopharmaceutical development, and the emergence of additional promising radioisotopes, each with its own unique properties, it is clear that there is no “one-size-fits-all" approach to selecting the right isotope for the job.
POINT is focused on staying at the forefront of targeted radionuclide therapy with a broad based research and development program. In addition to assessing new indications for existing radiopharmaceuticals, new targets and new targeting agents, our pipeline also includes a variety of unique isotopes. Instead of choosing a single isotope for our programs, we are committed to matching the right isotope to each radiopharmaceutical, with properties tailored to deliver the most effective therapy for patients. Through our isotope pipeline – which includes well-known isotopes established in the field of radiopharmaceuticals, as well as new and emerging isotopes with incredible potential, we are working tirelessly in pursuit of more safe and efficacious treatments.
Beyond isotopes, we are also investing in our innovative targeted canSEEK™ technology, designed to safely target a broad range of cancers thereby helping POINT achieve our mission of making targeted radioligand therapy applicable to more cancers, available to more people, and improving the lives of patients and their families.
Our Isotope Pipeline
The first clinical studies using lutetium-177 (Lu-177) for the treatment of neuroendocrine tumours began in 2000. Since then, Lu-177 has attracted increasing attention and has demonstrated significant potential for radionuclide therapy to improve outcomes for patients with otherwise untreatable cancers. Likewise, over the past 5 years, Lu-177 has become a key therapeutic isotope for the treatment of prostate cancer. Today, Lu-177 is being evaluated for the treatment of an expanding number of diseases, including lung cancer, breast cancer and lymphoma. The potential of Lu-177 targeted radioligand therapy is recognized globally with over 60 clinical trials currently evaluating Lu-177 for the treatment of a wide range of diseases.
The choice to use Lu-177 as a therapeutic isotope is based on its favourable properties , as well as sustainable and cost-effective availability. The 6.6-day half-life of Lu-177 is sufficiently short for use with a variety of radiopharmaceuticals, including small molecules, peptides, and antibodies, and long enough to minimize decay loss during preparation of the radiopharmaceutical, and ship to distant sites from the production facility. The average penetration of beta particles emitted by Lu-177 is equivalent to about 30 cell diameters, making this isotope ideal for delivering radiation to small tumours, including metastases. The type and energy of Lu-177 emissions also facilitate relatively straightforward handling procedures of this radioisotope at the production and patient administration sites, relative to other isotopes that require greater shielding and infrastructure due to higher energies. The steadily increasing demand for Lu-177 for clinical evaluation of new treatments has resulted in multiple commercial suppliers of high-quality FDA and EMA-approved isotope. As a result, Lu-177 is available in suitable quantities and quality for late-stage clinical and commercial manufacturing of radiopharmaceuticals.
Other beta particle emitters currently under investigation as part of clinical studies include iodine-131, rhenium-188, and copper-67.
Actinium-225 (Ac-225) is an emerging isotope for radioligand therapy. Since 1997, the US Department of Energy (DOE) has been a main supplier of Ac-225, which has historically been derived from decay of existing stocks of nuclear waste. The available stocks of waste limit the amount of Ac-225 that can be produced, and as demand for Ac-225 has steadily increased over the past decade, the present supply of Ac-225 derived from nuclear waste stocks is insufficient to meet demands.
The increase in demand for Ac-225 is reflected in the increasing number of clinical trials evaluating Ac-225 as part of treatments for prostate cancer, neuroendocrine tumours, multiple myeloma and leukemia. The choice to use Ac-225 for therapy is based on the unique properties of the isotope, including the emission of 4 alpha particles per decay, resulting in very high energy transfer (and therefore very high toxicity) to tumour cells compared to beta particles, a short travel distance of the emitted alpha particles spanning 2-5 cell diameters, and a 9.9-day half-life, which limits the long-term toxic effects of radiation but still has a sufficiently long half-life for practical production, shipment, and patient administration. Ac-225 may impart greater cell toxicity to tumours and may be better suited to small metastases and single-cell cancers like leukemia and lymphoma compared to beta particle-emitters.
To address the growing demand for Ac-225, new production methods have been developed and supply has expanded both at the US DOE and beyond to ensure that there is sufficient supply of Ac-225 for late-stage clinical trials and the development of new radiopharmaceuticals for targeted alpha therapy.
Developments in the targeted delivery of isotopes and the recent increased availability of alpha particle emitting isotopes have led to a growing number of clinical trials evaluating the safety and efficacy of radioligand therapy in a variety of cancers.
Other alpha particle emitters being investigated in preclinical and clinical studies include thorium-227, bismuth-213, astatine-211, and lead-212 for targeted alpha therapy of a variety of cancers, including lymphoma and leukemia.