Targeted alpha therapy (TAT) involves selective delivery of isotopes that emit highly energetic alpha particles to cancer cells leading to their ultimate destruction, while minimizing collateral damage to healthy surrounding cells. The high linear energy transfer of alpha particles makes it possible to consider targets with relatively low cellular expression levels (or concentration) and to treat hypoxic and chemotherapy resistant tumors. The limited emission of beta and gamma radiation from the appropriate alpha emitting isotopes significantly reduces the complexities of administration and decreases the chance of exposure to caregivers and family members. Despite the potential, clinical development of targeted alpha therapeutics has been slow due to a variety factors that will be discussed.
Radium-223 dichloride, the only approved alpha therapy in clinical medicine, provides the proof of concept for internal alpha emitting radioisotope therapy in cancer treatment. 223RaCl2 is “targeted” via its fundamental physicochemical properties as it incorporates into the bone matrix at sites of bone formation. The interest in TAT is based partly on the clinical usefulness of 223RaCl2 in castration resistant prostate cancer. However, 223RaCl2 is only suitable for treating bone metastases, so new targeted therapies that aim to treat liquid and solid soft tissue tumors are now under clinical development. The clinical experience to date with TAT will be reviewed focusing on the status, advantages and disadvantages of different radioisotope payloads (213Bi, 225Ac, 211At, 212Pb and 227Th), targets (CD33, CD20, CD22, PSMA, HER2, somatostatin receptor and others), and targeting agents (small molecules, peptide and antibodies) that have been employed to date.
The momentum in the TAT field is illustrated by a growing number of promising TAT compounds that are in or near starting clinical trials. The current status of these TAT molecules (225Ac-PSMA-617, 212Pb-AR-RMX, 225Ac-lintuzumab, FPX-01, 211At-BC8-B10, BAY1862864) will be discussed with particular attention to those agents that use 225Ac (t½ 10 days) and 227Th (t½ 18.7 days) as the therapeutic payload. The half-life of these two alpha emitting isotopes permits manufacturing and delivery of ready-to-use doses to patients. Biodistribution and dosimetry may require the use of a separate imaging radioimmunoconjugate when alpha isotopes with limited gamma emission are used.
The potential role of TAT in hematological malignancies and in solid tumor treatment will also be discussed along with systemic and local administrations strategies, both of which may prove to have clinical utility in coming years.
Fusion Pharmaceuticals
Fusion Pharmaceuticals
I. Molnar, E. Burak, J. Valliant: Employee and stockholder of Fusion Pharmaceuticals Inc. E. Burak, J. Valliant: Employee and stockholder of Fusion Pharmaceuticals. J. Forbes, R. Simms: Employee of Fusion Pharmaceuticals.