Current landscape and clinical progress of targeted alpha radioimmunotherapy

Theranostics is an interesting area of cancer research that describes the use of radiotracers to first diagnose and then treat cancer. By coupling a radioisotope to an agent that selectively targets malignant cells, one can distribute focused radiation to disease sites. There are a variety of different radiopharmaceutical vectors that have been utilized in this way, such as peptides, small molecules and antibodies. Because antibodies bind to highly specific antigens, radioimmunotherapy (RIT) offers a promising route to precisely targeted treatments with reduced systemic toxicity compared to conventional radiotherapy. Beta (β)-emitting isotopes (e.g., ¹³¹I, ⁹⁰Y) have been more commonly coupled in RIT, but the use of alpha (α)-emitters (e.g., ²²⁵Ac, ²¹²Pb), for RIT (α-RIT) has rising popularity due to their shorter tissue range and higher linear energy transfer. These characteristics decrease off-target effects in neighboring tissues and increase tumor cell destruction, respectively. However, there are several challenges to RIT. The production of daughter isotopes from α decay makes dosimetric assessments difficult and could potentially cause off target toxicities. Additionally, whole antibodies tend to accumulate in liver tissue and have long biological clearance times, which may cause excess radiation to the blood, marrow and liver. Yet, there are a variety of α-RIT agents currently in development to treat prostate cancer, hematologic malignancies, and other solid tumors. Many agents show promise, like ²²⁷Th-epratuzumab, a CD22-targeting antibody used in the treatment of relapsed or refractory acute myeloid leukemia (R/R AML). While notoriously deadly and difficult to treat, the disease control rate in patients with R/R AML taking ²²⁷Th-epratuzumab was 38%. Like many α-RIT therapies, follow-up studies are needed to continue to improve efficacy. Strategies to widen the therapeutic indices of these agents have been investigated such as pretargeting, use of antibody fragments, chelator optimization and combination therapies. This review describes the current landscape and clinical progress of targeted α radioimmunotherapy.