Case Study #1: Alpha Particle Therapy of Leukemia Using ²²⁵Ac-Lintuzumab

Abstract

²²⁵Ac-Lintuzumab (Actimab-A, Actinium Pharmaceuticals, Inc.) is an alpha particle emitting monoclonal antibody (mAb) drug targeting the CD33 antigen expressed on acute myeloid leukemia (AML) cells. The name “actinium” is derived from the Greek aktis meaning “ray” or “beam,” and the decay of each actinium-225 atom produces 4 alpha (α) particles during the cascade to stable ²⁰⁹Bi. Lintuzumab (HuM195) is a humanized immunoglobulin G (IgG) that was selected for specific bioactivity towards the CD33 antigen expressed on early myeloid cells, acute non-lymphoid leukemia cells, and monocytic cells. Humanized HuM195 was engineered from the murine M195 antibody, and both antibodies have demonstrated the ability to target leukemia cells in clinical trials without immunogenicity. The first-in-human α-emitting radioimmunoconjugate was ²¹³Bi-Lintuzumab. However, the short radionuclidic half-life of ²¹³Bi (t_1/2 = 46 min) presented a logistical challenge, i.e., the need for on-site production with no opportunity for ship**. However, the potent anti-tumor activity of this first-generation targeted radiotherapeutic provided proof-of-concept that α-based therapy using HuM195 was tumor-specific and produced only minimal off-tumor toxicity. The next-generation radioimmunoconjugate—²²⁵Ac-lintuzumab—was armed with ²²⁵Ac, which has a much longer radionuclidic half-life: 10 d. This change resolved the key logistical issue that limited widespread use. However, at that time, the radiochemistry of ²²⁵Ac³⁺ was relatively unexplored, and the stable coordination of the radiometal presented unique pharmacologic challenges with respect to controlling the in vivo fate of its radioisotopic daughters. This chapter will recount the developmental evolution of ²²⁵Ac-lintuzumab, including the challenges to translate this novel drug into the clinic.