Antibody-Based Alpha Targeted Therapy: Recent Advances and Prospects for Clinical Implementation from a DDS Perspective

Abstract

Nuclear medicine has evolved from early diagnostic use of radioisotopes to an integrated field combining molecular imaging and therapy. The concept of theranostics, using the same molecular carrier for both diagnosis and treatment, has placed antibodies at the center due to their high specificity and established clinical utility. Within this framework, Targeted Alpha Therapy（TAT） has emerged as a promising approach. Alpha particles deliver extremely high linear energy transfer（LET） over short ranges, inducing irreparable double-strand DNA breaks with only a few hits. This unique property makes TAT effective against radioresistant and hypoxic tumors but also imposes stringent requirements on carrier localization and pharmacokinetics. From a drug delivery system（DDS） perspective, optimal therapeutic outcomes rely on harmonizing isotope half-life with antibody trafficking, ensuring precise spatiotemporal delivery. Different alpha emitters pose distinct design challenges: ²²⁵Ac offers high dose density but risks daughter nuclide redistribution, whereas ²¹¹At, with a half-life of 7.2 hours and stable chemistry, aligns well with antibody kinetics and clinical logistics. Japan has pioneered ²¹¹At research, establishing GMP-compliant production and conducting the world’s first physician-initiated trial（Alpha-T1） in thyroid cancer, demonstrating safety and partial remission. In parallel, imaging-guided theranostics using ⁸⁹Zr for PET and ²¹¹At for therapy exemplify precision medicine, enabling patient-tailored dosing. Recent innovations include single-domain antibodies（VHH） and gold nanoparticles for improved tumor penetration and isotope stabilization, as well as dual immunological effects where α-irradiation enhances antitumor immunity and synergizes with checkpoint inhibitors. Despite progress, challenges remain: securing stable isotope supply, regulatory harmonization, logistics for short-lived isotopes, and balancing antibody size with tumor penetration and systemic toxicity. DDS approaches—including antibody fragment engineering, linker and chelator chemistry, and quantitative PET imaging—are key to overcoming these hurdles. The expansion of antibody-based therapeutics such as bispecific antibodies and ADCs further strengthens the foundation for TAT. Ultimately, integrating supply chains, regulatory frameworks, molecular design, and immunological strategies will transform antibody-based TAT from laboratory innovation into clinical routine, offering a new paradigm in oncology.