Case Study #3: Antibody Fragments in Radiopharmaceutical Therapy

Antibodies are widely used as versatile biological tools in cancer therapeutics. In radiopharmaceutical therapy, they have been extensively exploited as vehicles for the delivery of cytotoxic radionuclide payloads for killing tumor cells. However, their success has been impeded by high toxicity profiles due to their long circulatory half-life, which produces high radiation doses to healthy non-target tissues. This issue has prompted the development of smaller engineered antibody fragments that bind to the same epitopes as their parent antibodies but with increased pharmacokinetic profiles, deeper tumor penetration, and better safety profiles. Antibody fragments have produced promising results as vectors for radiopharmaceutical therapy, with an approved fragment-based radiotherapeutic in China and an increasing number of ongoing clinical trials. Nonetheless, concerns surrounding the stability, unfavorable tissue distribution, and reduced binding affinity of radiolabeled antibody fragments have inhibited their widespread application in radiopharmaceutical therapy. In response, a great deal of effort has been dedicated to optimize the pharmacokinetics of antibody fragments (especially reducing their retention in the kidneys) and improving the radiochemical techniques used to synthesize them. In this chapter, we explore the application of antibody fragments for radiopharmaceutical therapy, their methods of production, and their potential for clinical translation.