Pretargeted radioimmunodiagnosis and radioimmunotherapy aim to efficiently combine antitumor antibodies and medicinal radioisotopes for high-contrast imaging and high–therapeutic-index (TI) tumor targeting, respectively. As opposed to conventional radioimmunoconjugates, pretargeted approaches separate the tumor-targeting step from the payload step, thereby amplifying tumor uptake while reducing normal-tissue exposure. Alongside contrast and TI, critical parameters include antibody immunogenicity and specificity, availability of radioisotopes, and ease of use in the clinic. Each of the steps can be optimized separately; as modular systems, they can find broad applications irrespective of tumor target, tumor type, or radioisotopes. Although this versatility presents enormous opportunity, pretargeting is complex and presents unique challenges for clinical translation and optimal use in patients. The purpose of this article is to provide a brief historical perspective on the origins and development of pretargeting strategies in nuclear medicine, emphasizing 2 protein delivery systems that have been extensively evaluated (i.e., biotin–streptavidin and hapten-bispecific monoclonal antibodies), as well as radiohaptens and radioisotopes. We also highlight recent innovations, including pretargeting with bioorthogonal chemistry and novel protein vectors (such as self-assembling and disassembling proteins and Affibody molecules). We caution the reader that this is by no means a comprehensive review of the past 3 decades of pretargeted radioimmunodiagnosis and pretargeted radioimmunotherapy. But we do aim to highlight major developmental milestones and to identify benchmarks for success with regard to TI and toxicity in preclinical models and clinically. We believe this approach will lead to the identification of key obstacles to clinical success, revive interest in the utility of radiotheranostics applications, and guide development of the next generation of pretargeted theranostics.

预靶向放射免疫诊断和放射免疫治疗旨在有效地结合抗肿瘤抗体和医用放射性同位素，分别用于高对比度成像和高治疗指数（TI）肿瘤靶向。与传统的放射免疫缀合物相反，预靶向方法将肿瘤靶向步骤与有效负载步骤分开，从而放大肿瘤摄取，同时减少正常组织暴露。除了对比度和 TI 之外，关键参数还包括抗体免疫原性和特异性、放射性同位素的可用性以及在临床中的易用性。每个步骤都可以单独优化；作为模块化系统，它们可以找到广泛的应用，无论肿瘤靶标、肿瘤类型或放射性同位素如何。尽管这种多功能性带来了巨大的机会，但预靶向很复杂，并且对临床转化和患者的最佳使用提出了独特的挑战。本文的目的是提供关于核医学中预靶向策略的起源和发展的简要历史视角，强调两种已被广泛评估的蛋白质递送系统（即生物素-链霉亲和素和半抗原双特异性单克隆抗体），以及如放射性半抗原和放射性同位素。我们还重点介绍了最新的创新，包括生物正交化学的预靶向和新型蛋白质载体（例如自组装和拆卸蛋白质和 Affibody 分子）。我们提醒读者，这绝不是对过去30年预靶向放射免疫诊断和预靶向放射免疫治疗的全面回顾。但我们的目标是强调主要的发展里程碑，并确定临床前模型和临床中 TI 和毒性方面的成功基准。 我们相信，这种方法将有助于识别临床成功的关键障碍，重新激发人们对放射治疗应用的兴趣，并指导下一代预定位治疗诊断的开发。