Pretargeting in the context of theranostics and companion diagnostics in nuclear oncology

Abstract

Purpose: The concept of theranostics is well illustrated in nuclear oncology by radioactive iodide in thyroid diseases and by peptides or small molecular weight inhibitors in various cancers. It is also illustrated by radiolabeled antibodies, such as Zevalin, but radiolabeled antibodies have limitations that prompted the design of pretargeting. This review illustrates the achievements of pretargeting and focuses on its applications as theranostics or companion diagnostics. Method: The review does not aim at exhaustivity. Examples from the already long history of pretargeting are selected to depict achievements but also outstanding issues. Results: The idea of pretargeting, which separates antigen-binding from radionuclides, was proposed in the mid 1980s. Using avidin–biotin or bispecific antibodies and bivalent haptens, high contrast images and therapeutic efficacy were demonstrated in the clinic. However, the immunogenicity of streptavidin could not be abrogated, producing recombinant bispecific antibodies proved difficult and balancing between high tumor uptake and fast clearance of activity from normal tissues remains a challenge. These are the reasons for the continuing search for new approaches and new reagents. Some of these new approaches, particularly those based on biorthogonal chemistry or complementary oligonucleotides, are described and their potential as theranostics or companion diagnostics are discussed. Conclusion: The future of pretargeting remains uncertain, because clinical development is complex and cost of goods is high. However, pretargeting as a theranostic tool is clinical relevant, especially with short half-life radionuclides for PET imaging or targeted alpha-radionuclide therapy.