Targeted Nanobody-Based Molecular Tracers for Nuclear Imaging and Image-Guided Surgery

Abstract

Molecular imaging is paving the way towards noninvasive detection, staging, and treatment follow-up of diseases such as cancer and inflammation-related conditions. Monoclonal antibodies have long been one of the staples of molecular imaging tracer design, although their long blood circulation and high nonspecific background limits their applicability. Nanobodies, unique antibody-binding fragments derived from camelid heavy-chain antibodies, have excellent properties for molecular imaging as they are able to specifically find their target early after injection, with little to no nonspecific background. Nanobody-based tracers using either nuclear or fluorescent labels have been heavily investigated preclinically and are currently making their way into the clinic. In this review, we will discuss different important factors in nanobody-tracer design, as well as the current state of the art regarding their application for nuclear and fluorescent imaging purposes. Furthermore, we will discuss how nanobodies can also be exploited for molecular therapy applications such as targeted radionuclide therapy and photodynamic therapy.

The Therapeutic Potential of Nanobodies

“…High antigen specificity is crucial for reducing side effects and minimizing the chance of obtaining false positives [54]. However, for molecular imaging, nanobodies have to be labelled with a diagnostic radioisotope, which can be gamma-emitting nuclides for single photon emission computed tomography (SPECT) or positron-emitting nuclides for positron emission tomography (PET) [70]. PET isotopes 68 Ga and 18 F are most appropriate for human use due to the short half-lives of 68 and 110 min, respectively.…”

Nanobodies as non-invasive imaging tools

“…A nanobody-based drug that targets von Willebrand factor has received approval from the US Food and Drug Administration (FDA), 84,85 and several more nanobodies are in clinical trials. 37,65,86,87 As nanobodies are derived from camelid heavy-chain-only antibodies, they can be immunogenic in humans. However, the VHH framework regions are homologous to those of human IgGs, 88,89 which may explain their low immunogenicity in clinical settings.…”

Affibody Molecules as Targeting Vectors for PET Imaging

“…Empirical data suggest that a reduction in the size of targeting proteins permits the ability to obtain a high imaging contrast earlier than several days after the injection [9]. Indeed, the use of a single-domain antibody (sdAb) with a molecular weight of 12-15 kDa permits the development of imaging probes with a tumor-to-blood ratio of 10-30 at 1 h after injection in murine models [10]. Mathematical modeling predicts that a further size reduction would enable an increase in tumor accumulation if the affinity of imaging probes was high enough [11,12].…”