Single-Domain Antibody Theranostics on the Horizon

Abstract

Single-domain antibody (sdAb) is among the most promising vectors for developing molecular imaging tracers. Several sdAb tracers targeting human epidermal growth factor receptor 2 or programmed death ligand 1 have entered clinical practice. However, radiolabeled single-valent sdAbs generally have high kidney retention, limiting their therapeutic applications. Therefore, engineering strategies such as PEGylation or incorporation of renal cleavable linkers can be adapted to improve pharmacokinetics and reduce kidney retention. In this Focus on Molecular Imaging review, we try to summarize the latest developments in sdAb-derived agents and propose potential strategies that can be used to improve the theranostic value of radiolabeled sdAbs.

Keywords: cancer; immuno-PET; nanobody; radiopharmaceuticals; theranostics.

FIGURE 1.

^99mTc-NM-02 immuno-SPECT/CT imaging of breast cancers. (A) Whole-body SPECT images at different time points (10 min, 1 h, 2 h, 3 h, and 24 h) after injection of radiotracer. (B) Varying uptake patterns in patients with breast cancer. From left to right: heterogeneous uptake in primary tumor and in metastatic lymph node in patient with HER2 3+ breast cancer, and homogeneous uptake in primary tumor and in metastatic lymph node in another patient with HER2 3+ breast cancer. Primary and metastatic tumors are indicated by red circles. (Reprinted from (10).)

FIGURE 2.

Preclinical immuno-PET imaging of multiple myelomas. (A) Immuno-PET imaging with ⁶⁸Ga-NOTA-Nb1053 delineated subcutaneous MM.1S tumor (blue arrows) with excellent contrast. Unbound tracer was largely excreted from urinary system (kidneys indicated by yellow arrows and bladder by white arrow), and small proportion was catabolized in liver (red arrow). (B) In comparison, PET imaging with ¹⁸F-FDG visualized subcutaneous MM.1S tumor (blue arrows) with substantial uptake in normal tissues, such as bone joints (white circles) and muscles (red circles). (C) Immuno-PET imaging with ¹⁸F-Nb1053 also clearly outlined involved bones (red circles). (D) In contrast, no obvious ¹⁸F-Nb1053 uptake was observed in disseminated MM.1S models that were premedicated with CD38-targeting monoclonal antibody daratumumab. The gallbladder is indicated by the yellow arrow. %ID = percentage injected dose; Dara = daratumumab; HU = Hounsfield units. (Reprinted from (12,24).)