Evaluation of a Pretargeting Strategy for Molecular Imaging of the Prostate Stem Cell Antigen with a Single Chain Antibody

Abstract

In pretargeted radio-immunotherapy, the gradual administration of a non-radioactive tumor antigen-addressing antibody-construct and the subsequent application of a radioactive labeled, low molecular weight substance enable a highly effective and selective targeting of tumor tissue. We evaluated this concept in prostate stem cell antigen (PSCA)-positive cancers using the antigen-specific, biotinylated single chain antibody scFv(AM1)-P-BAP conjugated with tetrameric neutravidin. To visualize the systemic biodistribution, a radiolabeled biotin was injected to interact with scFv(AM1)-P-BAP/neutravidin conjugate. Biotin derivatives conjugated with different chelators for complexation of radioactive metal ions and a polyethylene glycol linker (n = 45) were successfully synthesized and evaluated in vitro and in a mouse xenograft model. In vivo, the scFv(AM1)-P-BAP showed highly PSCA-specific tumor retention with a PSCA+ tumor/PSCA- tumor accumulation ratio of ten. PEGylation of radiolabeled biotin resulted in lower liver uptake improving the tumor to background ratio.

Synthetic 18F labeled biomolecules that are selective and promising for PET imaging: major advances and applications

“…This approach combines the antibody and radioelement in vivo by individual administration with an optimized interval via a biorthogonal reaction. 114…”

IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications

“…The pretargeting concept was developed to overcome the limitations encountered during direct targeting of tumors with radiolabeled antibodies [14]. It relies on four main steps (Figure 1) [7,[15][16][17]. The first step consists of the administration of an unlabeled and modified biovector (i.e., monoclonal antibody) possessing the ability to bind an antigen or receptor and a radiolabeled small molecule.…”

Engineered Polymeric Materials for Biological Applications: Overcoming Challenges of the Bio–Nano Interface

“…Following a defined period of time depending on the known pharmacokinetics of the molecule, a second molecule is injected that will have fast clearance, unless it undergoes a chemical reaction with the initial probe molecule. By incorporating imaging modalities on the second molecule, signal-to-noise ratios can be significantly enhanced owing to the much lower background signal present [83,84,85]. By utilizing bio-orthogonal chemistry approaches, this technique can also be translated to therapeutic delivery and offers exciting new methods for improving nanomedicine efficacy, while decreasing off-target effects [86,87].…”