Single-chain Fv (scFv)
antibody fragments exhibit improved pharmacokinetics and biodistribution compared with intact
IgG. The
tumor uptake of scFvs is rapid, and the serum half-life is shorter than
IgG. However, scFvs exhibit lower net dose deposition in the
tumor due to a shorter residence time that limits their use in
radioimmunotherapy. To improve the
tumor uptake and retention of scFvs, we investigated the utility of
cell-penetrating peptides,
penetratin and
transactivator of transcription (TAT). Biodistribution studies were done in LS174T
tumor-bearing mice with divalent scFv derived from anti-
tumor-associated
glycoprotein 72
monoclonal antibody (mAb) CC49.
Penetratin increased the
tumor retention of scFvs without affecting the peak dose accumulation. The percentage of doses retained in
tumors at 24 hours post-administration with a control (no
peptide),
penetratin, and TAT were 27.25%, 79.84%, and 48.55%, respectively, of that accumulated at 8 hours postinjection. The
tumor-to-blood ratios at 24 hours postadministration were 7.14, 19.53, and 16.48 with control,
penetratin, and TAT treatment, respectively, whereas the pharmacokinetics were unaltered. Coinjection with TAT, however, resulted in increased uptake of the radioconjugate by the lungs. Autoradiography of the excised
tumors indicated a more homogenous distribution of the radiolabeled scFv with both
penetratin and TAT in comparison with the control treatment. Real-time whole-body imaging of the live animals confirmed improved
tumor localization with
penetratin without any increase in the uptake by normal tissues. In conclusion, a significant improvement in the
tumor retention of sc(Fv)2 was achieved by administration of
penetratin. Therefore, the combination of
penetratin and scFvs has the potential of improving the utility of mAb-based
radiopharmaceuticals.