Indirect Radioiodination Increases In Vivo Stability and Tumor Uptake of I-125-L19-SIP

Ziel/Aim:

The extradomain B of fibronectin (ED-B-FN) is an angiogenesis-associated marker of the tumoral extracellular matrix, which can be targeted by the human recombinant, high-affinity antibody fragment L19-SIP. By I-131-labeling L19-SIP becomes a radiotherapeutic agent, which is effective in several tumor models. In this study indirect and direct radioiodination methods were compared with regard to tumor uptake and in vivo stability of the obtained L19-SIP derivatives.

Methodik/Methods:

L-19-SIP was directly radioiodinate using the Iodogen methods, as well as indirectly by conjugation of I-125-Boltron Hunter reagent (I-125-BH) or I-125-succinimidylbenzoate (I-125-SIB). Pharmacokinetics and tumor accumulation of the iodinated L19-SIP derivatives were investigated in tumor bearing mice up to 72 h (F9, murine teratocarcinoma and U251, human glioblastoma) with subsequent dosimetry for the therapeutic isotope I-131.

Ergebnisse/Results:

In biodistribution studies the directly iodinated L-19-SIP showed increasing thyroid uptake over time due to dehalogenation of I-125 in vivo, whereas the indirectly iodinated L19-SIP showed improved stability of the iodine label. I-125-BH-L19-SIP and I-125-SIB-L19-SIP exhibited longer retenation in the tumor compared to I-125-L19-SIP. Tumor-to-blood ratios were significantly higher for the indirectly labelled compounds at later time points. It was calculated that activities of 48 MBq I-131-L19-SIP (Iodogen), 47 MBq I-131-BH-L19-SIP and 64 MBq I-131-SIB-L19-SIP could be injected per mouse before reaching the maximum tolerated dose of 2.5 Gy in the bone marrow, and would lead to doses of 42 Gy, 40 Gy and 144 Gy in 100 mg F9-tumors, respectively. The calculated tumor doses were comparable in both tumor models.

Schlussfolgerungen/Conclusions:

I-125-SIB-L19-SIP shows considerably higher in vivo stability and longer tumor retention compared to directly labelled L19-SIP leading to a substantially higher tumor dose.