Exploration of a F(ab′)(2) Fragment as the Targeting Agent of α-Radiation Therapy: A Comparison of the Therapeutic Benefit of Intraperitoneal and Intravenous Administered Radioimmunotherapy
التفاصيل البيبلوغرافية
العنوان:
Exploration of a F(ab′)(2) Fragment as the Targeting Agent of α-Radiation Therapy: A Comparison of the Therapeutic Benefit of Intraperitoneal and Intravenous Administered Radioimmunotherapy
Refinement of treatment regimens enlisting targeted α-radiation therapy (TAT) is an ongoing effort. Among the variables to consider are the target molecule, radionuclide, dosage, and administration route. The panitumumab F(ab′)(2) fragment targeting epidermal growth factor receptor tolerated modification with the TCMC chelate as well as radiolabeling with (203)Pb or (212)Pb. Good specific activity was attained when the immunoconjugate was labeled with (212)Pb (9.6 ± 1.4 mCi/mg). Targeting of LS-174T tumor xenografts with the (203)Pb-panitumumab F(ab′)(2) demonstrated comparable amounts of uptake to the similarly radiolabeled panitumumab IgG. A dose escalation study was performed to determine an effective working dose for both intraperitoneal (i.p.) and intravenous (i.v.) injections of (212)Pb-panitumumab F(ab′)(2). Therapeutic efficacy, with modest toxicity, was observed with 30 μCi given i.p. Results for the i.v. administration were not as definitive and the experiment was repeated with a higher dose range. From this study, 20 μCi given i.v. was selected as the effective working dose. A subsequent therapy study combined gemcitabine or paclitaxel with i.v. (212)Pb-panitumumab F(ab′)(2), which increased the median survival (MS) of LS-174T tumor-bearing mice to 208 and 239 d, respectively. Meanwhile, the MS of mice treated with i.v. (212)Pb-panitumumab F(ab′)(2) alone was 61 and 11 d for the untreated group of mice. In conclusion, the panitumumab F(ab′)(2) fragment whether given by i.p. or i.v. injection, is a viable candidate as a delivery vector for TAT of disseminated i.p. disease.
