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

Abstract

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 ²⁰³Pb or ²¹²Pb. Good specific activity was attained when the immunoconjugate was labeled with ²¹²Pb (9.6 ± 1.4 mCi/mg). Targeting of LS-174T tumor xenografts with the ²⁰³Pb-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 ²¹²Pb-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. ²¹²Pb-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. ²¹²Pb-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.