Exploration of a F(ab′)₂Fragment 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') fragment targeting epidermal growth factor receptor tolerated modification with the TCMC chelate as well as radiolabeling with Pb orPb. Good specific activity was attained when the immunoconjugate was labeled with Pb (9.6 ± 1.4 mCi/mg). Targeting of LS-174T tumor xenografts with thePb-panitumumab F(ab') 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 Pb-panitumumab F(ab'). 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. Pb-panitumumab F(ab'), 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. Pb-panitumumab F(ab') alone was 61 and 11 d for the untreated group of mice. In conclusion, the panitumumab F(ab') 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.

An Appendix of Radionuclides Used in Targeted Alpha Therapy

“…A derivative of DOTA with carbamoyl methyl arms on the cyclen ring (TCMC) instead of carboxylate arms have been studied in preclinical and clinical settings. A few targeting agents have been conjugated to TCMC to target different cancers and to be administrated through intravenous or intraperitoneal injection [9,[32][33][34].…”

Overview of the Most Promising Radionuclides for Targeted Alpha Therapy: The “Hopeful Eight”

“…In that context, 203 Pb/ 212 Pb pair is of interest and is currently being developed with the publication of an increasing number of preclinical studies. First, 203 Pb and 212 Pb-radioconjugates were respectively studied for comparison of tissue distribution as potential agent for SPECT imaging and for evaluation of therapeutic efficacy, after association with panitumumab F(ab’) 2 fragment and Mmelanocortin 1 receptor targeted peptide (MC1L) [ 213 , 214 ]. Thereafter, with the increasing interest for PSMA as promising target for TRT of prostate cancer, PSMA ligands were prepared for chelation of 203 / 212 Pb.…”

Nanoradiopharmaceuticals Based on Alpha Emitters: Recent Developments for Medical Applications

“…In 2016, Milenic et al evaluated the biodistribution, pharmacokinetics, and toxicity of 212 Pb-TCMC-trastuzumab in a phase I clinical trial in patients with HER2-expressing ovarian cancer. The results showed that the redistribution of radionuclide was minimal and the myelosuppression was not significant [ 63 ], Later, in 2018, Milenic et al evaluated the conjugation of panitumumab F(ab′) 2 with TCMC as a targeting agent for epidermal growth factor receptor [ 64 ].…”

“…In addition, preclinical and clinical trials with different monoclonal antibodies (mAbs) and peptides labeled with 213 Bi for treating leukemia ( 213 Bi-HuM195), lymphoma ( 213 Bi-anti-CD20 MAb), melanoma ( 213 Bi-9.2.27), bladder cancer ( 213 Bi-anti-EGFR MAb), glioblastoma ( 213 Bi-substance P), and neuroendocrine tumors ( 213 Bi-DOTATOC) have been reported [ 64 , 65 , 66 , 67 , 68 , 69 ], and 225 Ac-labeled mAbs and peptides for acute myeloid leukemia ( 225 Ac-DOTA-NCS with lintuzumab or 225 Ac-HuM195mAb), for prostate cancer ( 225 Ac-PSMA-617), glioma ( 225 Ac-Substance P), and neuroendocrine tumors ( 225 Ac-DOTATOC) have been evaluated [ 13 , 18 ]. In clinical trials, hundreds of patients with prostate cancer have undergone the treatment with 225 Ac and 213 Bi-labeled PSMA-617 and have presented excellent responses [ 67 , 70 ].…”