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Targeted ?-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab.

ABSTRACT: Identifying molecular targets and an appropriate targeting vehicle, i.e., monoclonal antibodies (mAb) and their various forms, for radioimmunotherapy (RIT) remains an active area of research. Panitumumab, a fully human and less immunogenic mAb that binds to the epidermal growth factor receptor (Erb1; HER1), was evaluated for targeted ?-particle radiation therapy using 212Pb, an in vivo ? generator. A single dose of 212Pb-panitumumab administered to athymic mice bearing LS-174T intraperitoneal (i.p.) tumor xenografts was found to have greater therapeutic efficacy when directly compared with 212Pb-trastuzumab, which binds to HER2. A dose escalation study determined a maximum effective working dose of 212Pb-panitumumab to be 20?Ci with a median survival of 35 days versus 25 days for the untreated controls. Pretreatment of tumor-bearing mice with paclitaxel and gemcitabine 24hours prior to injection of 212Pb-pantiumumab at 10 or 20?Ci resulted in the greatest enhanced therapeutic response at the higher dose with median survivals of 106 versus 192 days, respectively. The greatest therapeutic impact, however, was observed in the animals that were treated with topotecan 24hours prior to RIT and then again 24hours after RIT; the best response from this combination was also obtained with the lower 10-?Ci dose of 212Pb-panitumumab (median survival >280 days). In summary, 212Pb-panitumumab is an excellent candidate for the treatment of HER1-positive disseminated i.p. disease. Furthermore, the potentiation of the therapeutic impact of 212Pb-pantiumumab by chemotherapeutics confirms and validates the importance of developing a multimodal therapy regimen.

SUBMITTER: Milenic DE

PROVIDER: S-EPMC5458064 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Targeted α-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab.

Milenic Diane E DE Baidoo Kwamena E KE Kim Young-Seung YS Barkley Rachel R Brechbiel Martin W MW

Translational oncology 20170531 4

Identifying molecular targets and an appropriate targeting vehicle, i.e., monoclonal antibodies (mAb) and their various forms, for radioimmunotherapy (RIT) remains an active area of research. Panitumumab, a fully human and less immunogenic mAb that binds to the epidermal growth factor receptor (Erb1; HER1), was evaluated for targeted α-particle radiation therapy using <sup>212</sup>Pb, an in vivo α generator. A single dose of <sup>212</sup>Pb-panitumumab administered to athymic mice bearing LS-1 ...[more]

PMID: 28577439

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Project description:UNLABELLED:Panitumumab, a human monoclonal antibody that binds to the epidermal growth factor receptor (HER1), was approved by the Food and Drug Administration in 2006 for the treatment of patients with HER1-expressing carcinoma. In this article, we describe the preclinical development of (86)Y-CHX-A''-diethylenetriaminepentaacetic acid (DTPA)-panitumumab for quantitative PET of HER1-expressing carcinoma. Panitumumab was conjugated to CHX-A''-DTPA and radiolabeled with (86)Y. In vivo biodistribution, PET, blood clearance, area under the curve, area under the moment curve, and mean residence time were determined for mice bearing HER1-expressing human colorectal (LS-174T), prostate (PC-3), and epidermoid (A431) tumor xenografts. Receptor specificity was demonstrated by coinjection of 0.1 mg of panitumumab with the radioimmunoconjugate. RESULTS:(86)Y-CHX-A''-DTPA-panitumumab was routinely prepared with a specific activity exceeding 2 GBq/mg. Biodistribution and PET studies demonstrated a high HER1-specific tumor uptake of the radioimmunoconjugate. In mice bearing LS-174T, PC-3, or A431 tumors, the tumor uptake at 3 d was 34.6 +/- 5.9, 22.1 +/- 1.9, and 22.7 +/- 1.7 percentage injected dose per gram (%ID/g), respectively. The corresponding tumor uptake in mice coinjected with 0.1 mg of panitumumab was 9.3 +/- 1.5, 8.8 +/- 0.9, and 10.0 +/- 1.3 %ID/g, respectively, at the same time point, demonstrating specific blockage of the receptor. Normal organ and tumor uptake quantified by PET was closely related (r(2) = 0.95) to values determined by biodistribution studies. The LS-174T tumor had the highest area under the curve (96.8 +/- 5.6 %ID d g(-1)) and area under the moment curve (262.5 +/- 14.9 %ID d(2) g(-1)); however, the tumor mean residence times were identical for all 3 tumors (2.7-2.8 d). CONCLUSION:This study demonstrates the potential of (86)Y-CHX-A''-DTPA-panitumumab for quantitative noninvasive PET of HER1-expressing tumors and represents the first step toward clinical translation.

Project description:Anti-HER1 monoclonal antibody (mAb), panitumumab (Vectibix) is a fully human mAb approved by the FDA for the treatment of epidermal growth factor receptor (EGFR, HER1)-expressing colorectal cancers. By combining the targeted specificity of panitumumab with the quantitative in vivo imaging capabilities of PET, we evaluated the potential of (89)Zr-DFO-panitumumab PET/CT imaging and performed non-invasive, in vivo imaging of HER1 expression and estimated human dosimetry.Panitumumab was radiolabeled with (89)Zr using a derivative of desferrioxamine (DFO-Bz-NCS) and with (111)In using CHX-A" DTPA as bifunctional chelators. Comparative biodistribution/dosimetry of both radiotracers was performed in non-tumor bearing athymic nude mice (n=2 females and n=2 males) over 1-week following i.v. injection of either using (89)Zr-DFO-panitumumab or (111)In-CHX-A"-DTPA-panitumumab. Micro-PET/CT imaging of female athymic nude mice bearing human breast cancer tumors (n=5 per tumor group) with variable HER1-expression very low (BT-474), moderate (MDA-MB-231), and very high (MDA-MB-468) was performed at over 1 week following i.v. injection of (89)Zr-DFO-panitumumab.Radiochemical yield and purity of (89)Zr-Panitumumab was >70% and >98% respectively with specific activity 150 ± 10 MBq/mg of panitumumab in a ~4 hr synthesis time. Biodistribution of (111)In-CHX-A" DTPA -panitumumab and (89)Zr-DFO-panitumumab in athymic non-tumor bearing nude mice displayed similar percent injected dose per gram of tissue with prominent accumulation of both tracers in the lymph nodes, a known clearance mechanism of panitumumab. Also exhibited was prolonged blood pool with no evidence of targeted accumulation in any organ. Human radiation dose estimates showed similar biodistributions with estimated human effective doses of 0.578 and 0.183 mSv/MBq for (89)Zr-DFO-panitumumab and (111)In-CHX-A"-DTPA-panitumumab, respectively. Given the potential quantitative and image quality advantages of PET, imaging of tumor bearing mice was only performed using (89)Zr-DFO-panitumumab. Immuno-PET imaging of (89)Zr-DFO-panitumumab in mice bearing breast cancer xenograft tumors with variable HER1 expression showed high tumor uptake (SUV >7) in the MDA-MB-468 high HER1-expressing mice and a strong correlation between HER1-expression level and tumor uptake (R(2)= 0.857, P < .001).(89)Zr-DFO-panitumumab can prepared with high radiochemical purity and specific activity. (89)Zr-DFO-panitumumab microPET/CT showed uptake corresponding to HER-1 expression. Due to poor clearance, initial dosimetry estimates suggest that only a low dose (89)Zr-DFO-panitumumab shows favorable human dosimetry; however due to high tumor uptake, the use of (89)Zr-DFO-panitumumab is expected to be clinically feasible.

Project description:UnlabelledMalignant mesothelioma (MM), a rare form of cancer is often associated with previous exposure to fibrous minerals, such as asbestos. Asbestos exposure increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over-expression is observed in the majority of MM cases. In this study, the utility of HER1-targeted chimeric IgG(1), cetuximab, and a human IgG(2), panitumumab, radiolabeled with (86)Y, were evaluated for PET imaging to detect MM non-invasively in vivo, and to select an antibody candidate for radioimmunotherapy (RIT).MethodsRadioimmunoconjugates (RICs) of cetuximab and panitumumab were prepared by conjugation with CHX-A''-DTPA followed by radiolabeling with (86)Y. The HER1 expression of NCI-H226, NCI-H2052, NCI-H2452 and MSTO-211H human mesothelioma cells was characterized by flow cytometry. In vivo biodistribution, pharmacokinetic analysis, and PET imaging were performed in tumor bearing athymic mice.ResultsIn vivo studies demonstrated high HER1 tumor uptake of both RICs. Significant reduction in tumor uptake was observed in mice co-injected with excess mAb (0.1 mg), demonstrating that uptake in the tumor was receptor specific. Significant differences were observed in the in vivo characteristics of the RICs. The blood clearance T(½)? of (86)Y-cetuximab (0.9-1.1 h) was faster than (86)Y-panitumumab (2.6-3.1 h). Also, the tumor area under the curve (AUC) to liver AUC ratios of (86)Y-panitumumab were 1.5 to 2.5 times greater than (86)Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normal organs such as the liver.ConclusionThis study demonstrates the more favorable HER1-targeting characteristics of (86)Y-panitumumab than (86)Y-cetuximab for non-invasive assessment of the HER1 status of MM by PET imaging. Due to lower liver uptake, panitumumab based immunoconjugates may fare better in therapy than corresponding cetuximab based immunoconjugates.

Project description:The radiation bystander effect is an important component of the overall biological response of tissues and organisms to ionizing radiation. Little is known about the contribution of genome level changes in neighboring bystander cells to tissue and organ stress after irradiation. The timing of these changes is critical in the physiological context and these questions can only be answered by studying signaling and global transcriptomics in a chronological way. Here, we present a strategy to identify different biologically important signaling modules that act in concert in the radiation and bystander responses. We used time series gene expression analysis of normal human fibroblast cells measured at 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after exposure to radiation coupled with a novel clustering method targeted to short time series, Feature Based Partitioning around medoids Algorithm (FBPA), to look for genes that were potentially co-regulated. This method uses biologically meaningful features of the expression profile and dimension augmentation to address the analysis of sparse data sets such as ours. We applied FBPA and Short Time series Expression Miner (STEM) to the same datasets and present the results of our comparisons using computational metrics as well as biological enrichment. Enrichment showed that gene expression in irradiated cells fell into broad categories of signal transduction, cell cycle/cell death and inflammation/immunity; but only FBPA clustered functions well. In bystander cells, the gene expression response was also broadly categorized into functions associated with cell communication and motility, signal transduction and inflammation; but neither STEM nor FBPA separated biological functions as well as in irradiated samples. Network analysis revealed that p53 and NF-kappaB were central players in gene expression in both irradiated and bystander gene clusters. Analysis of individual clusters also suggested new regulators of gene expression in the radiation and bystander response that may act at the epigenetic level such as histone deacetylases (HDAC1 and HDAC2) and methylases (KDM5B) that can act as strong transcription repressors. Based on these results, we propose a novel time series clustering method, FBPA, as a powerful approach that can be applied to sparse data sets (including genomic profiling data), where the choice of features selected for clustering and stringent statistical outcome analysis can augment our knowledge of the underlying cellular mechanisms in biological processes.

Dataset Information

Targeted ?-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab.

Publications

Targeted α-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab.

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