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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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86Y-CHX-A''-diethylenetriamine pentaacetic acid-panitumumab

86Y-CHX-A''-DTPA-Panitumumab
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: December 8, 2011.

Chemical name:86Y-CHX-A''-diethylenetriamine pentaacetic acid-panitumumab
Abbreviated name:86Y-CHX-A''-DTPA-Panitumumab
Synonym:
Agent category:Chimeric monoclonal antibody
Target:Epidermal growth factor receptor (EGFR, HER1)
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:86Y
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about EGF.

Background

[PubMed]

Epidermal growth factor (EGF) is a 53-amino-acid cytokine (6.2 kDa) secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors, including EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2. However, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 as well as HER2 are overexpressed on many solid tumor cells, such as breast, non–small-cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with a poor prognosis (7-10).

Trastuzumab (a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) against the extracellular domain of recombinant HER2) (11) has been labeled as 111In-trastuzumab (12-14). C225 mAb (an anti-EGFR, mouse-human chimeric, monoclonal IgG1 antibody, also known as cetuximab) has been labeled as 99mTc-EC-C225 for use with single-photon emission computed tomography (SPECT) imaging of EGFR expression on solid tumors (15, 16). However, positron emission tomography (PET) offers better sensitivity, resolution, and quantification than SPECT (17). 64Cu is an attractive radionuclide for labeling cetuximab. Panitumumab has been approved by the United States Food and Drug Administration as a single agent for the treatment of EGFR-expressing, metastatic, colorectal carcinoma. For evaluation as a PET imaging agent, 64Cu (t1/2 = 12.7 h) was attached to panitumumab via 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) to form 64Cu-DOTA-panitumumab. Niu et al. (18) performed 64Cu-DOTA-panitumumab PET imaging studies in nude mice bearing human head and neck squamous cell carcinoma tumors with different expressions of EGFR. Nayak et al. (19) prepared 86Y-CHX-A''-diethylenetriamine pentaacetic acid (DTPA)-panitumumab (86Y, t1/2 = 14.7 h) for quantitative PET of HER1-expressing carcinoma. 86Y was chosen because of its suitability for internalizing mAbs, well-established chemistry, and potential use of 90Y for radiotherapy.

Synthesis

[PubMed]

Bifunctional CHX-A''-DTPA was used to conjugate panitumumab to form CHX-A''-DTPA-panitumumab (~150 kD), which was purified with column chromatography (19). There were 1.6 DTPA molecules per antibody. Next, 86Y solution (140–170 MBq (3.8–4.6 mCi)) was added to CHX-A''-DTPA-panitumumab (0.33 nmol) in ammonium acetate buffer (pH 5–6). The reaction mixture was incubated for 30 min at room temperature, and 86Y-CHX-A''-DTPA-panitumumab was purified with column chromatography. The yield of 86Y-CHX-A''-DTPA-panitumumab was 60%–75% with a specific activity of ~375 MBq/nmol (10 mCi/nmol). Radiochemical purity was not given, but 86Y-CHX-A''-DTPA-panitumumab exhibited excellent stability after storage in the refrigerator for 1 d at 4°C.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Nayak et al. (19) performed 86Y-CHX-A″-DTPA-panitumumab binding to fixed A431 cells, demonstrating good in vitro immunoreactivity (73.5 ± 4.8%) and low nonspecific binding (3.8 ± 1.7%) (n = 4).

Animal Studies

Rodents

[PubMed]

Nayak et al. (19) performed ex vivo biodistribution studies in nude mice (n = 4/group) bearing HER1-expressing human colorectal LS-174T (low EGFR expression) and prostate PC-3 (moderate EGFR expression) xenografts at 1-4 d after injection of 0.5 MBq (0.14 mCi, 0.03 nmol) 86Y-CHX-A''-DTPA-panitumumab. Accumulation into LS-174T tumors was high, with 28.4 ± 3.0% injected dose/gram (ID/g) and 34.3 ± 3.5% ID/g at 1 d and 4 d after injection, respectively. The tumor/blood ratios were 2.0 and 4.7 at 1 d and 4 d after injection, respectively. Accumulation into PC-3 tumors was 14.5 ± 1.3% ID/g and 27.6 ± 2.8% ID/g at 1 and 4 d after injection, respectively, with tumor/blood ratios of 1.3 and 3.2 at 1 d and 4 d after injection, respectively. On the other hand, normal tissues exhibited lower radioactivity than the tumors, with little change from 1 d to 4 d after injection. Co-injection of panitumumab (0.7 nmol) with 86Y-CHX-A''-DTPA-panitumumab was performed in mice bearing LS-174T, PC-3, and human epidermoid A431 (high EGFR expression) tumor xenografts. Radioactivity in the tumors and non-tumor tissues was measured at 3 d after injection. The accumulation in the non-blocked tumors was 34.7 ± 5.9% ID/g, 22.1 ± 1.9% ID/g, and 22.7 ± 1.7% ID/g, respectively. The accumulation in the blocked tumors was 9.3 ± 1.5% ID/g, 8.8 ± 0.9% ID/g, and 10.0 ± 1.3% ID/g, respectively. By contrast, little inhibition was observed in the non-tumor tissues. The mean tumor residence times were similar in the three tumors (2.7–2.8 d). The low HER1-expressing LS-174T tumors showed the highest accumulation of 86Y-CHX-A''-DTPA-panitumumab. This apparent dichotomy (LS-174T versus PC-3 and A431) may be explained by the fact that in vivo tumor accumulation is dependent on many physiological factors, such as tumor vasculature, blood flow, tumor interstitial pressure, factors present in the tumor microenvironment, and antigen shedding. Niu et al. (18) also reported the discrepancies of 64Cu-DOTA-panitumumab in tumor uptake and ex vivo HER1 expression levels determined with immunohistochemistry.

Nayak et al. (19) studied the whole-body distribution of ~2 MBq (0.054 mCi) 86Y-CHX-A''-DTPA-panitumumab with microPET imaging in the three xenograft tumor models in mice (n = 3/group) with static scans at various time points (0.5–3 d). The accumulation of 86Y-CHX-A''-DTPA-panitumumab was clearly visible in all the tumors at 1–3 d after injection. Co-injection of panitumumab inhibited accumulation of radioactivity in the tumors. There was a good correlation (r2 = 0.87) between the tracer accumulation in the tumors measured with microPET and that measured with ex vivo biodistribution studies.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

Intramural Research Program

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