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177Lu-Labeled humanized monoclonal antibody against human epidermal growth factor receptor 2

, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894, vog.hin.mln.ibcn@dacim

Created: ; Last Update: December 17, 2008.

Chemical name:177Lu-Labeled humanized monoclonal antibody against human epidermal growth factor receptor 2
Abbreviated name:[177Lu]Pertuzumab
Synonym:177Lu-labeled Omnitrag®; 177Lu-labeled rhuMAb 2C4
Agent Category:Humanized monoclonal antibody
Target:Human epidermal growth factor receptor 2 (HER2 or HrbB2/neu)
Target Category:Binding
Method of detection:Single-photon emission computed tomography (SPECT); gamma planar imaging
Source of Signal/Contrast:177Lu
  • Checkbox In vitro
  • Checkbox Rodents
Click here for the human nucleotide and protein sequence of HER2.



The human epidermal growth factor (EGF) receptor 2 (HER2 or Erb2/neu) is known to be overexpressed in cells of certain cancers and to play a key role in promoting the growth and proliferation of primary and metastasized cancer cells, particularly in breast, ovarian, and urinary bladder cancers (1-4). HER2 is a glycoprotein that belongs to the EGF receptor (EGFR or ErbB1) family (for details regarding other HER or ErbB receptors and their ligands, see Friedlander et al. and Adams et al. (5, 6)). The ErbB receptors have four domains (designated I to IV): an extracellular region, a membrane-spanning region, an intracellular tyrosine kinase (TK), and a noncatalytic domain (7). Under normal conditions the EGFR and ErbB exist as monomers, but the binding of a ligand to the extracellular domain of the receptor results in conformational changes that promote the interaction of receptor domains I and III (7, 8). This interaction between two receptor domains leads to the formation of homodimers or heterodimers of the receptor and activation of the intracellular tyrosine kinase (TK). Subsequently, a complex intracellular signaling pathway may be activated, which results in malignant transformation of cells, cancer progression and survival, possible resistance to anticancer drugs, and the formation of tumors (6). In addition, overexpression or mutations of the ErbB1 or ErbB2 receptors have also been shown to promote oncogenic transformations of cells (5).

Among the ErbB receptors, ErbB2 has been shown to be the preferred receptor for the formation of heterodimers with other ErbBs (ErbB1, ErbB3, and ErbB4) because it has an open extracellular domain confirmation that facilitates the formation of potent, mitogenic heterodimers (5). Formation of the ErbB2/ErbB3 heterodimers has been reported in breast, prostate, lung, and colorectal cancers (5, 9-12). Because ErbB receptors have been shown to have a prominent role in the development of cancers, these receptors have been targeted with different antibodies (Abs) for the molecular therapy of this disease (5). Among the various Abs directed against the EGF/ErbB receptor, trastuzumab and pertuzumab specifically bind to and inhibit ErbB2 receptor activity (5).

Trastuzumab is a humanized monoclonal antibody (MAb) that inhibits cell proliferation by binding to the extracellular domain of the ErbB2 receptor and by blocking activation of the intracellular TK; however, the exact mode by which it inhibits the TK is unknown, and several mechanisms have been proposed for its activity (5, 13). This MAb is commercially available in the United States and has been approved by the United States Food and Drug Administration for the treatment of breast cancer; some patients undergoing treatment with this MAb develop resistance against it or may experience cardiac toxicity (5). Pertuzumab is a new class of humanized MAbs against ErbB2 and is known as a receptor dimerization inhibitor. On binding to the dimerization domain of the ErbB2 receptor, pertuzumab sterically hinders receptor dimerization and inhibits the signal transduction pathway (7). It has been tested in vitro and in preclinical animal studies, and it is being evaluated in several clinical trials to treat a variety of cancers as a monotherapy or in combination with other drugs and MAbs (14-19). Pertuzumab has been labeled with radioactive lutetium (177Lu) to obtain [177Lu]pertuzumab and used for biodistribution and imaging studies in mice (20, 21).



The synthesis, development, purification, and characterization of pertuzumab have been described in detail by Adams et al. (6).

Pertuzumab was radiolabeled as described by Persson et al. (20). Briefly, the MAb was conjugated to 2-(p-isothiocyanatobenzyl)-cyclohexyl-diethylenetriamine pentaacetic acid (CHX-A DTPA) in 0.7 M borate buffer (pH 9.2) overnight at 37°C. The conjugated MAb was purified on a NAP-5 size exclusion column in sodium acetate buffer (pH 5.5) and divided into ten batches for storage (the storage conditions were not described) until required for chelation with 177Lu. Chelation was performed for 30 min at room temperature, and purity of the chelated product was checked with instant thin-layer chromatography (ITLC). Chelation efficiency of the reaction was reported to be ~90%, and the product purity was ~99%. The Rf values for the various products of the chelation reaction on ITLC analysis were not provided in the publication. The specific activity of [177Lu]pertuzumab used for the in vitro studies was reported to be 1 MBq/pmol Ab (0.027 mCi/pmol Ab). For imaging studies the specific activity of [177Lu]pertuzumab was 45 MBq/pmol Ab (1.21 mCi/pmol Ab). The stability of 177Lu chelated to pertuzumab was reported to be 96 ± 5% when stored overnight in presence of excess ethylenediaminetetraactetate. When stored in phosphate-buffered saline the stability of chelated 177Lu was 93 ± 4% at 37°C and 100% at 4°C.

In Vitro Studies: Testing in Cells and Tissues


The dissociation constant (Kd) for native pertuzumab and CHX-conjugated pertuzumab was determined with Biacore analysis using a CM5 Sensor Chip with the immobilized HER2 receptor (20). The native pertuzumab had a Kd of 2.2±0.4 nM, and the CHX-conjugated MAb had a Kd of 1.8 ± 1.1 nM. The affinity constant was determined to be 4.1 ± 0.7 nM using a saturation experiment with SKOV-3 cells exposed to [177Lu]pertuzumab. The [177Lu]pertuzumab retention in the SKOV-3 cells was 90 ± 2% after 20 h and dropped to 51 ± 3% at 90 h. Native pertuzumab was reported to block the uptake of [177Lu]pertuzumab by the SKOV-3 cells, indicating that the labeled MAb was specific for HER2 (20).

Animal Studies



The biodistribution (n = 12 animals) and imaging (n = 2 animals) characteristics of [177Lu]pertuzumab were studied in Balb/c (nu/nu) mice bearing SKOV-3 cell tumors on the right hind leg (20). For the biodistribution study the mice were euthanized 1, 3, and 7 days after administration of [177Lu]pertuzumab, and various organs (blood, heart, skin, bone, lungs, thyroid, liver, spleen, kidneys, and bladder) were harvested to determine uptake of the label. Maximum tumor uptake of the label was reported at 3 days with a tumor/blood ratio of ~6.7; this ratio increased to ~10 at day 7 primarily because the label in the blood was reduced to ~1.5% of the injected dose/gram tissue (% ID/g) from ~3% ID/g at day 3. Among all organs, the thyroid showed maximum retention of radioactivity after day 1 (8.7 ± 2.4% ID/g compared to 1–3% ID/g for other organs), which gradually decreased to ~1% ID/g, similar to the other organs, by day 7. Imaging was performed 1 day after administration of [177Lu]pertuzumab, and the radioactivity was primarily accumulated in the hind leg tumors (tumor/background ratios were 29 and 24 for the two animals, respectively).

In another study, mice (n = 9) bearing SKOV-3 tumors in the right front leg were treated with [177Lu]pertuzumab (20). To investigate specificity of the labeled MAb, of the four of nine mice were injected with an excess of unlabeled pertuzumab 30 min before the [177Lu]pertuzumab treatment. All the mice were euthanized, and the organs were harvested as detailed above to determine radioactivity accumulation in the tumors and organs. Little difference was reported in the radioactivity distribution in the various organs of the blocked and non-blocked mice. However, the tumors in the non-blocked mice showed ~4.4-fold greater accumulation of radioactivity compared with tumors from the blocked mice.

In another study, mice (n = 4/ time point) bearing SKOV-3 cell tumors were injected with [177Lu]pertuzumab and then euthanized at 8 h and 1, 3, 5, 7, and 14 d after injection (21). The tumors and various organs from the animals were harvested, and the accumulated radioactivity was determined. At 8 h after injection of [177Lu]pertuzumab, the tumor/blood ratio was 1.4, and this ratio increased to 19 after 14 days because the radioactivity decreased in the blood during this period.

Other Non-Primate Mammals


No publications are currently available.

Non-Human Primates


No publications are currently available.

Human Studies


No publications are currently available.

Supplemental Information



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