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European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 3/2013

01-02-2013 | Original Article

[99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours

Authors: Anna Orlova, Camilla Hofström, Joanna Strand, Zohreh Varasteh, Mattias Sandstrom, Karl Andersson, Vladimir Tolmachev, Torbjörn Gräslund

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2013

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Abstract

Purpose

Radionuclide imaging of insulin-like growth factor type 1 receptor (IGF-1R) expression in tumours might be used for selection of patients who would benefit from IGF-1R-targeted therapy. We have previously shown the feasibility of IGF-1R imaging using the Affibody molecule 111In-DOTA-His6-ZIGF1R:4551. The use of 99mTc instead of 111In should improve sensitivity and resolution of imaging, and reduce the dose burden to patients. We hypothesized that inclusion of a HEHEHE tag instead of a His6 tag in ZIGF1R:4551 would permit its convenient purification using IMAC, enable labelling with [99mTc(CO)3]+, and improve its biodistribution.

Methods

ZIGF1R:4551 was expressed with a HEHEHE tag in the N terminus. The resulting (HE)3-ZIGF1R:4551 construct was labelled with [99mTc(CO)3]+. Targeting of IGF-1R-expressing cells using [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 was evaluated in vitro and in vivo.

Results

(HE)3-ZIGF1R:4551 was stably labelled with 99mTc with preserved specific binding to IGF-1R-expressing DU-145 prostate cancer cells in vitro. In mice, [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 accumulated in IGF-1R-expressing organs (pancreas, stomach, lung and salivary gland). [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 demonstrated 3.6-fold lower accumulation in the liver and spleen than 111In-DOTA-ZIGF1R:4551. In NMRI nu/nu mice with DU-145 prostate cancer xenografts, the tumour uptake was 1.32 ± 0.11 %ID/g and the tumour-to-blood ratio was 4.4 ± 0.3 at 8 h after injection. The xenografts were visualized using a gamma camera 6 h after injection.

Conclusion

99mTc(CO)3]+-(HE)3-ZIGF1R:4551 is a promising candidate for visualization of IGF-1R expression in malignant tumours.
Literature
1.
Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.PubMedCrossRef
2.
Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65:11118–28.PubMedCrossRef
3.
Wu JD, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P, et al. Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors. Clin Cancer Res. 2006;12:6153–60.PubMedCrossRef
4.
Thomas F, Holly JM, Persad R, Bahl A, Perks CM. Fibronectin confers survival against chemotherapeutic agents but not against radiotherapy in DU145 prostate cancer cells: involvement of the insulin like growth factor-1 receptor. Prostate. 2010;70:856–65.PubMed
5.
Harris LN, You F, Schnitt SJ, Witkiewicz A, Lu X, Sgroi D, et al. Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res. 2007;13:1198–207.PubMedCrossRef
6.
Bruchim I, Attias Z, Werner H. Targeting the IGF1 axis in cancer proliferation. Expert Opin Ther Targets. 2009;13:1179–92.PubMedCrossRef
7.
Weroha SJ, Haluska P. IGF-1 receptor inhibitors in clinical trials – early lessons. J Mammary Gland Biol Neoplasia. 2008;13:471–83.PubMedCrossRef
8.
Rosenzweig SA, Atreya HS. Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem Pharmacol. 2010;80:1115–24.PubMedCrossRef
9.
Chi KN, Bjartell A, Dearnaley D, Saad F, Schröder FH, Sternberg C, et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment targets. Eur Urol. 2009;56:594–605.PubMedCrossRef
10.
Antonarakis ES, Carducci MA, Eisenberger MA. Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Cancer Lett. 2010;291:1–13.PubMedCrossRef
11.
Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele KP, Chawla SP, et al. R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol. 2011;29:4541–7.PubMedCrossRef
12.
Ramalingam SS, Spigel DR, Chen D, Steins MB, Engelman JA, Schneider CP, et al. Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer. J Clin Oncol. 2011;29:4574–80.PubMedCrossRef
13.
Juergens H, Daw NC, Geoerger B, Ferrari S, Villarroel M, Aerts I, et al. Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol. 2011;29:4534–40.PubMedCrossRef
14.
Huang F, Greer A, Hurlburt W, Han X, Hafezi R, Wittenberg GM, et al. The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. Cancer Res. 2009;69:161–70.PubMedCrossRef
15.
Gualberto A, Melvin CL, Dean A, Ang AL, Reynolds JM, Lee AV, et al. Characterization of NSCLC patients responding to anti-IGF-IR therapy. J Clin Oncol. 2008;26 Suppl:abstract 8000.
16.
Fleuren ED, Versleijen-Jonkers YM, van de Luijtgaarden AC, Molkenboer-Kuenen JD, Heskamp S, Roeffen MH, et al. Predicting IGF-1R therapy response in bone sarcomas: immuno-SPECT imaging with radiolabeled R1507. Clin Cancer Res. 2011;17:7693–703.PubMedCrossRef
17.
Cornelissen B, McLarty K, Kersemans V, Reilly RM. The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of (111)In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin). Nucl Med Biol. 2008;35:645–53.PubMedCrossRef
18.
Cao L, Yu Y, Darko I, Currier D, Mayeenuddin LH, Wan X, et al. Addiction to elevated insulin-like growth factor I receptor and initial modulation of the AKT pathway define the responsiveness of rhabdomyosarcoma to the targeting antibody. Cancer Res. 2008;68:8039–48.PubMedCrossRef
19.
Zha J, O’Brien C, Savage H, Huw LY, Zhong F, Berry L, et al. Molecular predictors of response to a humanized anti-insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer. Mol Cancer Ther. 2009;8:2110–21.PubMedCrossRef
20.
Ahlgren S, Tolmachev V. Radionuclide molecular imaging using Affibody molecules. Curr Pharm Biotechnol. 2010;11:581–9.PubMedCrossRef
21.
Baum RP, Prasad V, Müller D, Schuchardt C, Orlova A, Wennborg A, et al. Molecular imaging of HER2-expressing malignant tumors in breast cancer patients using synthetic 111In- or 68Ga-labeled affibody molecules. J Nucl Med. 2010;51:892–7.PubMedCrossRef
22.
Tolmachev V, Malmberg J, Hofström C, Abrahmsén L, Bergman T, Sjöberg A, et al. Imaging of IGF-1R in prostate cancer xenografts using the Affibody molecule 111In-DOTA-Z IGF1R:4551. J Nucl Med. 2012;53:146–53.PubMedCrossRef
23.
Tolmachev V, Hofström C, Malmbeg J, Ahlgren S, Hosseinimehr SJ, Sandström M, et al. HEHEHE-tagged affibody molecule may be purified by IMAC, is conveniently labeled with [99(m)Tc(CO)3](+), and shows improved biodistribution with reduced hepatic radioactivity accumulation. Bioconjug Chem. 2010;21:2013–22.PubMedCrossRef
24.
Hofström C, Orlova A, Altai M, Wångsell F, Gräslund T, Tolmachev V. The use of a HEHEHE-purification tag improves biodistribution of Affibody molecules site-specifically labeled with 99mTc, 111In and 125I compared to a hexahistidine-tag. J Med Chem. 2011;54:3817–26.PubMedCrossRef
25.
Lundberg E, Höidén-Guthenberg I, Larsson B, Uhlén M, Gräslund T. Site-specifically conjugated anti-HER2 Affibody molecules as one-step reagents for target expression analyses on cells and xenograft samples. J Immunol Methods. 2007;319:53–63.PubMedCrossRef
26.
Björkelund H, Gedda L, Barta P, Malmqvist M, Andersson K. Gefitinib induces epidermal growth factor receptor dimers which alters the interaction characteristics with 125I-EGF. PLoS One. 2011;6:e24739.PubMedCrossRef
27.
Orlova A, Nilsson FY, Wikman M, Widström C, Ståhl S, Carlsson J, et al. Comparative in vivo evaluation of technetium and iodine labels on an anti-HER2 affibody for single-photon imaging of HER2 expression in tumors. J Nucl Med. 2006;47:512–9.PubMed
28.
Olmos D, Martins AS, Jones RL, Alam S, Scurr M, Judson IR. Targeting the insulin-like growth factor 1 receptor in Ewing’s sarcoma: reality and expectations. Sarcoma. 2011;2011:402508.PubMedCrossRef
29.
Huang F, Hurlburt W, Greer A, Reeves KA, Hillerman S, Chang H, et al. Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res. 2010;70:7221–31.PubMedCrossRef
30.
van Dongen GA, Visser GW, Lub-de Hooge MN, de Vries EG, Perk LR. Immuno-PET: a navigator in monoclonal antibody development and applications. Oncologist. 2007;12:1379–89.PubMedCrossRef
31.
Heskamp S, van Laarhoven HW, Molkenboer-Kuenen JD, Franssen GM, Versleijen-Jonkers YM, Oyen WJ, et al. ImmunoSPECT and immunoPET of IGF-1R expression with the radiolabeled antibody R1507 in a triple-negative breast cancer model. J Nucl Med. 2010;51:1565–72.PubMedCrossRef
32.
Wållberg H, Orlova A, Altai M, Hosseinimehr SJ, Widström C, Malmberg J, et al. Molecular design and optimization of 99mTc-labeled recombinant affibody molecules improves their biodistribution and imaging properties. J Nucl Med. 2011;52:461–9.PubMedCrossRef
33.
Wållberg H, Löfdahl PK, Tschapalda K, Uhlén M, Tolmachev V, Nygren PK, et al. Affinity recovery of eight HER2-binding affibody variants using an anti-idiotypic affibody molecule as capture ligand. Protein Expr Purif. 2011;76:127–35.PubMedCrossRef
34.
Lindberg H, Hofström C, Altai M, Honorvar H, Wållberg H, Orlova A, et al. Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for (99m)Tc-labelling at the C terminus. Tumour Biol. 2012;33:641–51.PubMedCrossRef
35.
Surinya KH, Forbes BE, Occhiodoro F, Booker GW, Francis GL, Siddle K, et al. An investigation of the ligand binding properties and negative cooperativity of soluble insulin-like growth factor receptors. J Biol Chem. 2008;283:5355–63.PubMedCrossRef
36.
Tolmachev V, Orlova A. Influence of labelling methods on biodistribution and imaging properties of radiolabelled peptides for visualisation of molecular therapeutic targets. Curr Med Chem. 2010;17:2636–55.PubMedCrossRef
37.
Li J, Lundberg E, Vernet E, Larsson B, Höidén-Guthenberg I, Gräslund T. Selection of affibody molecules to the ligand-binding site of the insulin-like growth factor-1 receptor. Biotechnol Appl Biochem. 2010;55:99–109.PubMedCrossRef
Metadata
Title
[99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours
Authors
Anna Orlova
Camilla Hofström
Joanna Strand
Zohreh Varasteh
Mattias Sandstrom
Karl Andersson
Vladimir Tolmachev
Torbjörn Gräslund
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2013
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-012-2284-8

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