Preparation and preclinical evaluation of 177Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors

doi:10.1016/j.nucmedbio.2011.07.001

Nuclear Medicine and Biology

Volume 39, Issue 1, January 2012, Pages 3-13

https://doi.org/10.1016/j.nucmedbio.2011.07.001 Get rights and content

Abstract

Objectives

Nimotuzumab (h-R3) is a humanized monoclonal antibody (mAb) which recognizes the external domain of the epidermal growth factor receptor (EGFR) with high specificity. It was demonstrated that h-R3 has a unique clinical profile for immunotherapy of adult gliomas and pediatric pontine gliomas. The aim of this work was to evaluate the conjugate ¹⁷⁷Lu-h-R3 as a potential radioimmunoconjugate for radioimmunotherapy (RIT) of tumors overexpressing EGFR.

Methods

h-R3 was modified with the macrocylcic ligand S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA) and the acyclic ligand S-2-(4-Isothiocyanatobenzyl)-diethylenetriamine pentaacetic acid (p-SCN-Bn-DTPA); the immunoconjugates were labeled with no-carried added ¹⁷⁷Lu. Specificity and affinity were tested using radioimmunoassays in a cell line overexpressing EGFR. Biodistribution in mice, healthy or bearing A431 epithelial carcinoma xenografts, was performed for 11 days. Tumor uptake, the influence of the nature of the chelate and the way of administration were studied. Absorbed dose in tumor and selected organs was calculated using the OLINDA/EXM software; the data from the animals was extrapolated to humans.

Results

¹⁷⁷Lu-h-R3 conjugates were obtained with specific activity up to 915 MBq/mg without significant loss of immunoreactivity. The binding of ¹⁷⁷Lu-h-R3 conjugates to A431 cells showed to be EGFR specific, and the affinity was similar to native h-R3. Tumor uptake reached a maximum value of 22.4±3.1 %ID/g at 72 h and remained ∼20% ID/g over 1 week. Locoregional application showed better tumor/nontumor ratios than intravenous application.

Conclusions

¹⁷⁷Lu-h-R3 should be considered for further evaluations as a potential radiopharmaceutical for RIT of tumors overexpressing EGFR.

Introduction

Radioimmunotherapy (RIT) is a therapeutic modality that involves the use of monoclonal antibodies (mAb) to deliver the energy of beta- or alpha particles to targeted cells. Even when this technique is approved, it is still in the early stages of development [1]. Relevant results have been obtained in the treatment of refractory non-Hodgkin's lymphoma (NHL) employing ibritumomab tiuxetan (Zevalin) and/or iodine (¹³¹I) tositumomab (Bexxar), the first radioimmunoconjugates (RIC) approved by the US Food and Drug Administration (FDA) in 2002 and 2003, respectively. Nevertheless, the treatment of solid tumors using this modality remains to be thoroughly investigated. Discrete advances have been achieved in the treatment of minimal residual disease, locoregional applications, pretargeted RIT and as a combination of therapies [2], [3].

Epidermal growth factor receptor (EGFR) is a target of anticancer therapies due to its overexpression in a variety of malignant epithelial tumors and it is associated with a poor prognosis [4], [5]. In fibroblasts cells, the expression of EGFR ranges from 40,000 to 100,000 receptors per cell [6], [7]. In contrast, EGFR is overexpressed in the majority of solid tumors, including breast and ovarian cancer, colon cancer, head-and-neck cancer and non–small cell lung cancer (NSCLC), with some breast cancers expressing up to 2×10⁶ EGFR receptors per cell [8]. Several approaches have been used to inhibit the EGFR-associated signal transduction cascade. Monoclonal antibodies bound to a specific region of EGFR have been successfully used to inhibit its dimerization and autophosphorylation [5], [9], [10].

Nimotuzumab (TheraCIM, CIMher, Theraloc) is a humanized mAb (IgG1) obtained by transplanting the complementary determining regions of the murine monoclonal antibody ior-egf/r3 to human framework which recognizes the external domain of EGFR with high specificity [11], [12]. Unlike most of the drugs against the EGFR, h-R3 does not show severe adverse effects in the clinic; for example, no serious skin rashes have been reported [13]. h-R3 has demonstrated very encouraging results in pediatric pontine (brainstem) and adult gliomas [14]. It is undergoing clinical trials in non–small cell lung cancer and a Phase II monotherapy trial in Europe in patients with advanced metastatic pancreatic cancer [15]. ¹⁸⁸Re-labeled h-R3 showed promising results in a Phase I trial for the radiation treatment of gliomas via an in-dwelling catheter into the postoperative cavity following resection [16].

Beta radiation radionuclide emitters such as ¹³¹I (t_1/2=8.0 days; β⁻=0.6 MeV and Eγ=0.364 MeV) and ⁹⁰Y (t_1/2=2.67 days; β⁻=2.28 MeV) have been successfully used in RIT. Residualizing radionuclides, such as ⁹⁰Y and ¹⁷⁷Lu, are potentially more suitable radionuclides for RIT [17]. ¹⁷⁷Lu (t_1/2=6.7 days, Eγ=0.208 MeV, β⁻=0.497 MeV, max range in tissue penetration=2.0 mm) is being strongly considered for RIT since it combines the advantages of both ⁹⁰Y and ¹³¹I and the ability to form stable complexes with macrocyclic and acyclic ligands [18], [19], [20], [21]. Its half-life is appropriate for preparation, transport and successful delivery of therapeutic doses to the tumor by radioimmunoconjugates such as monoclonal antibodies. In addition, ¹⁷⁷Lu emits two low-energy γ lines with energy of 113 and 208 keV that are suitable for imaging and assessment of delivered doses.

The aim of this work was to evaluate the RIC ¹⁷⁷Lu-nimotuzumab (¹⁷⁷Lu-h-R3), in a model of human epithelial carcinoma, as a potential radioimmunoconjugate for RIT of tumors overexpressing EGFR. The effects of the nature of the bifunctional chelate used for ¹⁷⁷Lu labeling and the administration approach, intravenous vs. locoregional, were also studied.

Section snippets

Reagents and equipment

¹⁷⁷Lu no-carrier added (nca in 0.05 mol/L HCl), produced indirectly via the ¹⁷⁶Yb(n,γ)¹⁷⁷Yb→(β⁻)→¹⁷⁷Lu reaction, was generously donated by Isotope Technologies Garching (ITG, Munich, Germany). ⁹⁰YCl₃ (555 MBq in 22 μl of 0.05 M HCl) was purchased from PerkinElmer. Bifunctional chelators, p-SCN-Bn-DOTA and p-SCN-Bn-DTPA were purchased from Macrocyclics (Dallas, TX, USA). Nimotuzumab was purchased in 10-ml vials (5.0 mg/ml in phosphate-buffered saline) from Oncoscience AG (Wedel, Germany). Chelex

Conjugation and radiolabeling

The reaction of h-R3 with p-SCN-Bn-DOTA or p-SCN-Bn-DTPA at a molar ratio of 20:1 produced conjugates with an average of 4.1±1.3 (mean±S.D., n=5) chelating groups per protein molecule, while increasing the conjugation ratio to 50:1 for p-SCN-Bn-DOTA gave conjugates with 7.4±1.5 (mean±S.D., n=5) chelators per hR3. The concentration of conjugates ranged from 5.0 to 6.0 mg/ml as determined by Bradford assay. Immunoconjugates were successfully labeled with ¹⁷⁷Lu under relatively mild conditions.

Discussion

Even when in the early 2000s, Bexxar and Zevalin were approved by the FDA for RIT of non-Hodgkin's lymphoma with very encouraging results and a high percentage of patients entering long-term remission [26], so far no further radioimmunoconjugate has been approved for RIT of solid tumors. The above-mentioned fact has been due to physical, chemical, biological, clinical, regulatory and financial limitations that have impeded the progress of these drugs [27]. As an example, the doses shown to be

Conclusions

According to the results presented above, ¹⁷⁷Lu-DOTA-h-R3 could be obtained with high specific activity without significant loss of immunoreactivity and it specifically accumulated in EGFR overexpressing tumors. Consequently, ¹⁷⁷Lu-DOTA-h-R3 seems to have a potential for further evaluations as a radiopharmaceutical for RIT of EGFR overexpressing tumors. The results presented in this report could be of use for future preclinical and clinical studies using this radioimmunoconjugate. Further

Acknowledgments

We gratefully acknowledge Dr. Mark Harfensteller and Isotope Technologies Garching (ITG, Munich, Germany), for providing the n.c.a.¹⁷⁷Lu. The authors would like to thank Ing. Aliona Frai for her support in the animal study. We thank Lenka Maresova and Ludmila Jandova from the Department of Radiopharmacy, Institute of Nuclear Research, Husinec-Rez, Czech Republic, for outstanding support during the biodistribution studies.

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^☆: This research was supported by EUREKA Grant No. E08018 and Project NPVII 2B06165 from the Czech Ministry of Education, Youth and Sports.

^☆☆: Conflicts of interest statement: The authors declare that they have no conflicts of interest.

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Preparation and preclinical evaluation of 177Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors☆,☆☆

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Reagents and equipment

Conjugation and radiolabeling

Discussion

Conclusions

Acknowledgments

Semin Oncol

Semin Oncol

Immunotechnology

Appl Radiat Isot

Adv Drug Deliv Rev

Anal Biochem

Nucl Med Biol

Nucl Med Biol

Nucl Med Biol

Nucl Med Biol

Nucl Med Biol

Nucl Med Biol

Nucl Med Biol

Drug Discov Today

Nucl Med Biol

Nucl Med Biol

Radioimmunotherapy in non-Hodgkin lymphoma: opinions of U.S. medical oncologists and hematologists

J Nucl Med

Perspectives on cancer therapy with radiolabeled monoclonal antibodies

J Nucl Med

Immunoconjugate anticancer therapeutics

Discovery

EGFR targeting of solid tumors

Cancer Control

Epidermal growth factor

Annu Rev Biochem

Expression of epidermal growth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation

Cancer Res

Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation

Cancer Res

Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy

Clin Exp Immunol

A phase I study of 99mTc-hR3 (DiaCIM), a humanized immunoconjugate directed towards the epidermal growth factor receptor

Nucl Med Commun

Preparation and preclinical evaluation of ¹⁷⁷Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors☆,☆☆

A phase I study of ^99mTc-hR3 (DiaCIM), a humanized immunoconjugate directed towards the epidermal growth factor receptor