89Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I

Chekol, Rufael; Solomon, V. Raja; Alizadeh, Elahe; Bernhard, Wendy; Fisher, Darrell R.; Hill, Wayne; Barreto, Kris; DeCoteau, John F.; Parada, Ángel Casacó; Geyer, C. Ronald; Fonge, Humphrey

doi:10.18632/oncotarget.24965

Cited by 31 publications

(33 citation statements)

References 22 publications

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“…Recently, zirconium-89 labeled antibodies nimotuzumab [25], imgatuzumab [26], and panitumumab [27,28], and affibody ZEGFR:2377 [29] were investigated for use in imaging EGFR expression in vivo in addition to [ 89 Zr]Zrcetuximab [30]. All these studies established EGFR as a promising and robust target for immunoPET imaging and targeted radiotherapeutics [31].…”

Section: Discussionmentioning

confidence: 99%

Cetuximab PET delineated changes in cellular distribution of EGFR upon dasatinib treatment in triple negative breast cancer

et al. 2020

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Background: At least 50% of triple negative breast cancer (TNBC) overexpress the epidermal growth factor receptor, EGFR, which paved the way for clinical trials investigating its blockade. Outcomes remained dismal stemming from mechanisms of resistance particularly the nuclear cycling of EGFR, which is enhanced by Src activation. Attenuation of Src reversed nuclear translocation, restoring EGFR to the cell surface. Herein, we hypothesize that changes in cellular distribution of EGFR upon Src inhibition with dasatinib can be annotated through the EGFR immunopositron emission tomography (immunoPET) radiotracer, [ 89 Zr]Zr-cetuximab. Methods: Nuclear and non-nuclear EGFR levels of dasatinib-treated vs. untreated MDA-MB-231 and MDA-MB-468 cells were analyzed via immunoblots. Both treated and untreated cells were exposed to [ 89 Zr]Zr-cetuximab to assess binding at 4°C and 37°C. EGFR-positive MDA-MB-231, MDA-MB-468, and a patient-derived xenograft were treated with dasatinib or vehicle followed by cetuximab PET imaging to compare EGFR levels. After imaging, the treated mice were separated into two groups: one cohort continued with dasatinib with the addition of cetuximab while the other cohort received dasatinib alone. Correlations between the radiotracer uptake vs. changes in tumor growth and EGFR expression from immunoblots were analyzed.Results: Treated cells displayed higher binding of [ 89 Zr]Zr-cetuximab to the cell membrane at 4°C and with greater internalized activity at 37°C vs. untreated cells. In all tumor models, higher accumulation of the radiotracer in dasatinib-treated groups was observed compared to untreated tumors. Treated tumors displayed significantly decreased pSrc (Y416) with retained total Src levels compared to control. In MDA-MB-468 and PDX tumors, the analysis of cetuximab PET vs. changes in tumor volume showed an inverse relationship where high tracer uptake in the tumor demonstrated minimal tumor volume progression. Furthermore, combined cetuximab and dasatinib treatment showed better tumor regression compared to control and dasatinib-only-treated groups. No benefit was achieved in MDA-MB-231 xenografts with the addition of cetuximab, likely due to its KRAS-mutated status.Conclusions: Cetuximab PET can monitor effects of dasatinib on EGFR cellular distribution and potentially inform treatment response in wild-type KRAS TNBC.

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Section: Discussionmentioning

confidence: 99%

Cetuximab PET delineated changes in cellular distribution of EGFR upon dasatinib treatment in triple negative breast cancer

et al. 2020

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“…Subjecting humans to radioactive zirconium-89 ( 89 Zirconium)-labeled monoclonal antibodies has been medically validated. This is performed by applying nimotuzumab, which shows a strong affinity to the epidermal growth factor receptor (EGFR) [ 27 ], which is markedly often present in head and neck carcinomas [ 28 ]. Another agent that is applied is pertuzumab with an affinity to human epidermal growth factor receptor 2 (HER2), which occurs in HER2-positive breast cancer [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-Müllerian Hormone Type II Receptor Expression in Endometrial Cancer Tissue

Gowkielewicz

Lipka

Majewska

et al. 2020

Cells

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Anti-Müllerian hormone (AMH) is responsible for the Müllerian ducts’ regression in male fetuses. In cells of cancers with AMH receptors (AMHRII), AMH induces cell cycle arrest or apoptosis. As AMH occurs naturally and does not exhibit significant side effects while reducing neoplastic cell colonies, it can be considered as a potential therapeutic agent for cancer treatment. The purpose of this study was to assess the AMHRII expression in endometrial cancer (EC) in correlation to various demographic data and clinical conditions. Immunohistochemical analysis was used to assess AMHRII expression in EC tissue samples retrieved from 230 women with pre-cancerous state of endometrium (PCS) and EC. AMHRII was detected in 100% of samples. No statistical difference was observed for AMHRII expression depending on the histopathological type of EC, cancer staging, body mass index, and age, as well as the number of years of menstruation, births and miscarriages, and average and total breastfeeding time. Diabetes mellitus type 2 is the only factor that has an impact on AMHRII expression in EC tissue. Thus, this study supports the idea of theoretical use of AMH in EC treatment because all histopathological types of EC at all stages of advancement present receptors for AMH.

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“…Conjugation of 8709-scFv-Fc (domain I/II binder) was performed as reported earlier [ 19 ]. The excess unreacted chelator was removed by centrifugation using an Amicon Ultra-10 K (Burlington, MA, USA) molecular filtration device.…”

Section: Methodsmentioning

confidence: 99%

89Zr-Labeled Domain II-Specific scFv-Fc ImmunoPET Probe for Imaging Epidermal Growth Factor Receptor In Vivo

Alizadeh

Ahmed

Solomon

et al. 2021

Cancers

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Epidermal growth factor receptor I (EGFR) is overexpressed in many cancers. The extracellular domain of EGFR has four binding epitopes (domains I- IV). All clinically approved anti-EGFR antibodies bind to domain III. Imaging agents that bind to domains other than domain III of EGFR are needed for accurate quantification of EGFR, patient selection for anti-EGFR therapeutics and monitoring of response to therapies. We recently developed a domain II-specific antibody fragment 8709. In this study, we have evaluated the in vitro and in vivo properties of 89Zr-8709-scFv-Fc (105 kDa). We conjugated 8709-scFv-Fc with the deferoxamine (DFO) chelator and radiolabeled the DFO-8970-scFv with 89Zr. We evaluated the binding of 89Zr-DFO-8709-scFv-Fc in EGFR positive and negative cell lines DLD-1, MDA-MB-231 and MDA-MB-435, respectively, and in mouse xenograft models. Simultaneously, we have compared the binding of 89Zr-8709-scFv-Fc with 111In-nimotuzumab, a domain III anti-EGFR antibody. DFO-8709-scFv-Fc displayed similar cell binding specificity as 8709-scFv-Fc. Saturation cell binding assay and immunoreactive fraction showed that radiolabeling did not alter the binding of 8709-scFv-Fc. Biodistribution and microPET showed good uptake of 89Zr-8709-scFv-Fc in xenografts after 120 h post injection (p.i). and was domain-specific to EGFR domain II. 89Zr-8709-scFv-Fc did not compete for binding in vitro and in vivo with a known domain III binder nimotuzumab. The results show that 89Zr-8709-scFv-Fc is specific to domain II of EGFR making it favorable for quantification of EGFR in vivo, hence, patient selection and monitoring of response to treatment with anti-EGFR antibodies.

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89Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I

Cited by 31 publications

References 22 publications

Cetuximab PET delineated changes in cellular distribution of EGFR upon dasatinib treatment in triple negative breast cancer

Cetuximab PET delineated changes in cellular distribution of EGFR upon dasatinib treatment in triple negative breast cancer

Anti-Müllerian Hormone Type II Receptor Expression in Endometrial Cancer Tissue

89Zr-Labeled Domain II-Specific scFv-Fc ImmunoPET Probe for Imaging Epidermal Growth Factor Receptor In Vivo

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