Extracellular domain shedding influences specific tumor uptake and organ distribution of the EGFR PET tracer 89Zr-imgatuzumab

Pool, Martin; Kol, Arjan; Hooge, Marjolijn N. Lub-de; Gerdes, Christian; Jong, Steven de; Vries, Elisabeth G.E. de; Scheltinga, Anton G.T. Terwisscha van

doi:10.18632/oncotarget.11827

Cited by 16 publications

(21 citation statements)

References 43 publications

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“…This study reports large differences in tumor [ 89 Zr]Zrcetuximab uptake within and between patients [11,12], without a relation with treatment benefit of cetuximab. Understanding factors contributing to the imaging signal is important for the interpretation of [ 89 Zr]Zr-cetuximab PET/ CT imaging results, and relevant for future immuno-PET imaging studies.…”

Section: Discussionmentioning

confidence: 78%

“…In plasma, sEGFR was assessed to evaluate its effects on [ 89 Zr]Zr-cetuximab tumor uptake, as well as PK of cetuximab and [ 89 Zr]Zr-cetuximab [12]. Soluble EGFR is the cleaved or transcribed extracellular part of EGFR and can bind cetuximab in circulation.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the primary aims of this study were to evaluate if patients without tumor uptake on [ 89 Zr]Zr-cetuximab PET/CT with standard therapeutic pre-dose would have uptake upon dose escalation, and whether uptake would relate to treatment benefit. In addition, we assessed other factors that might contribute to drug accumulation and treatment efficacy, such as intra-patient variability in PK, tumor EGFR expression [10], plasma soluble EGFR (sEGFR) concentration [12], tumor perfusion on [ 15…”

Section: Introductionmentioning

confidence: 99%

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[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

Helden

Elias

Gerritse

et al. 2019

Eur J Nucl Med Mol Imaging

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Purpose One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [ 89 Zr]Zrcetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. Patients and methods PET/CT imaging of [ 89 Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m 2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [ 89 Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. Results Visual tumor uptake on [ 89 Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m 2) was applied, potentially influencing outcome in this group. None of the second [ 89 Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [ 89 Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUV peak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. Conclusion Tumor uptake on [ 89 Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

Helden

Elias

Gerritse

et al. 2019

Eur J Nucl Med Mol Imaging

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“…Shed EGFR in the circulation derived from the xenograft A431, that expresses high levels of EGFR, was able to redirect the 89 Zr-labeled imgatuzumab to the liver at a low tracer protein dose. 24 In that study, increasing the tracer protein dose led to a reduced liver and increased tumor uptake. Although we do not have data on the levels of circulating GPC3 protein in our study, in the presence of an excess of unlabeled ERY974 liver uptake of [ 89 Zr]Zr-N-suc-Df-ERY974 was reduced.…”

Section: In Vitro Characterization Of [ 89 Zr]zr-n-suc-df-ery974 and mentioning

confidence: 86%

Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate

Waaijer

Giesen

Ishiguro³

et al. 2020

J Immunother Cancer

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BackgroundBispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibodies, like ERY974, is scarce. Here, we report the biodistribution and tumor targeting of zirconium-89 (89Zr) labeled ERY974 in mouse models using immuno-positron emission tomography (PET) imaging.MethodsTo study both the role of GPC3 and CD3 on the biodistribution of [89Zr]Zr-N-suc-Df-ERY974,89Zr-labeled control antibodies targeting CD3 and non-mammalian protein keyhole limpet hemocyanin (KLH) or KLH only were used. GPC3 dependent tumor targeting of [89Zr]Zr-N-suc-Df-ERY974 was tested in xenograft models with different levels of GPC3 expression. In addition, CD3 influence on biodistribution of [89Zr]Zr-N-suc-Df-ERY974 was evaluated by comparing biodistribution between tumor-bearing immunodeficient mice and mice reconstituted with human immune cells using microPET imaging and ex vivo biodistribution. Ex vivo autoradiography was used to study deep tissue distribution.ResultsIn tumor-bearing immunodeficient mice, [89Zr]Zr-N-suc-Df-ERY974 tumor uptake was GPC3 dependent and specific over [89Zr]Zr-N-suc-Df-KLH/CD3 and [89Zr]Zr-N-suc-Df-KLH/KLH. In mice engrafted with human immune cells, [89Zr]Zr-N-suc-Df-ERY974 specific tumor uptake was higher than in immunodeficient mice. Ex vivo autoradiography demonstrated a preferential distribution of [89Zr]Zr-N-suc-Df-ERY974 to T cell rich tumor tissue. Next to tumor, highest specific [89Zr]Zr-N-suc-Df-ERY974 uptake was observed in spleen and lymph nodes.Conclusion[89Zr]Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development.

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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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Extracellular domain shedding influences specific tumor uptake and organ distribution of the EGFR PET tracer 89Zr-imgatuzumab

Cited by 16 publications

References 43 publications

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate

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

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