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TA-MUC1 as detected by the fully humanized, therapeutic antibody Gatipotzumab predicts poor prognosis in cervical cancer

Abstract

Background

Gatipotuzumab is a fully humanized antibody which was designed to detect a cancer-specific glyco-modification of MUC1 (termed ‘TA-MUC1’) and which was optimized to effectively trigger antibody-dependent-cell-mediated cytotoxicity (ADCC) in cancer cells. Clinical trials investigating therapeutic efficacy of this antibody have been published recently. The current analysis aimed to determine whether TA-MUC1—as detected by Gatipotuzumab—is expressed in cervical cancer tissue and whether binding of Gatipotuzumab is associated with clinico-pathological variables including recurrence free (RFS) and overall survival (OS).

Methods

Cervical cancer tissue (n = 250) was stained for TA-MUC1 using Gatipotuzumab employing a standardized immunohistochemistry protocol. Staining was scored by applying the IR-score. Results were binarized and tested for association to clinico-pathological parameters.

Results

TA-MUC1 as stained by Gatipotuzumab was detected in 188 (75.2%) out of the 250 cervical cancer cases investigated. Expression of TA-MUC1 was restricted to cancer cells and was positively correlated with viral oncoprotein E6. Membrane staining of TA-MUC1 predicted significantly reduced RFS and OS. Importantly, expression of TA-MUC1 at the cell surface identified a group of early stage cervical cancer patients with exceptional short RFS and OS.

Conclusions

We report TA-MUC1—the antigen detected by Gatipotzumab—to be widely expressed in cervical cancer tissue and to localize to the cell membrane. The latter is seen as a pre-requisite to target this epitope by antibody-drug conjugates or antibodies eliciting ADCC. Since especially, membrane localization of TA-MUC1 predicted poor prognosis, evaluating Gatipotuzumab for its therapeutic efficacy in cervical cancer may turn attractive.

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Abbreviations

ADCC:

Antibody-dependent-cell-mediated cytotoxicity

ADC:

Antibody-drug conjugate

AdenoCA:

Cervical adenocarcinoma

DAB:

3,3′-Diaminobenzidin

FFPE:

Formalin-fixed paraffin-embedded

IRS:

Immunoreactive score

OS:

Overall survival

REMARK:

Reporting recommendations for tumour marker prognostic studies

RFS:

Recurrence free survival

SCC:

Squamous cell cervical cancer

TA-MUC1:

Tumour-associated mucin-1

WHO:

World Health Organization

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Acknowledgements

The authors thank Irmgard Wiest for her excellent technical assistance. We would further like to acknowledge Jutta Engel and Max Wiedemann for their help with collecting follow-up data from the Munich Cancer Registry.

Funding

This project financed by the Department of Gynaecology and Obstetrics, Ludwig-Maximilians-University, Munich, Germany. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

SH participated in the design and coordination of the study, performed the statistical analysis, and drafted the manuscript. KF participated in the design and coordination of the study and significantly contributed to experimental analysis. BK participated in the selection of cases and carefully reviewed the manuscript for important intellectual content. FM carefully reviewed the manuscript for important intellectual content. CK significantly contributed to experimental analysis. SM carefully reviewed the manuscript for important intellectual content. CD carefully reviewed the manuscript for important intellectual content. DM supervised immunohistochemistry and participated in IHC scoring as a gynaecologic pathologist. UJ is one of the principal investigators of the study. UJ participated in the design, statistical analysis, and coordination of the study, provided funding, participated in the selection and validation of cases, and reviewed the manuscript. AV participated in the selection and validation of cases and reviewed the manuscript.

Correspondence to Sabine Heublein.

Ethics declarations

Ethics approval

The tissue samples used for this retrospective study had originally been collected for routine diagnostics at the time the patient had been treated at our institution (1993–2002). Since, meanwhile, all diagnostic procedures have already been fully completed, tissue samples have been classified as surplus material. FFPE material was retrieved from the archive of the Department of Gynaecology and Obstetrics, Ludwig-Maximilians-University, Munich, Germany and underwent irreversible anonymisation. The study was approved by the Ethics Committee of the Ludwig-Maximilians-University (approval number 259-16, 2016), and was performed according to the standards set in the declaration of Helsinki 1975. All researchers were blinded from patient data during experimental analysis.

Consent for publication

As per declaration of the local ethics committee [Ludwig-Maximilians-University Medical School (Munich, Germany)], no written informed consent of the participants is needed given the circumstances described above.

Availability of data and material

The data sets used and/or analysed during the current study available from the corresponding author on reasonable request.

Conflict of interest

The authors have no competing interests to declare.

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Heublein, S., Friese, K., Kost, B. et al. TA-MUC1 as detected by the fully humanized, therapeutic antibody Gatipotzumab predicts poor prognosis in cervical cancer. J Cancer Res Clin Oncol 144, 1899–1907 (2018). https://doi.org/10.1007/s00432-018-2706-5

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Keywords

  • MUC1
  • Gatipotuzumab
  • PankoMabGEX
  • Cervical cancer
  • Prognosis