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Therapeutic Targeting of Golgi Phosphoprotein 2 (GOLPH2) with Armed Antibodies: A Preclinical Study of Anti-GOLPH2 Antibody Drug Conjugates in Lung and Colorectal Cancer Models of Patient Derived Xenografts (PDX)

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Abstract

Background

Golgi phosphoprotein 2 (GOLPH2) has been shown to be involved in chronic inflammatory processes and carcinogenesis. GOLPH2 is prominently overexpressed in hepatocellular carcinoma, melanoma, glioblastoma, prostate, lung, and colorectal cancer. With a low and tightly regulated expression in non-malignant tissues, GOLPH2 has been proposed as an attractive target for cancer therapy. However, GOLPH2 is predominantly located intracellularly and when situated outside of the cell it is proteolytically cleaved and shed from the cell surface. Until now, GOLPH2 has been regarded as an “undruggable” target.

Objective

We sought to create antibodies that specifically bind to GOLPH2 overexpressing tumor cells.

Patients and Methods

Antibodies binding to membranous GOLPH2 despite shedding of the protein were generated from a scFV library screening. These antibodies target the part of GOLPH2 that remains at the cell surface after proteolytic cleavage. These antibodies were then tested in vitro and in vivo.

Results

Two candidates (G2-1 and G2-2) showed target specific binding in vitro. Utilizing a tumor array (n = 128 tumors) with G2-2 and a reference antibody, a GOLPH2 expression scoring system was established. Rapid internalization of the antibodies was noted so this was exploited to deliver a toxic payload of pyrrolobenzodiazepine (PBD). In two patient-derived xenograft (PDX)-models, colorectal and lung cancer, the G2-2 antibody drug conjugate (ADC) displayed high efficacy with significant tumor responses (P = 0.001; P = 0.013) and improved survival (P = 0.0001; P = 0.0011) compared with controls.

Conclusions

Treatment with GOLPH2-directed antibodies induces durable responses in colorectal and lung cancer models. With a robust companion assay for GOLPH2 positivity at hand our findings prepare for the translation into a clinical trial.

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Abbreviations

RTK:

Receptor tyrosine kinase

GOLPH2:

Golgi Phosphoprotein 2

mABs:

Monoclonal antibodies

ADC:

Antibody drug conjugate

FACS:

Fluorescence activated cell sorting

IHC:

Immunohistochemistry

IF:

Immunofluorescence

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Acknowledgements

The authors thank the team at Cureab and the Cancer Immunology Laboratory Basel staff for their contributions.

Author information

Authors and Affiliations

  1. Medical Oncology, University Hospital Basel & Laboratory Cancer Immunology, Department Biomedicine, University Basel, Petersgraben 4, 4031, Basel, Switzerland

    Heinz Läubli, Yang Liu, Christoph Renner, Alfred Zippelius & Frank Stenner

  2. Cureab GmbH, Benkenstrasse 254c, Technologiezentrum, 4108, Witterswil, Switzerland

    Heike Liewen & Norbert Markuly

  3. Institute of Pathology, University Hospital Basel, 4031, Basel, Switzerland

    Matthias S. Matter

  4. University of Cologne, Albertus-Magnus-Platz, 50923, Cologne, Germany

    Nora Liewen

Authors
  1. Heike Liewen
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Corresponding author

Correspondence to Frank Stenner.

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Ethical approval

All applicable international and institutional guidelines for the care and use of animals were followed.

Funding

This study was funded by Cureab GmbH.

Conflict of interest

Authors HL and NM own stocks in Cureab GmbH. Author FS is on the advisory board of Cureab GmbH. CR has given uncompensated advice to Cureab GmbH. Authors HLae, YL, MM, NL, CR, and AZ declare that they have no conflicts of interest that might be relevant to the contents of this article.

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Liewen, H., Markuly, N., Läubli, H. et al. Therapeutic Targeting of Golgi Phosphoprotein 2 (GOLPH2) with Armed Antibodies: A Preclinical Study of Anti-GOLPH2 Antibody Drug Conjugates in Lung and Colorectal Cancer Models of Patient Derived Xenografts (PDX). Targ Oncol 14, 577–590 (2019). https://doi.org/10.1007/s11523-019-00667-z

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  • DOI: https://doi.org/10.1007/s11523-019-00667-z

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