Universität zu Köln

Liewen, Heike ORCID: 0000-0002-6161-4749, Markuly, Norbert, Laeubli, Heinz, Liu, Yang, Matter, Matthias S., Liewen, Nora, Renner, Christoph, Zippelius, Alfred and Stenner, Frank ORCID: 0000-0003-4541-8817 (2019). 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). Target. Oncol., 14 (5). S. 577 - 591. DORDRECHT: SPRINGER. ISSN 1776-260X

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Liewen, Heike UNSPECIFIED orcid.org/0000-0002-6161-4749 UNSPECIFIED Markuly, Norbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Laeubli, Heinz UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Yang UNSPECIFIED UNSPECIFIED UNSPECIFIED Matter, Matthias S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Liewen, Nora UNSPECIFIED UNSPECIFIED UNSPECIFIED Renner, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Zippelius, Alfred UNSPECIFIED UNSPECIFIED UNSPECIFIED Stenner, Frank UNSPECIFIED orcid.org/0000-0003-4541-8817 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-132361
DOI:	10.1007/s11523-019-00667-z
Journal or Publication Title:	Target. Oncol.
Volume:	14
Number:	5
Page Range:	S. 577 - 591
Date:	2019
Publisher:	SPRINGER
Place of Publication:	DORDRECHT
ISSN:	1776-260X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPITHELIAL-MESENCHYMAL TRANSITION; HEPATOCELLULAR-CARCINOMA CELLS; PROSTATE-CANCER; SERUM MARKER; EXPRESSION; GP73; PROGRESSION; TECHNOLOGY; METASTASIS; BIOMARKER Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13236