Oncotarget

Research Papers:

Combining expression of GPC3 in tumors and CD16 on NK cells from peripheral blood to identify patients responding to codrituzumab

Gong Chen, Ya-Chi Chen, Bernhard Reis, Anton Belousov, Lori Jukofsky, Christine Rossin, Axel Muehlig, Chao Xu, Laurent Essioux, Toshihiko Ohtomo, Laura Di Laurenzio, Oscar Puig and Ray Lee _

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Oncotarget. 2018; 9:10436-10444. https://doi.org/10.18632/oncotarget.23830

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Abstract

Gong Chen1,*, Ya-Chi Chen1,*, Bernhard Reis2, Anton Belousov3, Lori Jukofsky1, Christine Rossin1, Axel Muehlig1, Chao Xu1, Laurent Essioux2, Toshihiko Ohtomo4, Laura Di Laurenzio1, Oscar Puig1 and Ray Lee1

1Roche Pharmaceutical Research and Early Development, Roche Innovation Center New York, New York, NY, USA

2Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

3Roche Pharmaceutical Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany

4Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

*These authors contributed equally to this work

Correspondence to:

Ray Lee, email: ruey-min.lee@roche.com

Keywords: hepatocellular carcinoma; antibody-dependent cellular cytotoxicity (ADCC); NK cell; GC33 monoclonal antibody; predictive biomarker

Received: January 11, 2017     Accepted: December 27, 2017     Published: January 02, 2018

ABSTRACT

Background: Codrituzumab, a monoclonal antibody targeting an oncofetal protein glypican-3 (GPC3) expressed on cell surface of hepatocellular carcinoma (HCC) induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits tumor growth in preclinical studies. Based on this mechanism, tumor GPC3 expression and CD16 expression on NK cells, which are the effector cells of ADCC, were investigated to correlate with codrituzumab’s clinical efficacy in patients with advanced HCC.

Results: Joint analyses of the two biomarkers revealed that both high levels of GPC3 and CD16 were required for patients to benefit from codrituzumab; lack of either one of them would lead to a loss of the therapeutic effect.

Conclusions: These results suggest the combination of tumor GPC3 expression and CD16 expression on NK cells from peripheral blood at baseline as a composite biomarker to select HCC patients for codrituzumab.

Impact: The conclusion warrants a future study in an HCC population with both high GPC3 expression and high levels of CD16 at baseline to establish codrituzumab’s therapeutic benefit in HCC.

Methods: Data from a phase II clinical trial of codrituzumab were used for the analyses. GPC3 expression in baseline tumor biopsies was determined by immunohistochemistry (IHC) analysis, and baseline CD16 expression on NK cells were quantified by peripheral blood lymphocyte immunophenotyping. According to high or low expression of GPC3 and CD16, different patient subgroups were formed; for each subgroup, overall survival of patients having high codrituzumab exposure was compared to that of patients receiving placebo.


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