1. Academic Validation
  2. Combining expression of GPC3 in tumors and CD16 on NK cells from peripheral blood to identify patients responding to codrituzumab

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

  • Oncotarget. 2018 Jan 2;9(12):10436-10444. doi: 10.18632/oncotarget.23830.
Gong Chen  # 1 Ya-Chi Chen  # 1 Bernhard Reis 2 Anton Belousov 3 Lori Jukofsky 1 Christine Rossin 1 Axel Muehlig 1 Chao Xu 1 Laurent Essioux 2 Toshihiko Ohtomo 4 Laura Di Laurenzio 1 Oscar Puig 1 Ray Lee 1
Affiliations

Affiliations

  • 1 Roche Pharmaceutical Research and Early Development, Roche Innovation Center New York, New York, NY, USA.
  • 2 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
  • 3 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Penzberg, Penzberg, Germany.
  • 4 Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
  • # Contributed equally.
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.

Keywords

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

Figures
Products