Abstract 4719: Exploratory biomarker program in Phase I clinical development of RG7155, a novel humanized anti-CSF-1R Mab, targeting Tumor Associated Macrophages (TAMs).
Authors: Cannarile Michael A. , Habben Kai , Heil Florian , Broeske Ann-Marie , Ruettinger Dominik , Culton Lisa , Feuerhake Friedrich , Ries Carola H. 
Published: August 2014

Abstract
Early Phase I clinical development of RG7155, a humanized anti-CSF-1R monoclonal antibody binding to dimerization interface of CSF-1 receptor and inducing apoptosis in CSF-1R expressing macrophages is accompanied by an extensive biomarker program. Phase I biosampling aims to enable monitoring of mode of action, drug efficacy and potential tumor escape mechanisms by identifying response prediction and mechanistic efficacy markers and therefore to support optimal biological dose (OBD) definition and patient stratification for subsequent clinical testing.
One biomarker hypothesis to support potential patient stratification assumes that response to treatment with RG7155 is enhanced in tumors with high CSF-1R positive macrophage infiltration and with high CSF-1 levels in the peripheral blood as the basis for tumor promoting macrophage recruitment and differentiation. The Phase I biomarker program comprises extensive biosampling including mandatory fresh baseline and on treatment tumor, skin biopsies as well as peripheral blood sampling to identify and monitor pharmacodynamic as well as mechanistic efficacy markers.
Pre- and on-treatment tumor tissue analysis involves tumor infiltrating macrophage subtype characterization via CD68/CD163/CSF-1R/MHC II, CD4 and CD8 T cell assessment by multiplex IHC assays. In order to detect early tissue response prediction markers in surrogate tissue, wound associated macrophages (WAMs) are assessed in wounded skin tissue samples. Further, systematic collection of peripheral blood samples before and during RG7155 administration aims at identifying CSF-1R expressing target populations, other potential RG7155 susceptible immune cell populations by flow cytometry using CD8/CD4/CD3/CD45/MHC II/CD14/CD16/CD56/CD19 markers and an extended cytokine profiling by Luminex 17-plex panel. These markers will be correlated to direct anti-tumor effects assessed using KI67 IHC, FDG-PET, DC-Ultrasound and clinical response.
Here we describe the development of the clinical biomarker strategy based on preclinical data and the specific assay developments, to enable the selection of the OBD, the correlation of TAM elimination with anti-tumor effects and the optimization of the biomarker sampling to minimize the burden of diagnostic procedures for patients in future clinical trials.
Citation Format: Michael A. Cannarile, Kai Habben, Florian Heil, Ann-Marie Broeske, Dominik Ruettinger, Lisa Culton, Friedrich Feuerhake, Carola H. Ries. Exploratory biomarker program in Phase I clinical development of RG7155, a novel humanized anti-CSF-1R Mab, targeting Tumor Associated Macrophages (TAMs). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4719. doi:10.1158/1538-7445.AM2013-4719