Abstract 5199: Preclinical activity of the FGFR2-targeted thorium-227 conjugate in preclinical models of colorectal, gastric and triple-negative breast cancer

Abstract

FGFR2 is a transmembrane tyrosine kinase receptor, consisting of three extracellular N-terminal immunoglobulin-like domains which are involved in ligand-binding as well as in receptor dimerization. Ligand-independent activation of FGFR2 signaling either via genomic amplification, gene fusion events, mRNA overexpression, or mutations has been observed e.g. in gastric cancer, colorectal cancer (CRC), and triple-negative breast cancer (TNBC). As such, FGFR2 has been described to be involved in cancer progression, promotion of oncogenesis, neoangiogenesis, as well as resistance to targeted therapies. Overexpression of FGFR2 and relatively low levels of cell surface expression of FGFR2 in normal human tissues renders FGFR2 an attractive candidate to explore targeted alpha therapy (TAT). We describe the generation of a high energy, alpha-particle emitting FGFR2 targeted thorium-227 conjugate (FGFR2-TTC). The FGFR2-TTC consists of a fully human FGFR2 binding IgG1 antibody (BAY 1179470) cross-reactive with mouse FGFR2, covalently linked via an amide bond to a chelator moiety (3,2 HOPO), enabling radiolabeling with the alpha particle emitting thorium-227 (227Th). In vitro cytotoxicity experiments with FGFR2-TTC demonstrated potency in the sub-picomolar range compared to a non-targeting control-TTC and a correlation between decrease in cell viability and increasing number of anti-FGFR2 antibodies bound per cell (ABC counts) in a panel of FGFR2-positive cancer cell lines. Upon treatment of cells with FGFR2-TTC, the DNA damage response marker protein γH2AX was up-regulated indicating that the mode-of-action involves induction of DNA double strand breaks. Furthermore, induction of the immunogenic cell death marker calreticulin was observed Biodistribution studies of the FGFR2-TTC in mouse models, evaluated by whole body autoradiography and acquisition of gamma-spectra specific for thorium-227, demonstrated specific accumulation of thorium-227 in FGFR2-positive tumors and very limited signal in murine organs and tissues. FGFR2-TTC exhibited in vivo tumor growth inhibition after a single dose in mouse xenograft models of CRC (NCI-H716) and gastric cancer (SNU-16). In addition, FGFR2-TTC showed anti-tumor activity in the aggressive murine syngeneic orthotopic 4T1 TNBC model. In summary, FGFR2-TTC has been established as a promising targeted alpha therapy (TAT) for efficacious and selective delivery of alpha emitter-based radiotherapy in several FGFR2-positive cancer indications. Further exploration for cancer therapy may thus be of interest. Citation Format: Urs B. Hagemann, Anette Sommer, Alexander Kristian, Ellen Wang, Åsmund Larsen, Uta Wirnitzer, Heidrun Ellinger-Ziegelbauer, Steffen Sandmann, Thorsten Poethko, Jenny Karlsson, Roger M. Bjerke, Lars Linden, Bertolt Kreft, Hanno Wild, Alan S. Cuthbertson. Preclinical activity of the FGFR2-targeted thorium-227 conjugate in preclinical models of colorectal, gastric and triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5199. doi:10.1158/1538-7445.AM2017-5199

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

“…FGFR2-TTC reduced the viability of FGFR2-expressing cells, resulting in accumulation of DNA DSBs and cell cycle arrest in the G2/M phase (Table 1). 77 In a preclinical murine model of human gastric cancer, whole-body autoradiography visualized the FGFR2-TTC tumor uptake in mice bearing subcutaneous xenografts. 77 Furthermore, treatment with a single dose of 500 kBq/kg specifically reduced the tumor growth in human colorectal, gastric cancer, and TNBC xenograft mouse models (Table 1).…”

“…77 FGFR2-TTC was well tolerated, with no significant body weight loss observed in any of the xenograft models tested. 77…”

Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model

“…Further, as thorium-227 is the progenitor of radium-223, the supply chain is established through Xofigo®. We have previously demonstrated that TTCs induce γ-H2A.X and G2/M cell cycle arrest in various cancer models indicating the involvement of DNA damage response [6,10]. Furthermore, the inhibition of multiple pathways of DNA repair has been described in the literature to have a radiosensitizing effect [16][17][18].…”

“…In contrast, thorium-227 (half-life of 18.7 days), the parental radionuclide of radium-223, can be complexed to several chelator families including those of the 3,2-hydroxypyridinone (3,2-HOPO) class [5]. We have previously reported on several examples of targeted thorium-227 conjugates (TTCs) targeting a multitude of tumor-associated antigens including the HER2-TTC [6][7][8][9][10]. Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor that is part of the human epidermal growth factor receptor (EGFR) family [11].…”

Quantitative Dual-Isotope Planar Imaging of Thorium-227 and Radium-223 Using Defined Energy Windows

“…227 Th has been successfully labeled to a number of such antibodies. [7][8][9][10][11][12][13][14] However, 223 Ra does not easily form stable complexes. 15 Therefore, it is possible that after the decay of 227 Th to 223 Ra, 223 Ra may dissociate from the antibody complex, resulting in free 223 Ra ions with a biodistribution independent of the 227 Th-labeled antibody.…”