Author: Martinez, Alberto ; Ciprotti, Marika ; Jansen, Mendel ; Shuster, Dale Edward ; Hanai, Masaharu ; Abraham, Reimar ; Tokuhiro, Shinya ; Oitate, Masataka

TPS2593Background: Fibroblast Growth Factor Receptor 4 (FGFR4) is the fourth member of a family of FGF tyrosine kinase receptors that regulate cellular pathways involved in proliferation, differentiation and survival. Fibroblast Growth Factor 19 (FGF19), a natural ligand of FGFR4, has unique specificity for its receptor and regulates bile acid synthesis and hepatocyte proliferation in the normal liver. Although FGF signalling has been found to be of importance in a number of tumour types, including prostate, breast, pancreatic, pituitary and gynaecological tumours, growing evidence suggests that FGF19/FGFR4 pathway is a key driver in the development of hepatocellular carcinoma (HCC). U3-1784 is a fully human IgG1 monoclonal antibody and antagonist to FGF19 ligand. It selectively targets FGFR4 without binding to FGFR 1, 2 and 3. Methods: The study is divided into 2 parts: in part 1 (Dose Escalation Phase) multiple ascending doses (3 + 3 design) of U3-1784 are given to patients with histologically or cytolo...

15 Apr 2012·Cancer Research

Abstract 2519: U3-1565, a fully human anti-HB-EGF monoclonal antibody, inhibits oncogenic signaling and tumor cell growth in vitro and in vivo

Author: Schramm, Julia ; Wagner, Tanja ; Pfeil, Ines ; Riffner, Yvonne ; aus dem Siepen, Patricia ; Zwick-Wallasch, Esther ; Hettmann, Thore

AbstractBackground: U3-1565 is a fully human monoclonal antibody directed against human heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family of ligands that bind to and activate the EGFR and HER4. HB-EGF-mediated activation of its target receptors results in oncogenic signaling. Methods: To determine inhibition of basal EGFR phosphorylation, human tumor cell lines were treated with U3-1565 or IgG2 and pEGFR levels were analyzed by ELISA. Inhibition of in vivo angiogenesis was analyzed by implanting HUVEC-based spheroids under the skin of SCID mice, which were treated with U3-1565, bevacizumab or PBS and analyzed for human neovasculature. To determine in vivo efficacy, SCID mice bearing EFO27-CL58 ovarian cancer xenografts were treated weekly with U3-1565, Cisplatin or with a combination of U3-1565 and Cisplatin. To perform xenograft analysis tumor-bearing mice were treated with U3-1565, cetuximab and erlotinib and primary xenograft tissue was collected, lyzed and pEGFR and pERK levels were analyzed by Western blotting. To determine expression of HB-EGF and pEGFR in human tumor tissue, Immunohistochemistry (IHC) stainings of human carcinoma samples were performed. Results: Inhibition of basal pEGFR levels by U3-1565 in comparison to control IgG2 treatment was demonstrated in various cancer cell lines. U3-1565 showed dose-dependent inhibition of HB-EGF-stimulated pHER4 and pERK activation in vitro (data not shown). Using a HUVEC-based spheroid in vivo system, inhibition of human endothelial cell sprouting by U3-1565 was shown. In a HB-EGF overexpressing ovarian cancer xenograft model U3-1565 demonstrated in vivo tumor cell growth inhibition as a single agent. Combination treatment of U3-1565 with Cisplatin resulted in tumor regression during the treatment phase and prevented re-growth of xenograft tumors after treatment stop. Analysis of EFO27-CL58 tumor xenograft tissue demonstrated strong reduction of pEGFR and partially reduced pERK levels after U3-1565 in vivo treatments. IHC staining of fresh human tumor samples revealed an overlapping expression pattern of HB-EGF and pEGFR. Conclusions: Our results demonstrate that U3-1565 inhibits basal activation of EGFR activation in vitro and reduces neo-vasculature formation (angiogenesis) in vivo. In a tumor xenograft model U3-1565 demonstrated tumor cell growth arrest as a single agent or in combination with Cisplatin or erlotinib. Analysis of xenograft material after in vivo exposure to U3-1565 strongly suggest that U3-1565's anti-tumor activity is based on inhibition of EGFR activation and prevention of oncogenic MAPK signaling. These data together with the evidence that human HB-EGF and activated EGFR are coexpressed in human tumor samples provide preclinical rational to develop U3-1565 as a clinical mAb candidate to treat cancer in human patients.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2519. doi:1538-7445.AM2012-2519

12 Nov 2011·Molecular Cancer Therapeutics

Abstract A182: U3–1287 (AMG 888), a fully human anti-HER3 mAb, demonstrates in vitro and in vivo efficacy in the FaDu model of human squamous cell carcinoma of the head and neck (SCCHN).

Author: Freeman, Daniel J. ; Bready, James ; Hettmann, Thore ; Ogbagabriel, Selam ; Radinsky, Robert ; Sun, Ji-Rong

AbstractBackground: Anti-EGFR mAbs have demonstrated clinical utility in SCCHN; however, most patients are resistant or acquire resistance to therapy. In preclinical models, activation of HER3 is a resistance mechanism to current HER inhibitors. Recent data (Wilson et al 2011) demonstrated that SCCHN cancer cell lines and primary tumors express both HER3 and heregulin, the ligand for HER3. This autocrine loop is one potential mechanism for the lack of sensitivity to anti-EGFR mAbs observed in SCCNH patients. Herein, we report in vitro and in vivo activity of U3–1287 (AMG 888) as a single agent and in combination with panitumumab, an anti-EGFR mAb, in the FaDu preclinical model of human SCCHN.Methods: FaDu (SCCHN) cells were treated with U3–1287 (AMG 888), panitumumab, the combination or control mAbs for 4 hours. To determine in vitro efficacy on cell proliferation, FaDu cells were treated with 1 μg/mL U3–1287 (AMG 888), 1 μg/ml panitumumab, the combination or control mAbs in serum containing medium. After 72 hours, the growth of treated cells was measured by ATPLite assay. Levels of pHER3, pEGFR, pERK1/2 and pAKT were measured by Western blot analyzes to determine the inhibition of HER3 oncogenic signaling. To determine in vivo efficacy, mice bearing ∼200 mm3 FaDu xenografts were treated 2×/week with U3–1287 (AMG 888), panitumumab, the combination or control mAbs. Results: Treatment with either U3–1287 (AMG 888) or panitumumab resulted in inhibition of pHER3 and pAKT or pEGFR and pERK1/2, respectively. Treatment with the combination resulted in inhibition of pHER3, pEGFR, pAKT and pERK1/2. Although treatment with panitumumab or U3–1287 (AMG 888) alone significantly inhibited in vitro cell proliferation versus control mAb treated cells (57% (p<0.001) and 38% (p<0.005), respectively), greater inhibition was observed with the combination versus either single agent alone (75% (p<0.01). A dose-dependent inhibition of FaDu xenograft growth was observed with panitumumab or U3–1287 (AMG 888) when used as single agents versus mAb controls (p<0.02 and p<0.01 versus mAb control, respectively). In the combination group (200 μg/ml U3–1287 (AMG 888) and 100 μg/ml panitumumab), treatment resulted in significant tumor inhibition and regressions in all tumors and versus either single agent alone (p<0.0001). To test the durability of the regressions, FaDu xenografts were treated in a separate study with 200 μg/ml U3–1287 (AMG 888) and 100 μg/ml panitumumab again resulting in regressions in all tumors with 8/10 animals remaining tumor free 45 days post the final treatment. Western blot analyzes confirmed a greater inhibition of pHER3 and pAKT in tumors from the combination-treated group versus the single agent-treated groups.Conclusions: U3–1287 (AMG 888) inhibits proximal and distal HER3 oncogenic signaling in FaDu SCCHN cells resulting in in vitro and in vivo growth inhibition. SCCHN xenografts were sensitive to U3–1287 (AMG 888) treatment as single agent or in combination with panitumumab. Combination treatment with U3–1287 (AMG 888) and panitumumab resulted durable regressions which was not observed with either single agent. These data together with the HER3/heregulin autocrine loop detected in patient samples (Wilson et al 2011) provides evidence for the potential clinical investigation of U3–1287 (AMG 888) in SCCHN.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A182.

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