In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C129-C129
Abstract:
While FGFR4 and its ligand FGF19 represent a promising target for cancers in which FGF19 is overexpressed or gene amplified, inhibition of this pathway carries a potential toxicity risk due to the role of FGFR4 in bile acid homeostasis. Treatment with an anti-FGF19 antibody caused significant toxicity in cynomolgus monkeys that was attributed to perturbations in the enterohepatic circulation of bile acids. Given that FGF19 signals through other FGFRs besides FGFR4, we hypothesized that the toxicity profile of an anti-FGFR4 antibody might be different than that of an anti-FGF19 antibody. To test this we set out to identify an anti-FGFR4 antibody that inhibits FGF19 binding and displays anti-tumor activity in models overexpressing FGF19, and then determine its toxicity profile. A phage screening effort yielded several anti-FGFR4 antibodies including H4, a high affinity fully human IgG1. H4 binds to the extracellular domain of FGFR4 (Kd = 12 pM) but does not cross react with FGFR1, FGFR2, or FGFR3. Furthermore, H4 efficiently blocks FGF19 binding to FGFR4 (IC50 = 589 pM) and inhibits FGF19-mediated downstream signaling in Hep3B2 cells. In human liver cancer cells that overexpress FGF19, H4 inhibits proliferation (IC50 250-1,100 nM). Anti-tumor activity was evaluated using cell line-derived xenograft tumors established from the FGF19 overexpressing and gene amplified cell lines HuH-7 and Hep3B2. H4 inhibited tumor growth in these models (T/C of 50% and 8%, respectively), and the antitumor effect was accompanied by alterations in several biomarkers associated with FGFR4 pathway inhibition including increased expression of CYP7A, the gene encoding the rate-limiting enzyme of bile acid synthesis. Finally, to assess the potential toxicity of H4 treatment, single dose intravenous toxicology studies were conducted in rats (20, 60, and 200 mg/kg) and cynomolgus monkeys (5, 20, and 100 mg/kg). Although H4 binds with similar affinity to monkey and rat FGFR4, the toxicology profiles were distinct. H4 was well tolerated in rats with no significant findings up to 200 mg/kg. Effects in monkeys included sporadic malformed feces, reduced food intake, elevated serum ALT (up to 44 fold over baseline) and AST activities, and elevated fecal bile acid concentrations at all doses. Hyperplasia of the gall bladder epithelium occurred at 100 mg/kg. There were no microscopic findings in the liver. Qualitatively this toxicity profile is similar to that of the anti-FGF19 antibody, although the maximum tolerated dose (MTD) of H4 in the monkey after a single dose was considered to be & gt;100 mg/kg. These data are relevant for drug development in Oncology in light of the efforts aimed at developing anti-FGFR4 antibodies and small molecule inhibitors specific for FGFR4. Citation Format: Timothy R. Mack, Colleen Burns Burns, Xuemei Guo, William John Feaver, Marie Prewett, Jennifer Gruber, Amelie Forest, Armando R. Irizarry, Ruslan Novosiadly, Nick Loizos, Andrew Dropsey. Antitumor efficacy and non-clinical safety of the high affinity anti-FGFR4 antibody H4: Implications for targeting the FGF19-FGFR4 axis in oncology. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C129.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-15-C129
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2062135-8
SSG:
12
