Preclinical development of a humanized neutralizing antibody targeting HGF

Abstract

Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101. To support clinical development, we also evaluated the preclinical pharmacokinetics and toxicokinetics in cynomolgus monkeys, and human and cynomolgus monkey tissue was stained with YYB-101 to test tissue cross-reactivity. We found that YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. Combination treatment with YYB-101 and temozolomide decreased tumor growth and increased overall survival compared with the effects of either agent alone. Five cancer-related genes (TMEM119, FST, RSPO3, ROS1 and NBL1) were overexpressed in YYB-101-treated mice that showed tumor regrowth. In the tissue cross-reactivity assay, critical cross-reactivity was not observed. The terminal elimination half-life was 21.7 days. Taken together, the in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer.

MET in glioma: signaling pathways and targeted therapies

“…The humanized monoclonal anti-HGF antibody, YYB-101, suppresses tumor growth in vitro and in an orthotopic mouse model of human glioblastoma; it also downregulates important cellular molecular effectors including p-MET, p-Gab1, p-FAK, MMP2, uPA/plasminogen, and Ki-67 [79, 80]. Combination treatment with YYB-101 and TMZ was found to decrease tumor growth and increase OS, compared to the effects of either agent alone, in mice bearing human glioblastoma xenografts [80]. There is also a clinical trial registered for this monoclonal antibody for solid tumors, but with no available results (NCT02499224).…”

Humanized Anti-hepatocyte Growth Factor Monoclonal Antibody (YYB-101) Inhibits Ovarian Cancer Progression

“…YYB-101 was developed as a humanized neutralizing monoclonal antibody against HGF. YYB-101 was shown to inhibit HGF-induced scattering in MDCK-2 cells and block the phosphorylation of ERK, a downstream signaling molecule of c-MET that affects cell proliferation (23). YYB-101 was also found to be effective in various cancer models, including mouse xenograft models of colorectal cancer and glioblastoma, when coadministered with a chemotherapeutic agent (22, 23).…”

“…Treatment of a mouse xenograft model of human colorectal cancer with a combination of YYB-101 and irinotecan, a chemotherapeutic agent used to treat colorectal cancer, effectively inhibited tumor progression (22). Treatment of a mouse xenograft model of human glioblastoma with YYB-101 and temozolomide (TMZ) resulted in a 2-fold higher survival rate than treatment with TMZ alone did (23). These findings suggested that combination therapy with YYB-101 and chemotherapeutic agents may inhibit tumor progression, including in ovarian cancer.…”

First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

“…YYB101 was shown to prevent HGF-induced scattering in MDCK-2 cells, thus blocking ERK phosphorylation, which is a downstream molecule of MET involved in cancer cell proliferation. 11 YYB101 specifically binds to human HGF to inhibit its activity. The HGF/MET axis is an important axis involved in metastasis of tumor cells from the primary site to distant organs by promoting epithelial-mesenchymal transition (EMT).…”