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Preclinical development of a humanized neutralizing antibody targeting HGF

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Effect of YYB-101 with or without temozolomide on tumor growth and survival in mice bearing human glioblastoma xenografts. On day 7 after tumor inoculation, the tumor-bearing mice began treatment with IgG (10 mg kg−1) or YYB-101 (5, 10 or 30 mg kg−1, n=10 per group), which was administered three times per week for 3 weeks. (a) MRI brain scans performed at 7 and 28 days. (b) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus each YYB-101-treated group, P<0.001; 5 mg kg−1 YYB-101 versus 30 mg kg−1 YYB-101, P=0.0024). On day 7 after tumor inoculation, the tumor-bearing mice received 10 mg kg−1 IgG (n=8), 10 mg kg−1 YYB-101 (n=7), 5 mg kg−1 temozolomide (TMZ, n=8), or YYB-101+TMZ (n=7). (c) MRI brain scans were performed at 7 and 28 days. (d) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus TMZ-treated groups, P=0.005; TMZ versus combination treatment, P=0.0001).
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fig2: Effect of YYB-101 with or without temozolomide on tumor growth and survival in mice bearing human glioblastoma xenografts. On day 7 after tumor inoculation, the tumor-bearing mice began treatment with IgG (10 mg kg−1) or YYB-101 (5, 10 or 30 mg kg−1, n=10 per group), which was administered three times per week for 3 weeks. (a) MRI brain scans performed at 7 and 28 days. (b) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus each YYB-101-treated group, P<0.001; 5 mg kg−1 YYB-101 versus 30 mg kg−1 YYB-101, P=0.0024). On day 7 after tumor inoculation, the tumor-bearing mice received 10 mg kg−1 IgG (n=8), 10 mg kg−1 YYB-101 (n=7), 5 mg kg−1 temozolomide (TMZ, n=8), or YYB-101+TMZ (n=7). (c) MRI brain scans were performed at 7 and 28 days. (d) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus TMZ-treated groups, P=0.005; TMZ versus combination treatment, P=0.0001).

Mentions: To determine the efficacy of YYB-101 against tumor growth and survival in vivo, nude mice bearing human glioblastoma xenografts were treated with YYB-101 (5, 10, or 30 mg kg−1; n=10 per group) three times a week for 3 weeks. MRI scans of the mouse brain showed that tumor growth was strongly inhibited by YYB-101, and the tumor growth rate negatively correlated with antibody dosage (Figure 2a). Overall survival was longer in YYB-101-treated mice than in IgG-treated control mice (P<0.0001; Figure 2b). In consideration of clinical practice, we also tested YYB-101 in combination with TMZ, the standard-of-care chemotherapy drug used for glioblastoma. Our results showed that combination treatment inhibited tumor growth more effectively than YYB-101 alone (P=0.0164) or TMZ alone (P=0.0001; Figure 2c) and increased overall survival compared with the survival observed with either agent alone (Figure 2d).


Preclinical development of a humanized neutralizing antibody targeting HGF
Effect of YYB-101 with or without temozolomide on tumor growth and survival in mice bearing human glioblastoma xenografts. On day 7 after tumor inoculation, the tumor-bearing mice began treatment with IgG (10 mg kg−1) or YYB-101 (5, 10 or 30 mg kg−1, n=10 per group), which was administered three times per week for 3 weeks. (a) MRI brain scans performed at 7 and 28 days. (b) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus each YYB-101-treated group, P<0.001; 5 mg kg−1 YYB-101 versus 30 mg kg−1 YYB-101, P=0.0024). On day 7 after tumor inoculation, the tumor-bearing mice received 10 mg kg−1 IgG (n=8), 10 mg kg−1 YYB-101 (n=7), 5 mg kg−1 temozolomide (TMZ, n=8), or YYB-101+TMZ (n=7). (c) MRI brain scans were performed at 7 and 28 days. (d) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus TMZ-treated groups, P=0.005; TMZ versus combination treatment, P=0.0001).
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fig2: Effect of YYB-101 with or without temozolomide on tumor growth and survival in mice bearing human glioblastoma xenografts. On day 7 after tumor inoculation, the tumor-bearing mice began treatment with IgG (10 mg kg−1) or YYB-101 (5, 10 or 30 mg kg−1, n=10 per group), which was administered three times per week for 3 weeks. (a) MRI brain scans performed at 7 and 28 days. (b) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus each YYB-101-treated group, P<0.001; 5 mg kg−1 YYB-101 versus 30 mg kg−1 YYB-101, P=0.0024). On day 7 after tumor inoculation, the tumor-bearing mice received 10 mg kg−1 IgG (n=8), 10 mg kg−1 YYB-101 (n=7), 5 mg kg−1 temozolomide (TMZ, n=8), or YYB-101+TMZ (n=7). (c) MRI brain scans were performed at 7 and 28 days. (d) A Kaplan–Meier curve was constructed, and survival was analyzed by log-rank test (control versus TMZ-treated groups, P=0.005; TMZ versus combination treatment, P=0.0001).
Mentions: To determine the efficacy of YYB-101 against tumor growth and survival in vivo, nude mice bearing human glioblastoma xenografts were treated with YYB-101 (5, 10, or 30 mg kg−1; n=10 per group) three times a week for 3 weeks. MRI scans of the mouse brain showed that tumor growth was strongly inhibited by YYB-101, and the tumor growth rate negatively correlated with antibody dosage (Figure 2a). Overall survival was longer in YYB-101-treated mice than in IgG-treated control mice (P<0.0001; Figure 2b). In consideration of clinical practice, we also tested YYB-101 in combination with TMZ, the standard-of-care chemotherapy drug used for glioblastoma. Our results showed that combination treatment inhibited tumor growth more effectively than YYB-101 alone (P=0.0164) or TMZ alone (P=0.0001; Figure 2c) and increased overall survival compared with the survival observed with either agent alone (Figure 2d).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus