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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.


Pharmacokinetic profile of YYB-101 in cynomolgus monkeys. Serum concentration-time curve of YYB-101 in male cynomolgus monkeys following a 2-h intravenous infusion at 10 mg kg−1. The inserted table describes selected pharmacokinetic parameters. The results are expressed as the mean±s.d. (n=3).
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fig4: Pharmacokinetic profile of YYB-101 in cynomolgus monkeys. Serum concentration-time curve of YYB-101 in male cynomolgus monkeys following a 2-h intravenous infusion at 10 mg kg−1. The inserted table describes selected pharmacokinetic parameters. The results are expressed as the mean±s.d. (n=3).

Mentions: The pharmacokinetics of YYB-101 was investigated in four male cynomolgus monkeys after a single intravenous injection (10 mg kg−1). The serum concentration versus time curves and pharmacokinetic parameters of YYB-101 are presented in Figure 4. The YYB-101 serum Tmax was 2 h, Cmax was 221.57 μg ml−1, and AUC(0–∞) was 94 802.96 μg ml−1 h−1. The t1/2z was ~21.7 days and clearance was 0.11 ml kg−1 h−1.


Preclinical development of a humanized neutralizing antibody targeting HGF
Pharmacokinetic profile of YYB-101 in cynomolgus monkeys. Serum concentration-time curve of YYB-101 in male cynomolgus monkeys following a 2-h intravenous infusion at 10 mg kg−1. The inserted table describes selected pharmacokinetic parameters. The results are expressed as the mean±s.d. (n=3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382562&req=5

fig4: Pharmacokinetic profile of YYB-101 in cynomolgus monkeys. Serum concentration-time curve of YYB-101 in male cynomolgus monkeys following a 2-h intravenous infusion at 10 mg kg−1. The inserted table describes selected pharmacokinetic parameters. The results are expressed as the mean±s.d. (n=3).
Mentions: The pharmacokinetics of YYB-101 was investigated in four male cynomolgus monkeys after a single intravenous injection (10 mg kg−1). The serum concentration versus time curves and pharmacokinetic parameters of YYB-101 are presented in Figure 4. The YYB-101 serum Tmax was 2 h, Cmax was 221.57 μg ml−1, and AUC(0–∞) was 94 802.96 μg ml−1 h−1. The t1/2z was ~21.7 days and clearance was 0.11 ml kg−1 h−1.

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.