Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma.

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.

Pharmacokinetics of YYB-101

The pharmacokinetics of YYB-101 was investigated in four male cynomolgus monkeys after a single intravenous injection (10 mg/kg). The YYB-101 serum T_max was 2 h, C_max was 221.57 μg ml−1, and AUC_(0-∞) was 94 802.96 μg ml^-1 h^-1. The t_1/2z was ~21.7 days and clearance was 0.11 ml kg^-1 h^-1.

Toxicokinetics of YYB-101 and anti-drug antibodies

Following intravenous administration of YYB-101, the mean systemic exposure (AUC_0-168 h) and C_max values of YYB-101 increased proportionally with dose. The mean peak and trough serum concentrations of YYB-101 appeared to approach steady state following the four weekly infusions of YYB-101. Serum concentrations were quantifiable in recovered animals 63 days after the last dose (~2.8% of C_max from day 22). Systemic exposure (AUC_0-168h) increased with repeated intravenous administration of YYB-101, with accumulation ratios ranging from 2.38 to 2.95. Anti-drug antibodies were detected on day 1 in one female monkey at 50 mg/kg per day YYB-101 but were not detected in samples collected from this animal on day 29 or 85. The C_max and AUC values of this animal were similar to those of animals in which no anti-drug antibodies were detected.

Pharmacokinetics, toxicokinetics and anti-drug antibodies of YYB-101 in cynomolgus monkeys were conducted by the Test and Control Article Department of Medicilon Preclinical Research, LLC, in accordance with regulations outlined in the USDA Animal Welfare act and conditions specified in The Guide for the Care and Use of Laboratory Animals. 

Reference:

Hyori Kim, et al. Preclinical development of a humanized neutralizing antibody targeting HGF. Exp Mol Med. 2017 Mar 24;49(3):e309. doi: 10.1038/emm.2017.21