Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis

Abstract

The hepatocyte growth factor (HGF)/c-Met signaling pathway is involved in lung tumor growth and progression, and agents that target this pathway have clinical potential for lung cancer treatment. L2G7, a single potent antihuman HGF neutralizing monoclonal antibody, showed profound inhibition of human HGF-induced phosphorylated mitogen-activated protein kinase induction, wound healing, and invasion in lung tumor cells in vitro. Transgenic mice that overexpress human HGF in the airways were used to study the therapeutic efficacy of L2G7 for lung cancer prevention. Mice were treated with the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, over 4 weeks. Beginning at week 3, i.p. treatment with 100 Mg L2G7 or isotype-matched antibody control, 5G8, was initiated and continued through week 15. The mean number of tumors per mouse in the L2G7-treated group was significantly lower than in the control group (1.58 versus 3.19; P = 0.0005). Proliferative index was decreased by 48% (P = 0.013) in tumors from L2G7-treated mice versus 5G8-treated mice, whereas extent of apoptosis was increased in these same tumors by 5-fold (P = 0.0013). Phosphorylated mitogen-activated protein kinase expression was also significantly decreased by 84% in tumors from L2G7-treated mice versus 5G8-treated mice (P = 0.0003).Tumors that arose in HGF transgenic animals despite L2G7 treatment were more likely to contain mutant K-ras, suggesting that targeting the HGF/c-Met pathway may not be as effective if downstream signaling is activated by a K-ras mutation. These preclinical results show that blocking the HGF/c-Met interaction with a single monoclonal antibody delivered systemically can have profound inhibitory effects on development of lung tumors. [Mol Cancer Ther 2008;7(7):1913 -22]

Therapeutic potential of hepatocyte growth factor/scatter factor neutralizing antibodies: Inhibition of tumor growth in both autocrine and paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma

“…In the present study, we found that AMG 102 significantly inhibited the growth of SK-LMS-1 tumors in huHGF/SF-SCID mice, suggesting that it can efficiently block paracrine HGF/SF:c-Met signaling. This result is consistent with the report that single anti-HGF antibody decrease carcinogen-induced lung carcinogenesis in human HGF transgenic mice (22), suggesting that targeting paracrine HGF/SF is potential therapeutic strategy for various human cancer. Furthermore, AMG 102 was able to significantly inhibit the growth of the SK-LMS-1 tumors in the slowergrowing, autocrine setting in SCID mice.…”

Mimics of the Dimerization Domain of Hepatocyte Growth Factor Exhibit Anti-Met and Anticancer Activity

“…The earliest step to be targeted in the Met activation process is the interaction between Met and HGF. HGF antagonists, like HGF-directed antibodies (Burgess et al, 2006;Stabile et al, 2008) or soluble fragments of Met extracellular domains, which act as "decoy" molecules (Michieli et al, 2004), can interfere with this interaction act by sequestering HGF. Metneutralizing antibodies can also obstruct this step in the signaling cascade (Martens et al, 2006) by either directly blocking HGF access to Met or causing down-regulation of Met by inducing receptor internalization.…”

Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers

“…The first involves the development of single-arm humanized antibodies to HGF (Burgess et al, 2006;Stabile et al, 2008) or Met (Martens et al, 2006). The second approach uses "kinase inhibitors" that block the intracellular consequences of Met activation.…”