Abstract
AMG 102 is a fully human monoclonal antibody that selectively targets and neutralizes hepatocyte growth factor/scatter factor (HGF/SF). A detailed biochemical and functional characterization of AMG 102 was done to support its clinical development for the treatment of cancers dependent on signaling through the HGF/SF:c-Met pathway. In competitive equilibrium binding experiments, AMG 102 bound to human and cynomolgus monkey HGF with affinities of approximately 19 pmol/L and 41 pmol/L, respectively. However, AMG 102 did not detect mouse or rabbit HGF on immunoblots. Immunoprecipitation experiments showed that AMG 102 preferentially bound to the mature, active form of HGF, and incubation of AMG 102/HGF complexes with kallikrein protease indicated that AMG 102 had no apparent effect on proteolytic processing of the inactive HGF precursor. AMG 102 inhibited human and cynomolgus monkey HGF-induced c-Met autophosphorylation in PC3 cells with IC(50) values of 0.12 nmol/L and 0.24 nmol/L, respectively. AMG 102 also inhibited cynomolgus monkey HGF-induced migration of human MDA-MB-435 cells but not rat HGF-induced migration of mouse 4T1 cells. Epitope-mapping studies of recombinant HGF molecules comprising human/mouse chimeras and human-to-mouse amino acid substitutions showed that amino acid residues near the NH(2)-terminus of the beta-chain are critical for AMG 102 binding. Bound AMG 102 protected one trypsin protease cleavage site near the NH(2)-terminus of the beta-chain of human HGF, further substantiating the importance of this region for AMG 102 binding. Currently, AMG 102 is in phase II clinical trials in a variety of solid tumor indications. Mol Cancer Ther; 9(2); 400-9.
Highlights
Hepatocyte growth factor [HGF; known as scatter factor (SF)] is the only known ligand for c-Met, a receptor tyrosine kinase expressed in epithelial tissues that plays an essential role in the growth and maintenance of cells [1]
We show that AMG 102: (a) binds and neutralizes human and cynomolgus monkey HGF but not mouse, rat, or rabbit HGF; (b) preferentially binds to the mature, active, heterodimeric form of HGF; (c) has no apparent effect on the proteolytic processing leading to HGF activation; and (d) interacts functionally with regions of human HGF including the NH2-terminal portion of the β-chain
We extended the characterization of fully human anti-HGF–neutralizing monoclonal antibodies described by Burgess et al [24] by focusing on the most promising candidate for clinical investigation, called AMG 102 [25]
Summary
Hepatocyte growth factor [HGF; known as scatter factor (SF)] is the only known ligand for c-Met, a receptor tyrosine kinase expressed in epithelial tissues that plays an essential role in the growth and maintenance of cells [1]. Mutations in c-Met resulting in constitutive activation have been described in hereditary and sporadic human cancers [10], and expression of some of these mutant alleles in mice enhances their tumorigenicity [11, 12]. Some of these c-Met mutants remain sensitive to HGF activation, and can be blocked by HGF antagonists [10, 13]. Protein fragments derived from NH2-terminal regions of HGF (e.g., NK1, NK2, and NK4) contain a high-affinity c-Met receptor binding domain and can act as HGF agonists or as antagonists, showing that HGF binds to c-Met
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