Biochemical Characterization of AMG 102: A Neutralizing, Fully Human Monoclonal Antibody to Human and Nonhuman Primate Hepatocyte Growth Factor
| Autor: | Qing Chen, Jan Sun, Ke Zhang, Angela Coxon, Trace Tsuruda, Teresa L. Burgess, Will F. Barron, Susanne Meyer, Todd Juan, Jilin Sun, Richard Kendall, Gary Elliott, Mitsuru Haniu |
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| Rok vydání: | 2010 |
| Předmět: |
Primates
Cancer Research medicine.drug_class Immunoprecipitation medicine.medical_treatment Immunoblotting Antibodies Monoclonal Humanized Monoclonal antibody law.invention Inhibitory Concentration 50 Mice Peptide Library law medicine Animals Humans Phosphorylation Protease Hepatocyte Growth Factor Chemistry Autophosphorylation Antibodies Monoclonal Kallikrein Trypsin Molecular biology Recombinant Proteins Macaca fascicularis Oncology Recombinant DNA Hepatocyte growth factor Rabbits Epitope Mapping medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 9:400-409 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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 IC50 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 NH2-terminus of the β-chain are critical for AMG 102 binding. Bound AMG 102 protected one trypsin protease cleavage site near the NH2-terminus of the β-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 |
| Databáze: | OpenAIRE |
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