Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys

Kakkar, Tarundeep; Ma, Mark; Zhuang, Yingping; Patton, Aaron; Hu, Zheng; Mounho, Barbara

doi:10.1007/s11095-007-9316-2

Cited by 34 publications

(31 citation statements)

References 16 publications

(20 reference statements)

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“…AMG102 is a fully human IgG2 monoclonal antibody against HGF. This compound has completed both preclinical trials and phase Ⅰ dosing trials [33] . Although, the dose-escalating trials were performed on a variety of solid tumors, there is not current data on cholangiocarcinoma.…”

Section: Cholangiocarcinomamentioning

confidence: 99%

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c-Met targeted therapy of cholangiocarcinoma

Socoteanu¹,

Mott²,

Alpini³

et al. 2008

WJG

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Cholangiocarcinoma continues to be a challenging disease to treat. Systemic therapy is used in unresectable disease, disease progression after surgery, and in the palliative setting. Unfortunately, results of multiple phase Ⅱ trials have rarely yielded positive results. As data on the molecular carcinogenesis of cholangiocarcinoma is developing, we are more able to understand the disease process and can use this understanding to create unique targeted therapies. We reviewed the role of c-Met/ hepatocyte growth factor (HGF) in the development of cholangiocarcinoma. Furthermore, we explored the use of the c-Met guided cascade as a target to treat cholangiocarcinoma. We reviewed the current use and options for future development of c-Met agents to treat this disease.

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Section: Cholangiocarcinomamentioning

confidence: 99%

“…Liver transplantation HGF/c-met monoclonal antibody AMG102 [33] Phase Ⅱ Soluble c-met receptor Decoy met [35] Phase Ⅰ Tyrosine kinase inhibition ARQ 197 [42] Phase Ⅱ XL880 [36,37] Phase Ⅱ PHA665752 [38] Animal testing…”

mentioning

confidence: 99%

c-Met targeted therapy of cholangiocarcinoma

Socoteanu¹,

Mott²,

Alpini³

et al. 2008

WJG

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“…The results were consistent with the species specificity of AMG 102 binding/activity seen in our in vitro experiments. Based on the species specificity shown here and by Kakkar et al, cynomolgus monkeys were deemed to be a pharmacologically relevant species for further pharmacokinetic and safety studies of AMG 102 (32).…”

Section: Discussionmentioning

confidence: 84%

“…As we have previously reported (24), the efficacy of AMG 102 was shown only in preclinical models that were dependent on human HGF. Kakkar et al (32) did cross-reactivity studies using fluorescein-conjugated AMG 102 on a wide variety of human and cynomolgus monkey tissues as well as on a smaller panel of mouse, rat, and rabbit tissues. The results were consistent with the species specificity of AMG 102 binding/activity seen in our in vitro experiments.…”

Section: Discussionmentioning

confidence: 99%

Biochemical Characterization of AMG 102: A Neutralizing, Fully Human Monoclonal Antibody to Human and Nonhuman Primate Hepatocyte Growth Factor

Burgess

Sun

Meyer

et al. 2010

Molecular Cancer Therapeutics

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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 β-chain are critical for AMG 102 binding. Bound AMG 102 protected one trypsin protease cleavage site near the NH 2 -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. ©2010 AACR.

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“…A mechanism called "kinase switch" confers the secondary resistance to [77,78]. ARQ197 (ArQule) is a non-ATP competitive agent which was highly selective of c-MET receptor after biochemical assessment in a panel of 230 kinases.…”

Section: Met Amplificationsmentioning

confidence: 99%

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

Vijayalakshmi

2011

Indian J Surg Oncol

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Lung cancer remains the leading cause of cancerrelated mortality in the world despite advances in the field of cancer therapeutics. Traditional treatment with empirically chosen cytotoxic chemotherapeutic agents, have given small, but real survival benefits. Recent advances and insights into molecular pathogenesis of lung cancers have provided some novel molecular targets, offering newer strategies and agents that are tumor specific. Studies have identified mutations in specific genes that are involved in driving the development of lung cancer and so it is important to subsequently target them with specific drugs thus changing paradigms of management of this type of cancer. Recently, Lung Cancer Mutation Consortium (LCMC) has identified at least one of the many recognized "driver mutations" in nearly two thirds of the patients with advanced cancer. This study suggests that identification of driver mutations can help in molecular targeted therapeutics and in addition supplant tumor histology in guiding treatment decisions, identifying subset of patients who may benefit therapy. This review focuses on these mutations identified in specific genes serving as "drivers" of lung tumorigenesis and suggests that clear promise for the future of lung cancer treatment is indeed personalized therapy with drugs chosen according to the patient mutation profile. Most clinically relevant translational advances made in genes involved in lung tumorigenesis namely EML4-ALK fusions, HER2, PIK3CA, AKT, BRAF, MAP2K1, MET mutations and amplifications along with the well established EGFR and KRAS mutations are discussed in the context of NSCLCs. These studies emphasize the need for treatment management based on mutation profile along with routine histology based classification of these tumors in future for a directed therapy and thus a better therapeutic outcome.

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Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys

Abstract: The nonclinical pharmacokinetic and safety profile of AMG 102 effectively supports clinical investigation.

Cited by 34 publications

References 16 publications

c-Met targeted therapy of cholangiocarcinoma

c-Met targeted therapy of cholangiocarcinoma

Biochemical Characterization of AMG 102: A Neutralizing, Fully Human Monoclonal Antibody to Human and Nonhuman Primate Hepatocyte Growth Factor

Targetable “Driver” Mutations in Non Small Cell Lung Cancer

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