Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, MetMAb, in patients with advanced solid tumors.

Bai, Shuang; Yan, Xin; Jin, Denise; Kaur, Surinder; Nijem, Ihsan; Bothos, John; Peterson, A. C.; Patel, Premal H.

doi:10.1200/jco.2011.29.15_suppl.2571

Cited by 7 publications

(13 citation statements)

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“…These increases were dependent on the presence of onartuzumab, indicating that onartuzumab is engaging MET, however, they were independent of dose and, therefore, of limited value as pharmacodynamics endpoints. In addition, there was no correlation of sMET levels with patient disease parameters or clinical benefit (46,47). Importantly, one patient in the phase I trial with a metastatic gastric tumor with characteristics consistent with an autocrine HGF/MET biology, had an immediate and sustained drop in serum HGF and a 2-year complete remission in response to onartuzumab treatment (13), consistent with the effects observed here in the preclinical U-87 MG tumor model.…”

Section: Discussionsupporting

confidence: 69%

“…Likewise, sMET levels were found to increase by day 22 at doses greater than 4 mg/kg, however, the increase in sMET did not correlate with exposure to onartuzumab (47). These increases were dependent on the presence of onartuzumab, indicating that onartuzumab is engaging MET, however, they were independent of dose and, therefore, of limited value as pharmacodynamics endpoints.…”

Section: Discussionmentioning

confidence: 77%

“…Despite these preclinical data, the onartuzumab phase I (single agent) and phase II (combination with erlotinib) trials demonstrated an immediate and sustained approximate 2-fold increase in serum HGF in the majority of patients (46,47). Likewise, sMET levels were found to increase by day 22 at doses greater than 4 mg/kg, however, the increase in sMET did not correlate with exposure to onartuzumab (47).…”

Section: Discussionmentioning

confidence: 82%

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Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab

Mai

Zheng

Chen

et al. 2014

Molecular Cancer Therapeutics

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Onartuzumab, a humanized, monovalent monoclonal anti-MET antibody, antagonizes MET signaling by inhibiting binding of its ligand, hepatocyte growth factor (HGF). We investigated the effects of onartuzumab on cell-associated and circulating (shed) MET (sMET) and circulating HGF in vitro and nonclinically to determine their utility as pharmacodynamic biomarkers for onartuzumab. Effects of onartuzumab on cell-associated MET were assessed by flow cytometry and immunofluorescence. sMET and HGF were measured in cell supernatants and in serum or plasma from multiple species (mouse, cynomolgus monkey, and human) using platebased immunoassays. Unlike bivalent anti-MET antibodies, onartuzumab stably associates with MET on the surface of cells without inducing MET internalization or shedding. Onartuzumab delayed the clearance of human xenograft tumor-produced sMET from the circulation of mice, and endogenous sMET in cynomolgus monkeys. In mice harboring MET-expressing xenograft tumors, in the absence of onartuzumab, levels of human sMET correlated with tumor size, and may be predictive of MET-expressing tumor burden. Because binding of sMET to onartuzumab in circulation resulted in increasing sMET serum concentrations due to reduced clearance, this likely renders sMET unsuitable as a pharmacodynamic biomarker for onartuzumab. There was no observed effect of onartuzumab on circulating HGF levels in xenograft tumor-bearing mice or endogenous HGF in cynomolgus monkeys. Although sMET and HGF may serve as predictive biomarkers for MET therapeutics, these data do not support their use as pharmacodynamic biomarkers for onartuzumab. Mol Cancer Ther; 13(2); 540-52. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 82%

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Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab

Mai

Zheng

Chen

et al. 2014

Molecular Cancer Therapeutics

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“…The mean t 1/2 of onartuzumab at doses of 3, 10, and 30 mg/kg in athymic nude mice is approximately 6 d, with a mean clearance of 21 mL·d −1 ·kg −1 (32-34). The serum concentration-effect relationship observed in tumorbearing mice for OA5D5 and onartuzumab supported a once every 1-to 3-wk dosing schedule, providing flexibility for clinical application (18,(32)(33)(34)(35).…”

Section: Resultsmentioning

confidence: 99%

“…S6). Indeed, no anti-onartuzumab antibodies toward the knob and hole regions of onartuzumab in cynomolgus monkeys or humans have been identified (32)(33)(34)48). Finally, onartuzumab is expressed in E. coli, thus aglycosylated and devoid of Fc effector functions (27), such as ADCC or CDC (Fig.…”

Section: Discussionmentioning

confidence: 99%

Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent

Merchant¹,

Ma²,

Maun

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

211

221

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Binding of hepatocyte growth factor (HGF) to the receptor tyrosine kinase MET is implicated in the malignant process of multiple cancers, making disruption of this interaction a promising therapeutic strategy. However, targeting MET with bivalent antibodies can mimic HGF agonism via receptor dimerization. To address this limitation, we have developed onartuzumab, an Escherichia coliderived, humanized, and affinity-matured monovalent monoclonal antibody against MET, generated using the knob-into-hole technology that enables the antibody to engage the receptor in a one-to-one fashion. Onartuzumab potently inhibits HGF binding and receptor phosphorylation and signaling and has antibody-like pharmacokinetics and antitumor activity. Biochemical data and a crystal structure of a ternary complex of onartuzumab antigen-binding fragment bound to a MET extracellular domain fragment, consisting of the MET Sema domain fused to the adjacent Plexins, Semaphorins, Integrins domain (MET Sema-PSI), and the HGF β-chain demonstrate that onartuzumab acts specifically by blocking HGF α-chain (but not β-chain) binding to MET. These data suggest a likely binding site of the HGF α-chain on MET, which when dimerized leads to MET signaling. Onartuzumab, therefore, represents the founding member of a class of therapeutic monovalent antibodies that overcomes limitations of antibody bivalency for targets impacted by antibody crosslinking.scatter factor | HGFR | MetMAb | OA5D5

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Pharmacokinetic and Pharmacodynamic‐Based Drug Interactions for Therapeutic Proteins

Lü¹,

Girish²,

Theil³

et al. 2013

Pharmaceutical Sciences Encyclopedia

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This chapter reviews the major absorption, distribution, metabolism, and excretion(ADME) pathways of therapeutic proteins (TPs), summarizes the potential mechanisms of pharmacokinetic (PK) and pharmacodynamic (PD)‐based TP‐drug interactions (DIs), and recommends a question‐based therapeutic protein‐drug interaction risk assessment strategy during clinical development. The DIs for some nonprotein biologics such as nucleic acid‐based derivatives are reviewed in other chapters.

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Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, MetMAb, in patients with advanced solid tumors.

Cited by 7 publications

References 0 publications

Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab

Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab

Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent

Pharmacokinetic and Pharmacodynamic‐Based Drug Interactions for Therapeutic Proteins

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