Phase I, Pharmacokinetic, and Pharmacodynamic Study of AMG 479, a Fully Human Monoclonal Antibody to Insulin-Like Growth Factor Receptor 1

Tolcher, Anthony W.; Sarantopoulos, John; Patnaik, Amita; Papadopoulos, Kyriakos P.; Lin, Chia Chi; Rodón, Jordi; Murphy, Barbara A.; Roth, Bruce J.; McCaffery, Ian; Gorski, Kevin; Kaiser, Bruce A.; Zhu, Min; Deng, Hongjie; Friberg, Greg; Puzanov, Igor

doi:10.1200/jco.2009.23.6745

Cited by 304 publications

(248 citation statements)

References 18 publications

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“…In their study, SCH 717454 showed antitumor activity against a panel of pediatric tumor models with the most potent activities in Ewing's sarcoma, osteosarcoma, and neuroblastoma models. Recently, several anti-IGF-IR monoclonal antibodies including SCH 717454 have shown single-agent activity in Ewing's sarcoma in phase II clinical trials providing clinical proof of concept supporting importance of the IGF-IR pathway in Ewing's sarcoma (37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

Wang¹,

Lipari²,

Wang³

et al. 2010

Molecular Cancer Therapeutics

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The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in the growth, survival, and metastasis of a broad range of malignancies including pediatric tumors. Blocking the IGF-IR action is a potential cancer treatment. A fully human neutralizing monoclonal antibody, SCH 717454 (19D12, robatumumab), specific to IGF-IR, has shown potent antitumor effects in ovarian cancer in vitro and in vivo. In this study, SCH 717454 was evaluated in several pediatric solid tumors including neuroblastoma, osteosarcoma, and rhabdomyosarcoma. SCH 717454 is shown here to downregulate IGF-IR as well as inhibit IGF-IR and insulin receptor substrate-1 phosphorylation in pediatric tumor cells. IGF-IR and insulin receptor substrate-1 phosphorylation in the tumor cells. In vivo, SCH 717454 exhibits activity as a single agent and significantly inhibited growth of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor xenografts. Combination of SCH 717454 with cisplatin or cyclophosphamide enhanced both the degree and the duration of the in vivo antitumor activity compared with single-agent treatments. Furthermore, SCH 717454 treatment markedly reduced Ki-67 expression and blood vessel formation in tumor xenografts, showing that the in vivo activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity. Mol Cancer Ther; 9(2); 410-8. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

Wang¹,

Lipari²,

Wang³

et al. 2010

Molecular Cancer Therapeutics

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“…As such, it is critical to understand the relationship between RO and downstream PD/clinical effects when dose prediction is based on RO. For antagonistic drugs that block cell surface receptors without depletion of cells, high level of RO is required for maximum blockade of down‐stream receptor signaling 4, 5, 13 and the RO level is usually proportional to therapeutic effects. As such, RO is highly relevant as a PD.…”

Section: Considerations When Developing Flow Cytometry‐based Ro Assaysmentioning

confidence: 99%

“…To improve efficiency and reduce the costs associated with drug development, pharmacodynamic (PD) biomarkers have demonstrated promise in aiding in the rational design of clinical trials 2, 3, 4, 5, 6.…”

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Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

Liang¹,

Schwickart²,

Schneider³

et al. 2015

Cytometry Part B Clinical

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Receptor occupancy (RO) assays are designed to quantify the binding of therapeutics to their targets on the cell surface and are frequently used to generate pharmacodynamic (PD) biomarker data in nonclinical and clinical studies of biopharmaceuticals. When combined with the pharmacokinetic (PK) profile, RO data can establish PKPD relationships, which are crucial for informing dose decisions. RO is commonly measured by flow cytometry on fresh blood specimens and is subject to numerous technical and logistical challenges. To ensure that reliable and high quality results are generated from RO assays, careful assay design, key reagent characterization, data normalization/reporting, and thorough planning for implementation are of critical importance during development. In this article, the authors share their experiences and perspectives in these areas and discuss challenges and potential solutions when developing and implementing a flow cytometry‐based RO method in support of biopharmaceutical drug development. © 2015 The Authors Cytometry Part B: Clinical Cytometry Published by Wiley Periodicals, Inc.

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“…Target occupancy is often determined using peripheral blood specimens as many targets are present on the surface of circulating blood cells and blood collections are relatively noninvasive. Studies that evaluate receptor occupancy in whole blood have been reported for CD862, β7 3, 4, CD14 5, IgF‐1 receptor 6, and IL21‐receptor 7. Some of these studies were performed with peripheral blood mononuclear cells (PBMCs), and it is likely that drug bound to the blood cells partially dissociates during PBMC preparation, leading to underestimation of drug binding.…”

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confidence: 99%

Evaluation of assay interference and interpretation of CXCR4 receptor occupancy results in a preclinical study with MEDI3185, a fully human antibody to CXCR4

Schwickart¹,

Chavez²,

Henderson³

et al. 2015

Cytometry Part B Clinical

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BackgroundReceptor occupancy (RO) assays provide a means to measure the direct interaction of therapeutics with their cell surface targets. Free receptor assays quantify cell‐surface receptors not bound by a therapeutic while total receptor assays quantify the amount of target on the cell surface.MethodsWe developed both a flow cytometry‐based free RO assay to detect free surface CXCR4, and a total surface CXCR4 assay. In an effort to evaluate potential displacement interference, we performed in vitro experiments to compare on‐cell affinity with the IC50 values from in vitro and in vivo from the free CXCR4 assay. We determined free and total surface CXCR4 on circulating blood cells in cynomolgus monkeys dosed with MEDI3185, a fully human monoclonal antibody to CXCR4.ResultsWe devised an approach to evaluate displacement interference during assay development and showed that our free assay demonstrated little to no displacement interference. After dosing cynomolgus monkeys with MEDI3185, we observed dose‐dependence in the magnitude and duration of receptor occupancy and found CXCR4 to increase on lymphocytes, monocytes, and granulocytes. In a multiple dose study, we observed time points where surface CXCR4 appeared fully occupied but MEDI3185 was not detectable in serum. These paradoxical results represented a type of assay interference, and by comparing pharmacokinetic, ADA and total CXCR4 results, the most likely reason for the free CXCR4 results was the emergence of neutralizing anti‐drug antibodies (ADA). The total CXCR4 assay was unaffected by ADA and provided a reliable marker of target modulation in both in vivo studies. © 2015 The Authors Cytometry Part B: Clinical Cytometry Published byWiley Periodicals, Inc.

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Phase I, Pharmacokinetic, and Pharmacodynamic Study of AMG 479, a Fully Human Monoclonal Antibody to Insulin-Like Growth Factor Receptor 1

Abstract: AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent.

Cited by 304 publications

References 18 publications

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

Evaluation of assay interference and interpretation of CXCR4 receptor occupancy results in a preclinical study with MEDI3185, a fully human antibody to CXCR4

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