Tumor penetration and epidermal growth factor receptor saturation by panitumumab correlate with antitumor activity in a preclinical model of human cancer

Freeman, Daniel J.; McDorman, Kevin S.; Ogbagabriel, Selam; Kozlosky, Carl J.; Yang, Bing‐Bing; Doshi, Sameer; Perez-Ruxio, Juan Jose; Fanslow, William C.; Starnes, Charlie; Radinsky, Robert

doi:10.1186/1476-4598-11-47

Cited by 29 publications

(25 citation statements)

References 25 publications

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“…S2B). We hypothesized that the lack of durable remissions could be caused by insufficient tumor saturation with the immunocytokine, because antitumor activity has been correlated with a therapeutic antibody's ability to penetrate throughout tumor tissue (13). Because antitumor antibodies such as TA99 are generally far better tolerated than cytokines and can independently elicit tumoricidal immunity (14), we combined our original TA99-IL2 dose with additional TA99 murine IgG2a antibody to attain a dosage theoretically predicted to fully saturate the tumors (15).…”

Section: Resultsmentioning

confidence: 99%

Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution

Tzeng

Kwan

Opel

et al. 2015

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

101

116

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Cytokine therapy can activate potent, sustained antitumor responses, but collateral toxicity often limits dosages. Although antibody-cytokine fusions (immunocytokines) have been designed with the intent to localize cytokine activity, systemic dose-limiting side effects are not fully ameliorated by attempted tumor targeting. Using the s.c. B16F10 melanoma model, we found that a nontoxic dose of IL-2 immunocytokine synergized with tumor-specific antibody to significantly enhance therapeutic outcomes compared with immunocytokine monotherapy, concomitant with increased tumor saturation and intratumoral cytokine responses. Examination of cell subset biodistribution showed that the immunocytokine associated mainly with IL-2R-expressing innate immune cells, with more bound immunocytokine present in systemic organs than the tumor microenvironment. More surprisingly, immunocytokine antigen specificity and Fcγ receptor interactions did not seem necessary for therapeutic efficacy or biodistribution patterns because immunocytokines with irrelevant specificity and/or inactive mutant Fc domains behaved similarly to tumor-specific immunocytokine. IL-2-IL-2R interactions, rather than antibody-antigen targeting, dictated immunocytokine localization; however, the lack of tumor targeting did not preclude successful antibody combination therapy. Mathematical modeling revealed immunocytokine size as another driver of antigen targeting efficiency. This work presents a safe, straightforward strategy for augmenting immunocytokine efficacy by supplementary antibody dosing and explores underappreciated factors that can subvert efforts to purposefully alter cytokine biodistribution.immunocytokine | biodistribution | immunotherapy | antibody | IL-2

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Section: Resultsmentioning

confidence: 99%

Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution

Tzeng

Kwan

Opel

et al. 2015

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

101

116

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“…For example, the percent of EGFR saturation by panitumumab was determined in dissociated tumor tissue from xenograft models 36. In fact, RO in the tissue relevant to drug action may be more appropriate than assessment in blood, particularly when drug partitioning to the tissue is low.…”

Section: Considerations When Developing Flow Cytometry‐based Ro Assaysmentioning

confidence: 99%

“…To limit enzymatic cleavage and receptor internalization, RO assays may be performed at 4°C as lower temperatures reduce these activities. Other approaches, such as prior treatment of cells with sodium azide 36, 43, 44 to abolish ATP‐depended receptor internalization or the use of protease inhibitors to inhibit rapid receptor shedding 45, may be effective means in overcoming such challenges.…”

Section: Considerations When Developing Flow Cytometry‐based Ro Assaysmentioning

confidence: 99%

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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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“…remains disappointing since the average response rate has generally been low in human, at around 15% of patients (1). A better characterization of drug mechanism of action and target engagement coupled with a better understanding of the relationship between drug pharmacokinetic and pharmacodynamics is needed (2). Robust data to support dose selection and optimization of regimen before pivotal trials are critical to substantially shorten the time to reach strategic points during the clinical development.…”

mentioning

confidence: 99%

How validated receptor occupancy flow cytometry assays can impact decisions and support drug development

Moulard¹,

Ozoux

2015

Cytometry Part B Clinical

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Because of the pressure of significant attrition in drug development, demonstration of target engagement after drug administration enables dose and regimen optimization, patient selection, and stratification from the earliest stages of drug development. The determination of receptor occupancy (RO) can support these efforts. Flow cytometry is one of the preferred technologies to be used based on the important advances in the technology over the last years enabling the simultaneous determination on target cells, of multi intra or surface cell parameters with adequate precision in a regulated environment. Nevertheless, compared to other platforms using the same antigen-antibody binding concept, the flow cytometry approach has faced several challenges, not only due to the technology per se and the diversity of receptor occupancy approaches, but also related to the nature of the matrix where the determination is performed. To illustrate these points, three case studies (antibody-drug conjugate and naked antibody) are provided here to highlight the importance of the choice of the right antibody pair to measure both receptor density (RD) and occupancy by the drug on cancer cells in blood and in bone marrow and the possibility to circumvent the lack of a critical reagent with an innovative approach. In addition, the use of RO data to determine the minimum anticipated biological effect level (MABEL) with translational data from preclinical to human studies, selection of starting dose for the first in man study will be discussed. In the last couple of years, the advent of molecular medicine and targeted therapy has opened up innovative areas of investigation, allowing not only the development of new highly specific drugs but also a concomitant progress for the discovery of new approaches. These approaches fit perfectly with the development of antibody-based therapeutics since the drug and its target are clearly identified and unique. Nevertheless, the clinical development of targeted therapies (naked antibodies, immunoconjugates, etc.) remains disappointing since the average response rate has generally been low in human, at around 15% of patients (1). A better characterization of drug mechanism of action and target engagement coupled with a better understanding of the relationship between drug pharmacokinetic and pharmacodynamics is needed (2). Robust data to support dose selection and optimization of regimen before pivotal trials are critical to substantially shorten the time to reach strategic points during the clinical development. The use of RO in early phases of the drug discovery process to demonstrate proof of mechanism of the drug could eventually reduce the development risks, including the Cytometry Part B (Clinical Cytometry) 90B: 150-158 (2016)

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Tumor penetration and epidermal growth factor receptor saturation by panitumumab correlate with antitumor activity in a preclinical model of human cancer

Cited by 29 publications

References 25 publications

Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution

Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution

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

How validated receptor occupancy flow cytometry assays can impact decisions and support drug development

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