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  • 1
    Online Resource
    Online Resource
    Fit-for-purpose biomarker immunoassay qualification and validation: three case studies
    Future Science Ltd ; 2016
    In:  Bioanalysis Vol. 8, No. 22 ( 2016-11), p. 2329-2340
    Details
    In: Bioanalysis, Future Science Ltd, Vol. 8, No. 22 ( 2016-11), p. 2329-2340
    Abstract: Aim: To improve on the efficiency of biomarker assay readiness, and for reliable biomarker data to support three drug programs, we implemented a fit-for-purpose approach, qualifying two biomarker assays and validating a third. Results/methodology: The qualification strategy and selection of experiments for two exploratory biomarkers (CXCL1, CCL19) was determined by the intended use of the biomarker data. The third biomarker, IL-6, was validated as the data would be used in monitoring patient safety during dose-escalation studies in a Phase I trial. All three assays passed a priori acceptance criteria. Conclusion: These assays highlight strategies and methodologies for a fit-for-purpose approach. Minimum qualification, full qualification and validation were chosen and supported programs at different stages of drug development.
    Type of Medium: Online Resource
    ISSN: 1757-6180 , 1757-6199
    URL: Article
    DOI: 10.4155/bio-2016-0184
    Language: English
    Publisher: Future Science Ltd
    Publication Date: 2016
    SSG: 15,3
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  • 2
    Online Resource
    Online Resource
    Crystalline Antibody‐Laden Alginate Particles: A Platform for Enabling High Concentration Subcutaneous Delivery of Antibodies
    Wiley ; 2023
    In:  Advanced Healthcare Materials Vol. 12, No. 15 ( 2023-06)
    Details
    In: Advanced Healthcare Materials, Wiley, Vol. 12, No. 15 ( 2023-06)
    Abstract: Subcutaneous (SC) administration is a desired route for monoclonal antibodies (mAbs). However, formulating mAbs for small injection volumes at high concentrations with suitable stability and injectability is a significant challenge. Here, this work presents a platform technology that combines the stability of crystalline antibodies with injectability and tunability of soft hydrogel particles. Composite alginate hydrogel particles are generated via a gentle centrifugal encapsulation process which avoids use of chemical reactions or an external organic phase. Crystalline suspension of anti‐programmed cell death protein 1 (PD‐1) antibody (pembrolizumab) is utilized as a model therapeutic antibody. Crystalline forms of the mAb encapsuled in the hydrogel particles lead to stable, high concentration, and injectable formulations. Formulation concentrations as high as 315 mg mL −1 antibody are achieved with encapsulation efficiencies in the range of 89–97%, with no perceivable increase in the number of antibody aggregates. Bioanalytical studies confirm superior maintained quality of the antibody in comparison with formulation approaches involving organic phases and chemical reactions. This work illustrates tuning the alginate particles’ disintegration by using partially oxide alginates. Crystalline mAb‐laden particles are evaluated for their biocompatibility using cell‐based in vitro assays. Furthermore, the pharmacokinetics (PK) of the subcutaneously delivered human anti‐PD‐1 mAb in crystalline antibody‐laden alginate hydrogel particles in Wistar rats is evaluated.
    Type of Medium: Online Resource
    ISSN: 2192-2640 , 2192-2659
    URL: Issue
    URL: Article
    DOI: 10.1002/adhm.v12.15
    DOI: 10.1002/adhm.202202370
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2645585-7
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  • 3
    Online Resource
    Online Resource
    HGF as a Circulating Biomarker of Onartuzumab Treatment in Patients with Advanced Solid Tumors
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 6 ( 2013-06-01), p. 1122-1130
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 6 ( 2013-06-01), p. 1122-1130
    Abstract: The objective of this study was to evaluate circulating hepatocyte growth factor (cHGF) as a pharmacodynamic biomarker of Met inhibition for onartuzumab (MetMAb, OA5D5v2) in a phase I trial in patients with advanced cancers and a phase II trial in non–small cell lung cancer (NSCLC). The phase I study was a dose escalation trial with onartuzumab administered i.v. once every three weeks. The phase II study was a randomized two-arm trial in which onartuzumab or placebo was administered in combination with erlotinib in 137 patients with second and third line (2/3L) NSCLC. cHGF levels were evaluated by ELISA at multiple time points over the treatment period. Onartuzumab administration resulted in an acute and sustained rise in cHGF in both the phase I and phase II studies. Elevation in cHGF was independent of dose or drug exposure and was restricted to onartuzumab treatment. Neither higher baseline nor elevated change in cHGF levels upon treatment could simply be attributed to tumor burden or number of liver metastasis. We have shown that elevated cHGF can consistently and reproducibly be measured as a pharmacodynamic biomarker of onartuzumab activity. The elevation in cHGF is independent of tumor type, dose administered, or dose duration. Although these studies were not powered to directly address the contribution of cHGF as a predictive, on-treatment, circulating biomarker, these data suggest that measurement of cHGF in future expanded studies is warranted. Mol Cancer Ther; 12(6); 1122–30. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-13-0015
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Biomarker Analyses from a Placebo-Controlled Phase II Study Evaluating Erlotinib ± Onartuzumab in Advanced Non–Small Cell Lung Cancer: MET Expression Levels Are Predictive of Patient Benefit
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 17 ( 2014-09-01), p. 4488-4498
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 17 ( 2014-09-01), p. 4488-4498
    Abstract: Purpose: In a recent phase II study of onartuzumab (MetMAb), patients whose non–small cell lung cancer (NSCLC) tissue scored as positive for MET protein by immunohistochemistry (IHC) experienced a significant benefit with onartuzumab plus erlotinib (O+E) versus erlotinib. We describe development and validation of a standardized MET IHC assay and, retrospectively, evaluate multiple biomarkers as predictors of patient benefit. Experimental Design: Biomarkers related to MET and/or EGF receptor (EGFR) signaling were measured by IHC, FISH, quantitative reverse transcription PCR, mutation detection techniques, and ELISA. Results: A positive correlation between IHC, Western blotting, and MET mRNA expression was observed in NSCLC cell lines/tissues. An IHC scoring system of MET expression taking proportional and intensity-based thresholds into consideration was applied in an analysis of the phase II study and resulted in the best differentiation of outcomes. Further analyses revealed a nonsignificant overall survival (OS) improvement with O+E in patients with high MET copy number (mean ≥5 copies/cell by FISH); however, benefit was maintained in “MET IHC-positive”/MET FISH-negative patients (HR, 0.37; P = 0.01). MET, EGFR, amphiregulin, epiregulin, or HGF mRNA expression did not predict a significant benefit with onartuzumab; a nonsignificant OS improvement was observed in patients with high tumor MET mRNA levels (HR, 0.59; P = 0.23). Patients with low baseline plasma hepatocyte growth factor (HGF) exhibited an HR for OS of 0.519 (P = 0.09) in favor of onartuzumab treatment. Conclusions: MET IHC remains the most robust predictor of OS and progression-free survival benefit from O+E relative to all examined exploratory markers. Clin Cancer Res; 20(17); 4488–98. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-1836
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
    Online Resource
    Online Resource
    A RP-HPLC Method for the Analysis of Neostigmine Methylsulfate and Process-Related Impurities, Forced Degradation Studies, in the Injection Formulation
    Hindawi Limited ; 2021
    In:  International Journal of Analytical Chemistry Vol. 2021 ( 2021-5-11), p. 1-14
    Details
    In: International Journal of Analytical Chemistry, Hindawi Limited, Vol. 2021 ( 2021-5-11), p. 1-14
    Abstract: Neostigmine methylsulfate is an anticholinesterase agent and is clinically used for treating myasthenia gravis. It is also used for reversing nondepolarising neuromuscular blocking agents. Neostigmine methylsulfate may be administered by intravenous, intramuscular, or subcutaneous injection. In this research paper, a distinct stability-indicating reverse phase HPLC method was developed and validated for the quantitative determination of related impurities and degradation impurities in neostigmine methylsulfate API and injection formulation. The specific objective was to improve the resolution between European Pharmacopoeia listed impurity A and impurity B and degradation impurity of neostigmine methylsulfate API and injection formulation. The analysis was performed using Kromasil C18 column at 30°C of column oven temperature with phosphate-buffer/acetonitrile in a gradient mode. The RP-HPLC method was developed and validated for in-house neostigmine methylsulfate synthesis process sample and injection formulation. The injection formulation sample was studied for accelerated stability, temperature cycling stability, and photostability. The validation studies for neostigmine methylsulfate synthesis process API were studied using impurity A, impurity B, and impurity C. The analytical method validation parameters studied were specificity, precision, linearity, limit of detection, limit of quantitation, accuracy, and robustness. The API and the injection formulation were subjected to forced degradation under acid, alkali, oxidation, and photolytic and thermal conditions. The proposed method showed a significantly improved RRT (Relative Retention Time) of impurity A and impurity B with a resolution greater than 1.5. The developed method eliminates the use of an ion-pairing agent and thereby a good performance of column was established.
    Type of Medium: Online Resource
    ISSN: 1687-8779 , 1687-8760
    URL: Article
    DOI: 10.1155/2021/5570173
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2021
    detail.hit.zdb_id: 2494714-3
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