Quantitative Evaluation of Insoluble Particulate Matters in Therapeutic Protein Injections Using Light Obscuration and Flow Imaging Methods

Shibata, Hiroko; Harazono, Akira; Kiyoshi, Masato; Ishii‐Watabe, Akiko

doi:10.1016/j.xphs.2021.09.047

Cited by 12 publications

(3 citation statements)

References 25 publications

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“…The FlowCam is a relatively new instrument that is beginning to be used to accelerate the morphological analysis of particles and microorganisms but has yet to be widely employed in the field of colloidal synthesis. [28][29][30][33][34][35][36][37][38][39] The FlowCam uses flow imaging microscopy for the rapid acquisition of particle images, in conjunction with VisualSpreadsheet 6 software for rapid analysis of 39 geometric parameters (e.g., edge gradient, length, width, aspect ratio). Flow imaging microscopy digitally captures particles by streaming a particle-containing liquid through a microscope.…”

Section: Resultsmentioning

confidence: 99%

Toward One‐Way Smoke: Synthesis of Copper‐Based Microclubs with Asymmetric Scattering and Absorption

Guo,

Boyarsky,

Vigil

et al. 2024

Adv Funct Materials

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The ultimate goal of this work is to create an engineered aerosol that acts as one‐way smoke, i.e. it creates an asymmetric vision environment in which the ability to image objects depends on the viewing direction. To this end, a rapid, one‐pot synthesis of copper‐based microclubs is developed that consists of a Cu2O octahedron attached to a Cu2O@Cu shaft. Millions of synthesized particles are analyzed in minutes with a FlowCam to provide a robust statistical analysis of their geometry, and rapidly elucidate the roles of the reaction constituents on the particle shape and yield. The combination of asymmetry in both shape and composition introduces a 30% difference in scattering of light propagating parallel to the microclub axis from opposing directions. This work represents a first step toward the creation of an asymmetric imaging environment with an aerosol consisting of acoustically aligned microclubs.

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Section: Resultsmentioning

confidence: 99%

Toward One‐Way Smoke: Synthesis of Copper‐Based Microclubs with Asymmetric Scattering and Absorption

Guo,

Boyarsky,

Vigil

et al. 2024

Adv Funct Materials

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“…3 Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD, USA. * email: Scott.Lute@fda.hhs.gov; Ashwinkumar.Bhirde@fda.hhs.gov been reported that LO typically underestimates the counts and sizes of proteinaceous particles as these values are significantly influenced by the optical property of a sample [9][10][11] . MM systems can render particle images and morphological data along with particle counts, however, chemical identification of the particles is not possible 12,13 .…”

mentioning

confidence: 99%

“…Unlike the post-filtration analysis of MM, MDRS can evaluate the SVP in their native state, avoiding distortion of soft proteinaceous particles. In addition, previous high-throughput particle analysis studies have focused on particle quantitation and conducted particle identification solely depending on their images [9][10][11][12][13] . Our findings show that along with detailed morphological information, MDRS provides chemical identification of individual particles, which is more definitive approach.…”

mentioning

confidence: 99%

Morphologically-Directed Raman Spectroscopy as an Analytical Method for Subvisible Particle Characterization in Therapeutic Protein Product Quality

Kim,

Ma,

Srinivasan

et al. 2023

Sci Rep

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Subvisible particles (SVPs) are a critical quality attribute of injectable therapeutic proteins (TPs) that needs to be controlled due to potential risks associated with drug product quality. The current compendial methods routinely used to analyze SVPs for lot release provide information on particle size and count. However, chemical identification of individual particles is also important to address root-cause analysis. Herein, we introduce Morphologically-Directed Raman Spectroscopy (MDRS) for SVP characterization of TPs. The following particles were used for method development: (1) polystyrene microspheres, a traditional standard used in industry; (2) photolithographic (SU-8); and (3) ethylene tetrafluoroethylene (ETFE) particles, candidate reference materials developed by NIST. In our study, MDRS rendered high-resolution images for the ETFE particles (> 90%) ranging from 19 to 100 μm in size, covering most of SVP range, and generated comparable morphology data to flow imaging microscopy. Our method was applied to characterize particles formed in stressed TPs and was able to chemically identify individual particles using Raman spectroscopy. MDRS was able to compare morphology and transparency properties of proteinaceous particles with reference materials. The data suggests MDRS may complement the current TPs SVP analysis system and product quality characterization workflow throughout development and commercial lifecycle.

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Fcγ Receptor-Dependent Internalization and Off-Target Cytotoxicity of Antibody-Drug Conjugate Aggregates

et al. 2021

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Purpose Antibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific delivery of payloads in accordance with mAbs’ function. On the other hand, the conjugation of payloads often increases the hydrophobicity of mAbs, resulting in reduced stability and increased aggregation. It is considered that mAb aggregates have potential risk for activating Fcγ receptors (FcγRs) on immune cells, and are internalized into cells via FcγRs. Based on the mechanism of action of ADCs, the internalization of ADCs into target-negative cells may cause the off-target toxicity. However, the impacts of aggregation on the safety of ADCs including off-target cytotoxicity have been unclear. In this study, we investigated the cytotoxicity of ADC aggregates in target-negative cells. Methods The ADC aggregates were generated by stirring stress or thermal stress. The off-target cytotoxicity of ADC aggregates was evaluated in several target-negative cell lines, and FcγR-activation properties of ADC aggregates were characterized using a reporter cell assay. Results Aggregation of ADCs enhanced the off-target cytotoxicity in several target-negative cell lines compared with non-stressed ADCs. Notably, ADC aggregates with FcγR-activation properties showed dramatically enhanced cytotoxicity in FcγR-expressing cells. The FcγR-mediated off-target cytotoxicity of ADC aggregates was reduced by using a FcγR-blocking antibody or Fc-engineering for silencing Fc-mediated effector functions. Conclusions These results indicated that FcγRs play an important role for internalization of ADC aggregates into non-target cells, and the aggregation of ADCs increases the potential risk for off-target toxicity.

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Quantitative Evaluation of Insoluble Particulate Matters in Therapeutic Protein Injections Using Light Obscuration and Flow Imaging Methods

Abstract: Quantitative evaluation of insoluble particulate matters in therapeutic protein injections using light obscuration and flow imaging methods.,

Cited by 12 publications

References 25 publications

Toward One‐Way Smoke: Synthesis of Copper‐Based Microclubs with Asymmetric Scattering and Absorption

Toward One‐Way Smoke: Synthesis of Copper‐Based Microclubs with Asymmetric Scattering and Absorption

Morphologically-Directed Raman Spectroscopy as an Analytical Method for Subvisible Particle Characterization in Therapeutic Protein Product Quality

Fcγ Receptor-Dependent Internalization and Off-Target Cytotoxicity of Antibody-Drug Conjugate Aggregates

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