Of [hamsters] and men

Gutiérrez, Andres H.; Moise, Leonard; Groot, Anne S. De

doi:10.4161/hv.22378

Cited by 39 publications

(11 citation statements)

References 23 publications

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“…It is impossible to predict the human response to trace HCP impurities, but it is hypothesized that the more dissimilar an impurity is to human proteins, the more likely the impurity is to elicit an immune response in humans (Wang et al, 2009). While it is uncommon, two clinical trials were recently withdrawn due to anti-CHO responses in human patients (Gutierrez et al, 2012; Hanania et al, 2015). In addition to adverse health consequences for the patient, enzymatically-active HCP impurities can potentially impact product quality during processing or long-term storage (Gao et al, 2011; Robert et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Knockout of a difficult‐to‐remove CHO host cell protein, lipoprotein lipase, for improved polysorbate stability in monoclonal antibody formulations

Chiu

Valente

Levy

et al. 2016

Biotech & Bioengineering

166

154

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While the majority of host cell protein (HCP) impurities are effectively removed in typical downstream purification processes, a small population of HCPs are particularly challenging. Previous studies have identified HCPs that are challenging for a variety of reasons. Lipoprotein lipase (LPL) – a Chinese hamster ovary (CHO) HCP that functions to hydrolyze esters in triglycerides – was one of ten HCPs identified in previous studies as being susceptible to retention in downstream processing. LPL may degrade polysorbate 80 (PS-80) and polysorbate 20 (PS-20) in final product formulations due to the structural similarity between polysorbates and triglycerides. In this work, recombinant LPL was found to have enzymatic activity against PS-80 and PS-20 in a range of solution conditions that are typical of mAb formulations. LPL knockout CHO cells were created with CRISPR and TALEN technologies and resulting cell culture harvest fluid demonstrated a significantly reduced polysorbate degradation without significant impact on cell viability when compared to wild type samples.

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Section: Introductionmentioning

confidence: 99%

Knockout of a difficult‐to‐remove CHO host cell protein, lipoprotein lipase, for improved polysorbate stability in monoclonal antibody formulations

Chiu

Valente

Levy

et al. 2016

Biotech & Bioengineering

166

154

View full text Add to dashboard Cite

show abstract

“…In addition to identifying individual epitopes within a protein, EpiMatrix can then also assess the overall immunogenicity risk of a protein according to its epitope density relative to benchmark proteins (De Groot and Martin, 2009 ; Koren et al, 2007 ). Publication of the CHO genome in 2011 ( Xu et al, 2011 ) made it possible to examine the entire genome for potentially immunogenic proteins, using well-validated epitope prediction tools ( Gutierrez et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

CHOPPI: A web tool for the analysis of immunogenicity risk from host cell proteins in CHO‐based protein production

Bailey‐Kellogg

Gutiérrez

Moise

et al. 2014

Biotech & Bioengineering

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Despite high quality standards and continual process improvements in manufacturing, host cell protein (HCP) process impurities remain a substantial risk for biological products. Even at low levels, residual HCPs can induce a detrimental immune response compromising the safety and efficacy of a biologic. Consequently, advanced-stage clinical trials have been cancelled due to the identification of antibodies against HCPs. To enable earlier and rapid assessment of the risks in Chinese Hamster Ovary (CHO)-based protein production of residual CHO protein impurities (CHOPs), we have developed a web tool called CHOPPI, for CHO Protein Predicted Immunogenicity. CHOPPI integrates information regarding the possible presence of CHOPs (expression and secretion) with characterizations of their immunogenicity (T cell epitope count and density, and relative conservation with human counterparts). CHOPPI can generate a report for a specified CHO protein (e.g., identified from proteomics or immunoassays) or characterize an entire specified subset of the CHO genome (e.g., filtered based on confidence in transcription and similarity to human proteins). The ability to analyze potential CHOPs at a genomic scale provides a baseline to evaluate relative risk. We show here that CHOPPI can identify clear differences in immunogenicity risk among previously validated CHOPs, as well as identify additional “risky” CHO proteins that may be expressed during production and induce a detrimental immune response upon delivery. We conclude that CHOPPI is a powerful tool that provides a valuable computational complement to existing experimental approaches for CHOP risk assessment and can focus experimental efforts in the most important directions. Biotechnol. Bioeng. 2014;111: 2170–2182.

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“…Despite rigorous clean-up procedures during downstream processing, minor amounts of these host cell proteins (HCPs) may be co-purified with the therapeutic protein and remain in the final drug product (DP) [1][2][3][4][5]. Since these contaminating proteins may affect DP quality [6][7][8][9][10][11][12] or provoke immune responses when the drug is administered [13,14], HCPs are generally considered in the context of critical quality attributes (CQAs) and product quality attributes (PQAs) [15]. Hence, sensitive and reliable analytical procedures for identifying and quantifying these impurities are indispensable for the production and release of biopharmaceuticals.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Exploring sample preparation and data evaluation strategies for enhanced identification of host cell proteins in drug products of therapeutic antibodies and Fc-fusion proteins

et al. 2020

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Manufacturing of biopharmaceuticals involves recombinant protein expression in host cells followed by extensive purification of the target protein. Yet, host cell proteins (HCPs) may persist in the final drug product, potentially reducing its quality with respect to safety and efficacy. Consequently, residual HCPs are closely monitored during downstream processing by techniques such as enzyme-linked immunosorbent assay (ELISA) or high-performance liquid chromatography combined with tandem mass spectrometry (HPLC-MS/MS). The latter is especially attractive as it provides information with respect to protein identities. Although the applied HPLC-MS/MS methodologies are frequently optimized with respect to HCP identification, acquired data is typically analyzed using standard settings. Here, we describe an improved strategy for evaluating HPLC-MS/MS data of HCP-derived peptides, involving probabilistic protein inference and peptide detection in the absence of fragment ion spectra. This data analysis workflow was applied to data obtained for drug products of various biotherapeutics upon protein A affinity depletion. The presented data evaluation strategy enabled in-depth comparative analysis of the HCP repertoires identified in drug products of the monoclonal antibodies rituximab and bevacizumab, as well as the fusion protein etanercept. In contrast to commonly applied ELISA strategies, the here presented workflow is process-independent and may be implemented into existing HPLC-MS/MS setups for drug product characterization and process development.

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Of [hamsters] and men

Cited by 39 publications

References 23 publications

Knockout of a difficult‐to‐remove CHO host cell protein, lipoprotein lipase, for improved polysorbate stability in monoclonal antibody formulations

Knockout of a difficult‐to‐remove CHO host cell protein, lipoprotein lipase, for improved polysorbate stability in monoclonal antibody formulations

CHOPPI: A web tool for the analysis of immunogenicity risk from host cell proteins in CHO‐based protein production

Exploring sample preparation and data evaluation strategies for enhanced identification of host cell proteins in drug products of therapeutic antibodies and Fc-fusion proteins

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