Coupling of Aggregation and Immunogenicity in Biotherapeutics: T- and B-Cell Immune Epitopes May Contain Aggregation-Prone Regions

Kumar, Sandeep; Singh, Satish K.; Wang, Xiaoling; Rup, Bonita; Gill, Davinder

doi:10.1007/s11095-011-0414-9

Cited by 83 publications

(65 citation statements)

References 46 publications

(86 reference statements)

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“…Macromolecular aggregates are one of several potential risk factors for adverse immunogenic responses to biotherapeutic drugs. 4,5 Moreover, aggregation might lead to a decrease in biotherapeutic activity, and has implications for regulatory approval and delivery methods.…”

Section: Introductionmentioning

confidence: 99%

Aggregation in Protein-Based Biotherapeutics: Computational Studies and Tools to Identify Aggregation-Prone Regions

Agrawal

Kumar

Wang

et al. 2011

Journal of Pharmaceutical Sciences

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129

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Section: Introductionmentioning

confidence: 99%

Aggregation in Protein-Based Biotherapeutics: Computational Studies and Tools to Identify Aggregation-Prone Regions

Agrawal

Kumar

Wang

et al. 2011

Journal of Pharmaceutical Sciences

Self Cite

129

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“…The immunogenicity studies indicated that Sak(E80C-PEG) had greatly reduced immunogenicity in guinea pigs. Some researchers thought that immunogenicity of protein was associated with protein aggregate [26]. However, aggregates of Sak(E80C-PEG) were not observed in either SDS-PAGE or SEC-HPLC analysis.…”

Section: Discussionmentioning

confidence: 99%

Effect of site-specific PEGylation on the fibrinolytic activity, immunogenicity, and pharmacokinetics of staphylokinase

Liu¹,

Wang²,

He³

et al. 2014

ABBS

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The bacterial plasminogen-activator staphylokinase (Sak) is a promising thrombolytic agent for treating acute myocardial infarction. To effectively reduce the immunogenicity of Sak while maintaining its fibrinolytic activity, site-specific PEGylation was performed in the present study. The chemoselective cysteine PEGylation site was selected within an immunodominant region (amino acid residues 71-87) using an in silico approach. The PEGylated Sak variants prepared in this study showed a purity of >97.0%. PEGylation at Position 80 resulted in a Sak variant Sak(E80C-PEG) which has similar fibrinolytic activity and thermostability compared with the native recombinant staphylokinase (r-Sak). The immunogenicity of Sak(E80C-PEG) in guinea pigs was greatly reduced compared with the native r-Sak. Furthermore, preliminary pharmacokinetic results suggested that the plasma clearance of Sak(E80C-PEG) from the blood stream of rabbit was significantly decreased compared with that of r-Sak, resulting in a 2.8-fold increase of initial half-life and a 3.8-fold increase of systemic availability. In summary, these results demonstrated that site-specific PEGylation yielded a novel Sak variant Sak(E80C-PEG) with remarkable advantages over the unmodified Sak.

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“…Thus, it is desirable to use in silico or in vitro human cell-based assessments for the immunogenicity prediction, including predictions of aggregation prone regions and T and B cell epitopes. To this end, Kumar et al described the importance of investigating the impact of aggregation on immunogenicity and potential coupling of T and B cell epitopes and aggregation-prone regions (61). Computational tools that can predict aggregation prone regions as well as T-and B-cell immune epitopes from protein sequence and structure have become available recently from several commercial vendors (58,(62)(63)(64).…”

Section: In Vitro Predictive Tools For Immunogenicitymentioning

confidence: 99%

Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics

Vugmeyster

2012

AAPS J

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Abstract. With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for delivering therapeutic biologics (e.g., needle-free devices, nanoparticle complexes), as well as novel approaches for disease treatments (e.g., stem cell therapy, individualized medicine), continue to be developed. While pharmacokinetic studies are routinely carried out for therapeutic biologics, experiments that elucidate underlying mechanisms for clearance and biodistribution or identify key factors that govern absorption, distribution, metabolism, and excretion (ADME) of biologics often are not thoroughly conducted. Realizing the importance of biologics as therapeutic agents, pharmaceutical industry has recently begun to move the research focus from small molecules only to a blended portfolio consisting of both small molecules and biologics. This trend brings many opportunities for scientists working in the drug disposition research field. In anticipation of these opportunities and associated challenges, this review highlights impact of ADME studies on clinical and commercial success of biologics, with a particular focus on emerging applications and technologies and linkage with mechanistic pharmacokinetic/pharmacodynamic modeling and biomarker research.

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Coupling of Aggregation and Immunogenicity in Biotherapeutics: T- and B-Cell Immune Epitopes May Contain Aggregation-Prone Regions

Cited by 83 publications

References 46 publications

Aggregation in Protein-Based Biotherapeutics: Computational Studies and Tools to Identify Aggregation-Prone Regions

Aggregation in Protein-Based Biotherapeutics: Computational Studies and Tools to Identify Aggregation-Prone Regions

Effect of site-specific PEGylation on the fibrinolytic activity, immunogenicity, and pharmacokinetics of staphylokinase

Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics

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