Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Tomar, Dheeraj S.; Kumar, Sandeep; Singh, Satish K.; Goswami, Sumit; Li, Li

doi:10.1080/19420862.2015.1128606

Cited by 160 publications

(156 citation statements)

References 89 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…6,7,18,21,23 Potential strategies to mitigate self-association and other undesired high concentration solution properties may include protein engineering approaches, 20,[24][25][26] as well as formulation development and optimization efforts. [5][6][7]9,18,19,21,23,27 While the former can be limited due to the degree of knowledge of sites of interactions, the latter can be time and resource intensive and may not always be fully successful to a desired degree for all antibodies. Historically, a number of computational and analytical screening methods have been used to predict aggregation [28][29][30] and high concentration formulation risks.…”

Section: Introductionmentioning

confidence: 99%

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Geoghegan¹,

Fleming²,

Damschroder³

et al. 2016

mAbs

View full text Add to dashboard Cite

Undesired solution behaviors such as reversible self-association (RSA), high viscosity, and liquid-liquid phase separation can introduce substantial challenges during development of monoclonal antibody formulations. Although a global mechanistic understanding of RSA (i.e., native and reversible proteinprotein interactions) is sufficient to develop robust formulation controls, its mitigation via protein engineering requires knowledge of the sites of protein-protein interactions. In the study reported here, we coupled our previous hydrogen-deuterium exchange mass spectrometry findings with structural modeling and in vitro screening to identify the residues responsible for RSA of a model IgG1 monoclonal antibody (mAb-C), and rationally engineered variants with improved solution properties (i.e., reduced RSA and viscosity). Our data show that mutation of either solvent-exposed aromatic residues within the heavy and light chain variable regions or buried residues within the heavy chain/light chain interface can significantly mitigate RSA and viscosity by reducing the IgG's surface hydrophobicity. The engineering strategy described here highlights the utility of integrating complementary experimental and in silico methods to identify mutations that can improve developability, in particular, high concentration solution properties, of candidate therapeutic antibodies.

show abstract

Section: Introductionmentioning

confidence: 99%

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Geoghegan¹,

Fleming²,

Damschroder³

et al. 2016

mAbs

View full text Add to dashboard Cite

show abstract

“…In particular, those involved in methionine oxidation, lysine glycation, asparagine deamidation and aspartate isomerization are discussed with help of case studies. However, applications of computational modelling also extend towards assessing other issues in biologic drug developability, such as aggregation, immunogenicity, viscosity of concentrated antibody solutions and pharmacology . In recent years, computational approaches are finding ever‐increasing applications in the biologics drug development (see different chapters in the book by Kumar and Singh).…”

Section: What Is Biopharmaceutical Informatics?mentioning

confidence: 99%

“…Chemical degradation of proteins not only represents problems in formulation and pharmacological properties of biologic drug products, but it is also associated with several ageing‐related diseases in humans . Although this review has focused on chemical degradation liabilities, similar computational approaches are also being used to study other challenges faced in development of biologic drugs including aggregation, purification and high viscosity . Computation can also be used to understand and estimate pharmacokinetics, pharmacodynamics and immunogenicity of biologics in vivo .…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Biopharmaceutical Informatics: supporting biologic drug development via molecular modelling and informatics

Kumar

Plotnikov

Rouse

et al. 2018

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

Objectives The purpose of this article is to introduce an emerging field called 'Biopharmaceutical Informatics'. It describes how tools from Information technology and Molecular Biophysics can be adapted, developed and gainfully employed in discovery and development of biologic drugs. Key Findings The findings described here are based on literature surveys and the authors' collective experiences in the field of biologic drug product development. A strategic framework to forecast early the hurdles faced during drug product development is weaved together and elucidated using chemical degradation as an example. Efficiency of translating biologic drug discoveries into drug products can be significantly improved by combining learnings from experimental biophysical and analytical data on the drug candidates with molecular properties computed from their sequences and structures via molecular modeling and simulations. Summary Biopharmaceutical Informatics seeks to promote applications of computational tools towards discovery and development of biologic drugs. When fully implemented, industry-wide, it will enable rapid materials-free developability assessments of biologic drug candidates at early stages as well as streamline drug product development activities such as commercial scale production, purification, formulation, analytical characterization, safety and in vivo performance.

show abstract

“…In case of high protein doses that need to be administered, being typically the case for monoclonal antibodies, high protein concentrations are required. For single‐entity products, it is well described in the literature that high protein concentrations may result into increased viscosity, protein aggregation and/or decreased solubility as the solution conditions deviate more and more from being ideal resulting into increased protein–protein interactions due to molecular crowding phenomena . Elevated protein aggregation may become problematic when long‐term stability issues result into insufficient product safety and/or insufficient shelf life.…”

Section: Considerations For Fdc Pharmaceutical Technical Developmentmentioning

confidence: 99%

Challenges for the pharmaceutical technical development of protein coformulations

Mueller

Altenburger

Mohl

2018

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives This review discusses challenges to stability, analytics and manufacturing of protein coformulations. Furthermore, general considerations to be taken into account for the pharmaceutical development of coformulated protein drug products are highlighted. Key findings Coformulation of two or more active substances in one single dosage form has recently seen increasing use offering several advantages, such as increased efficacy and/or the overall reduction of adverse event incidents in patients. Most marketed coformulated drug products are composed of small molecules. As proteins are not only comparatively large but also complex molecules, the maintenance of their physicochemical integrity within a formulation throughout pharmaceutical processing, storage, transport, handling and patient administration to ensure proper pharmacokinetics and pharmacodynamics in vivo already represents various challenges for single-entity products. Thus, nowadays, only sparse biologics-based coformulations can be found, as additional complexity during development is given for these products. Summary The complexity of the dosage form and the protein molecules results into additional challenges to formulation, manufacture, storage, transport, handling and patient administration, stability and analytics during the pharmaceutical development of protein coformulations. Various points have to be considered during different stages of development in order to obtain a safe and efficacious product.

show abstract

Molecular basis of high viscosity in concentrated antibody solutions: Strategies for high concentration drug product development

Cited by 160 publications

References 89 publications

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering

Biopharmaceutical Informatics: supporting biologic drug development via molecular modelling and informatics

Challenges for the pharmaceutical technical development of protein coformulations

Contact Info

Product

Resources

About