Protein aggregation, particle formation, characterization & rheology

In this review, we attempt to give a concise overview of recent progress made in mechanistic understanding of protein aggregation, particulate formation and protein solution rheology. Recent advances in analytical techniques and methods for characterizing protein aggregation and the formed protein particles as well as advancements, technique limitations and controversies in the field of protein solution rheology are discussed. The focus of the review is primarily on biotherapeutics and proteins/antibodies that are relevant to that area. As per the remit of Current Opinion in Colloid and Interface Science, here we attempt to stimulate interest in areas of debate. While the field is certainly not mature enough that all problems may be considered resolved and accepted by consensus, we wish to highlight some areas of controversy and debate that need further attention from the scientific community.

[1]  J. King,et al.  Glutamine Deamidation Destabilizes Human γD-Crystallin and Lowers the Kinetic Barrier to Unfolding* , 2006, Journal of Biological Chemistry.

[2]  Arpan Nayak,et al.  Characterization of subvisible particle formation during the filling pump operation of a monoclonal antibody solution. , 2011, Journal of pharmaceutical sciences.

[3]  Peter Fischer,et al.  The self-assembly, aggregation and phase transitions of food protein systems in one, two and three dimensions , 2013, Reports on progress in physics. Physical Society.

[4]  William Leach,et al.  Explaining the non-newtonian character of aggregating monoclonal antibody solutions using small-angle neutron scattering. , 2014, Biophysical journal.

[5]  G. Tiana,et al.  Kinetics of different processes in human insulin amyloid formation. , 2007, Journal of molecular biology.

[6]  K. Wittrup,et al.  Context‐dependent mutations predominate in an engineered high‐affinity single chain antibody fragment , 2006, Protein science : a publication of the Protein Society.

[7]  Wim Jiskoot,et al.  Particles in therapeutic protein formulations, Part 1: overview of analytical methods. , 2012, Journal of pharmaceutical sciences.

[8]  D. Dunstan,et al.  The effects of shear flow on protein structure and function , 2011, Biopolymers.

[9]  Stefan Fischer,et al.  Protein Aggregation and Particle Formation: Effects of Formulation, Interfaces, and Drug Product Manufacturing Operations , 2010 .

[10]  D. Durand,et al.  Controlled food protein aggregation for new functionality , 2013 .

[11]  William F. Weiss,et al.  Characterization of high-molecular-weight nonnative aggregates and aggregation kinetics by size exclusion chromatography with inline multi-angle laser light scattering. , 2009, Journal of pharmaceutical sciences.

[12]  P. Schurtenberger,et al.  A new instrument for time-resolved static and dynamic light-scattering experiments in turbid media. , 2009, Journal of colloid and interface science.

[13]  A. Grillo,et al.  Conformational origin of the aggregation of recombinant human factor VIII. , 2001, Biochemistry.

[14]  Christopher J Roberts,et al.  A Lumry-Eyring nucleated polymerization model of protein aggregation kinetics: 1. Aggregation with pre-equilibrated unfolding. , 2007, The journal of physical chemistry. B.

[15]  S. Shire,et al.  Influence of the cosolute environment on IgG solution structure analyzed by small-angle X-ray scattering. , 2012, The journal of physical chemistry. B.

[16]  S. Shire,et al.  Characterization of Particles in Protein Solutions: Reaching the Limits of Current Technologies , 2010, The AAPS Journal.

[17]  S. D. Hudson,et al.  The limitations of an exclusively colloidal view of protein solution hydrodynamics and rheology. , 2013, Biophysical journal.

[18]  Sandeep Yadav,et al.  The influence of charge distribution on self-association and viscosity behavior of monoclonal antibody solutions. , 2012, Molecular pharmaceutics.

[19]  Nicholas J. Clark,et al.  Small-angle neutron scattering study of a monoclonal antibody using free-energy constraints. , 2013, The journal of physical chemistry. B.

[20]  Christopher J Roberts,et al.  Non‐native protein aggregation kinetics , 2007, Biotechnology and bioengineering.

[21]  A. Minton Implications of macromolecular crowding for protein assembly. , 2000, Current opinion in structural biology.

[22]  Jared S. Bee,et al.  Production of particles of therapeutic proteins at the air–water interface during compression/dilation cycles , 2012 .

[23]  L. Silbert,et al.  THE RHEOLOGY AND MICROSTRUCTURE OF CONCENTRATED, AGGREGATED COLLOIDS , 1999 .

[24]  David E. Williams,et al.  Orientation of a monoclonal antibody adsorbed at the solid/solution interface: a combined study using atomic force microscopy and neutron reflectivity. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[25]  P. Baglioni,et al.  Lysozyme protein solution with an intermediate range order structure. , 2011, The journal of physical chemistry. B.

[26]  Babatunde A. Ogunnaike,et al.  Multi-variate approach to global protein aggregation behavior and kinetics: effects of pH, NaCl, and temperature for alpha-chymotrypsinogen A. , 2010, Journal of pharmaceutical sciences.

[27]  Jens Feder,et al.  Scaling behavior and cluster fractal dimension determined by light scattering from aggregating proteins , 1984 .

[28]  S. Manalis,et al.  Integrated measurement of the mass and surface charge of discrete microparticles using a suspended microchannel resonator. , 2009, Analytical chemistry.

[29]  A. Minton,et al.  Static light scattering from concentrated protein solutions II: experimental test of theory for protein mixtures and weakly self-associating proteins. , 2009, Biophysical journal.

[30]  J. Philo,et al.  A critical review of methods for size characterization of non-particulate protein aggregates. , 2009, Current pharmaceutical biotechnology.

[31]  Christopher J Roberts,et al.  Aggregation of anti-streptavidin immunoglobulin gamma-1 involves Fab unfolding and competing growth pathways mediated by pH and salt concentration. , 2013, Biophysical chemistry.

[32]  L. Margulis,et al.  Aggregation of Recombinant Bovine Granulocyte Colony Stimulating Factor in Solution , 2002, Journal of protein chemistry.

[33]  William F Weiss,et al.  Principles, approaches, and challenges for predicting protein aggregation rates and shelf life. , 2009, Journal of pharmaceutical sciences.

[34]  S. Shire,et al.  A critical review of analytical ultracentrifugation and field flow fractionation methods for measuring protein aggregation , 2006, The AAPS Journal.

[35]  E. Foegeding,et al.  Stability and mechanism of whey protein soluble aggregates thermally treated with salts , 2012 .

[36]  J. Ouyang,et al.  High‐pressure refolding of bikunin: Efficacy and thermodynamics , 2004, Protein science : a publication of the Protein Society.

[37]  T. Dillon,et al.  Conformational implications of an inversed pH-dependent antibody aggregation. , 2009, Journal of pharmaceutical sciences.

[38]  R. Murphy,et al.  Evaluation of Nanoparticle Tracking for Characterization of Fibrillar Protein Aggregates. , 2014, AIChE journal. American Institute of Chemical Engineers.

[39]  P. Baglioni,et al.  Distinguishing the monomer to cluster phase transition in concentrated lysozyme solutions by studying the temperature dependence of the short-time dynamics , 2012, Journal of physics. Condensed matter : an Institute of Physics journal.

[40]  Dean C Ripple,et al.  Protein particles: what we know and what we do not know. , 2012, Journal of pharmaceutical sciences.

[41]  Michael Sztucki,et al.  Viscosity and diffusion: crowding and salt effects in protein solutions , 2011, 1109.3101.

[42]  Lars Linden,et al.  Salt-induced aggregation of a monoclonal human immunoglobulin G1. , 2013, Journal of pharmaceutical sciences.

[43]  N. Ban,et al.  Atomic structures of the eukaryotic ribosome. , 2012, Trends in biochemical sciences.

[44]  P. Schurtenberger,et al.  A closer look at arrested spinodal decomposition in protein solutions , 2009, Journal of physics. Condensed matter : an Institute of Physics journal.

[45]  Christopher J Roberts,et al.  Therapeutic protein aggregation: mechanisms, design, and control. , 2014, Trends in biotechnology.

[46]  P. Pranay,et al.  Characterization of protein rheology and delivery forces for combination products. , 2012, Journal of pharmaceutical sciences.

[47]  Yatin Gokarn,et al.  Small-angle neutron scattering characterization of monoclonal antibody conformations and interactions at high concentrations. , 2013, Biophysical journal.

[48]  Sandeep Yadav,et al.  Monoclonal antibody self-association, cluster formation, and rheology at high concentrations. , 2013, The journal of physical chemistry. B.

[49]  Linda O. Narhi,et al.  Chemical Modifications in Therapeutic Protein Aggregates Generated under Different Stress Conditions , 2011, The Journal of Biological Chemistry.

[50]  D. Foguel,et al.  Hydrostatic pressure rescues native protein from aggregates. , 1999, Biotechnology and bioengineering.

[51]  R. Colby,et al.  Both protein adsorption and aggregation contribute to shear yielding and viscosity increase in protein solutions. , 2014, Soft matter.

[52]  M. Verheul,et al.  Kinetics of Heat-Induced Aggregation of β-Lactoglobulin , 1998 .

[53]  J. Kelly,et al.  Partitioning conformational intermediates between competing refolding and aggregation pathways: insights into transthyretin amyloid disease. , 2005, Biochemistry.

[54]  Patrick Garidel,et al.  Viscosity measurements of antibody solutions by photon correlation spectroscopy: an indirect approach – limitations and applicability for high-concentration liquid protein solutions , 2013, Pharmaceutical development and technology.

[55]  Theodore W Randolph,et al.  Surface adsorption of recombinant human interferon-gamma in lyophilized and spray-lyophilized formulations. , 2002, Journal of pharmaceutical sciences.

[56]  T. Patapoff,et al.  Polysorbate 20 prevents the precipitation of a monoclonal antibody during shear , 2009 .

[57]  C. Rega,et al.  Detection of viscoelasticity in aggregating dilute protein solutions through dynamic light scattering-based optical microrheology , 2012, Rheologica Acta.

[58]  Kholodenko,et al.  Generalized Stokes-Einstein equation for spherical particle suspensions. , 1995, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[59]  P. Schurtenberger,et al.  A small-angle scattering study on equilibrium clusters in lysozyme solutions. , 2006, The journal of physical chemistry. B.

[60]  D. Svergun,et al.  Absence of equilibrium cluster phase in concentrated lysozyme solutions , 2008, Proceedings of the National Academy of Sciences.

[61]  A. Minton,et al.  Rapid quantitative characterization of protein interactions by composition gradient static light scattering. , 2006, Biophysical journal.

[62]  A. Robinson,et al.  Rapid refolding and polishing of single-chain antibodies from Escherichia coli inclusion bodies. , 2002, Protein expression and purification.

[63]  M. Manning,et al.  Aggregation of recombinant human interferon gamma: kinetics and structural transitions. , 1998, Journal of pharmaceutical sciences.

[64]  Vincenzo Martorana,et al.  Protein–Protein Interactions in Dilute to Concentrated Solutions: α-Chymotrypsinogen in Acidic Conditions , 2014, The journal of physical chemistry. B.

[65]  Erinc Sahin,et al.  Predicting solution aggregation rates for therapeutic proteins: approaches and challenges. , 2011, International journal of pharmaceutics.

[66]  M. Manning,et al.  Effect of Tween 20 on freeze-thawing- and agitation-induced aggregation of recombinant human factor XIII. , 1998, Journal of pharmaceutical sciences.

[67]  D. Kalonia,et al.  Ultrasonic storage modulus as a novel parameter for analyzing protein-protein interactions in high protein concentration solutions: correlation with static and dynamic light scattering measurements. , 2007, Biophysical journal.

[68]  B. Halle,et al.  Protein hydration dynamics in solution: a critical survey. , 2004, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[69]  William F. Weiss,et al.  Aggregation and pH-temperature phase behavior for aggregates of an IgG2 antibody. , 2012, Journal of pharmaceutical sciences.

[70]  Vasco Filipe,et al.  Critical Evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the Measurement of Nanoparticles and Protein Aggregates , 2010, Pharmaceutical Research.

[71]  A. Robinson,et al.  Competing aggregation pathways for monoclonal antibodies , 2014, FEBS letters.

[72]  N. Hooper,et al.  Families of zinc metalloproteases , 1994, FEBS letters.

[73]  A. Minton Hard quasispherical particle models for the viscosity of solutions of protein mixtures. , 2012, Journal of Physical Chemistry B.

[74]  C. Roberts,et al.  A quasichemical approach for protein-cluster free energies in dilute solution. , 2007, The Journal of chemical physics.

[75]  Theodore W Randolph,et al.  Aggregation of a monoclonal antibody induced by adsorption to stainless steel , 2010, Biotechnology and bioengineering.

[76]  Vladimir I Razinkov,et al.  Native-state solubility and transfer free energy as predictive tools for selecting excipients to include in protein formulation development studies. , 2012, Journal of pharmaceutical sciences.

[77]  R. Narwal,et al.  Do clustering monoclonal antibody solutions really have a concentration dependence of viscosity? , 2013, Biophysical journal.

[78]  A. Heck,et al.  Towards the understanding of molecular mechanisms in the early stages of heat-induced aggregation of beta-lactoglobulin AB. , 2002, Journal of chromatography. A.

[79]  William F. Weiss,et al.  Molecular level insights into thermally induced α-chymotrypsinogen A amyloid aggregation mechanism and semiflexible protofibril morphology. , 2010, Biochemistry.

[80]  Massimo Morbidelli,et al.  Population balance modeling of antibodies aggregation kinetics. , 2012, The journal of physical chemistry. B.

[81]  C. Roberts,et al.  Nonnative aggregation of an IgG1 antibody in acidic conditions, part 2: nucleation and growth kinetics with competing growth mechanisms. , 2011, Journal of pharmaceutical sciences.

[82]  Theodore W Randolph,et al.  Adsorption of monoclonal antibodies to glass microparticles. , 2011, Journal of pharmaceutical sciences.

[83]  H. Gadgil,et al.  Elucidation of Acid-induced Unfolding and Aggregation of Human Immunoglobulin IgG1 and IgG2 Fc , 2011, The Journal of Biological Chemistry.

[84]  Thomas J. Dougherty,et al.  A Mechanism for Non‐Newtonian Flow in Suspensions of Rigid Spheres , 1959 .

[85]  G. Abraham,et al.  Reversible self-association of a human myeloma protein. Thermodynamics and relevance to viscosity effects and solubility. , 1984, Biochemistry.

[86]  Erinc Sahin,et al.  Relating particle formation to salt- and pH-dependent phase separation of non-native aggregates of alpha-chymotrypsinogen A. , 2012, Journal of pharmaceutical sciences.

[87]  Randal R. Ketchem,et al.  Entanglement model of antibody viscosity. , 2014, The journal of physical chemistry. B.

[88]  D. Kalonia,et al.  Nature and consequences of protein-protein interactions in high protein concentration solutions. , 2008, International journal of pharmaceutics.

[89]  Gareth H. McKinley,et al.  Rheology of globular proteins: apparent yield stress, high shear rate viscosity and interfacial viscoelasticity of bovine serum albumin solutions , 2011 .

[90]  W. Jiskoot,et al.  Micro-flow imaging and resonant mass measurement (Archimedes)--complementary methods to quantitatively differentiate protein particles and silicone oil droplets. , 2013, Journal of pharmaceutical sciences.

[91]  S. Singh,et al.  Measuring and modeling hemoglobin aggregation below the freezing temperature. , 2013, The journal of physical chemistry. B.

[92]  C. Roberts,et al.  Lumry-Eyring nucleated-polymerization model of protein aggregation kinetics. 2. Competing growth via condensation and chain polymerization. , 2009, The journal of physical chemistry. B.

[93]  Shahid Uddin,et al.  Factors influencing antibody stability at solid–liquid interfaces in a high shear environment , 2009, Biotechnology progress.

[94]  A. Minton Static light scattering from concentrated protein solutions, I: General theory for protein mixtures and application to self-associating proteins. , 2007, Biophysical journal.

[95]  A. Fink Protein aggregation: folding aggregates, inclusion bodies and amyloid. , 1998, Folding & design.

[96]  Jared S. Bee,et al.  Monoclonal antibody interactions with micro- and nanoparticles: adsorption, aggregation, and accelerated stress studies. , 2009, Journal of pharmaceutical sciences.

[97]  Shahid Uddin,et al.  Determining Antibody Stability: Creation of Solid‐Liquid Interfacial Effects within a High Shear Environment , 2007, Biotechnology progress.

[98]  B. Nidetzky,et al.  Renewal of the air-water interface as a critical system parameter of protein stability: aggregation of the human growth hormone and its prevention by surface-active compounds. , 2013, Langmuir : the ACS journal of surfaces and colloids.

[99]  M. Morbidelli,et al.  Aggregation Mechanism of an IgG2 and two IgG1 Monoclonal Antibodies at low pH: From Oligomers to Larger Aggregates , 2012, Pharmaceutical Research.

[100]  Wei Wang,et al.  Antibody structure, instability, and formulation. , 2007, Journal of pharmaceutical sciences.