The Viscoelasticity of High Concentration Monoclonal Antibodies Using Particle Tracking Microrheology

Overview

Journal APL Bioeng

Date 2024 Apr 29

PMID 38680995

Authors

Conor M Lewis

Charles T Heise

Natalia Harasimiuk

Jennifer Tovey

Jian R Lu

Thomas A Waigh

Affiliations

Soon will be listed here.

Abstract

The viscoelasticity of monoclonal antibodies (mAbs) is important during their production, formulation, and drug delivery. High concentration mAbs can provide higher efficacy therapeutics (e.g., during immunotherapy) and improved efficiency during their production (economy of scale during processing). Two humanized mAbs were studied (mAb-1 and mAb-2) with differing isoelectric points. Using high speed particle tracking microrheology, we demonstrated that the mAb solutions have significant viscoelasticities above concentrations of 40 mg/ml. Power law viscoelasticity was observed over the range of time scales (-1 s) probed for the high concentration mAb suspensions. The terminal viscosity demonstrated an exponential dependence on mAb concentration (a modified Mooney relationship) as expected for charged stabilized Brownian colloids. Gelation of the mAbs was explored by lowering the pH of the buffer and a power law scaling of the gelation transition was observed, i.e., the exponent of the anomalous diffusion of the probe particles scaled inversely with the gelation time.

References

Han D, Korabel N, Chen R, Johnston M, Gavrilova A, Allan V . Deciphering anomalous heterogeneous intracellular transport with neural networks. Elife. 2020; 9. PMC: 7141808. DOI: 10.7554/eLife.52224. View

Yadav S, Liu J, Shire S, Kalonia D . Specific interactions in high concentration antibody solutions resulting in high viscosity. J Pharm Sci. 2009; 99(3):1152-68. DOI: 10.1002/jps.21898. View

Manjula B, Tsai A, Upadhya R, Perumalsamy K, Smith P, Malavalli A . Site-specific PEGylation of hemoglobin at Cys-93(beta): correlation between the colligative properties of the PEGylated protein and the length of the conjugated PEG chain. Bioconjug Chem. 2003; 14(2):464-72. DOI: 10.1021/bc0200733. View

Waigh T . Advances in the microrheology of complex fluids. Rep Prog Phys. 2016; 79(7):074601. DOI: 10.1088/0034-4885/79/7/074601. View

Evans R, Tassieri M, Auhl D, Waigh T . Direct conversion of rheological compliance measurements into storage and loss moduli. Phys Rev E Stat Nonlin Soft Matter Phys. 2009; 80(1 Pt 1):012501. DOI: 10.1103/PhysRevE.80.012501. View

Cai P, Krajina B, Kratochvil M, Zou L, Zhu A, Burgener E . Dynamic light scattering microrheology for soft and living materials. Soft Matter. 2021; 17(7):1929-1939. PMC: 7938343. DOI: 10.1039/d0sm01597k. View

Jiskoot W, Hawe A, Menzen T, Volkin D, Crommelin D . Ongoing Challenges to Develop High Concentration Monoclonal Antibody-based Formulations for Subcutaneous Administration: Quo Vadis?. J Pharm Sci. 2021; 111(4):861-867. DOI: 10.1016/j.xphs.2021.11.008. View

Tein Y, Zhang Z, Wagner N . Competitive Surface Activity of Monoclonal Antibodies and Nonionic Surfactants at the Air-Water Interface Determined by Interfacial Rheology and Neutron Reflectometry. Langmuir. 2020; 36(27):7814-7823. DOI: 10.1021/acs.langmuir.0c00797. View

Liu J, Nguyen M, Andya J, Shire S . Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution. J Pharm Sci. 2005; 94(9):1928-40. DOI: 10.1002/jps.20347. View

10.

Yearley E, Godfrin P, Perevozchikova T, Zhang H, Falus P, Porcar L . Observation of small cluster formation in concentrated monoclonal antibody solutions and its implications to solution viscosity. Biophys J. 2014; 106(8):1763-70. PMC: 4008822. DOI: 10.1016/j.bpj.2014.02.036. View

11.

Rogers S, Waigh T, Zhao X, Lu J . Precise particle tracking against a complicated background: polynomial fitting with Gaussian weight. Phys Biol. 2007; 4(3):220-7. DOI: 10.1088/1478-3975/4/3/008. View

12.

Arzensek D, Kuzman D, Podgornik R . Colloidal interactions between monoclonal antibodies in aqueous solutions. J Colloid Interface Sci. 2012; 384(1):207-16. DOI: 10.1016/j.jcis.2012.06.055. View

13.

Shah M, Corbett D, Lanzaro A, Roche A, Sibanda N, Davis P . Micro- and macro-viscosity relations in high concentration antibody solutions. Eur J Pharm Biopharm. 2020; 153:211-221. DOI: 10.1016/j.ejpb.2020.06.007. View

14.

Savin T, Doyle P . Static and dynamic errors in particle tracking microrheology. Biophys J. 2004; 88(1):623-38. PMC: 1305040. DOI: 10.1529/biophysj.104.042457. View

15.

Lu R, Hwang Y, Liu I, Lee C, Tsai H, Li H . Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020; 27(1):1. PMC: 6939334. DOI: 10.1186/s12929-019-0592-z. View

16.

Skar-Gislinge N, Ronti M, Garting T, Rischel C, Schurtenberger P, Zaccarelli E . A Colloid Approach to Self-Assembling Antibodies. Mol Pharm. 2019; 16(6):2394-2404. DOI: 10.1021/acs.molpharmaceut.9b00019. View

17.

Ross P, Minton A . Hard quasispherical model for the viscosity of hemoglobin solutions. Biochem Biophys Res Commun. 1977; 76(4):971-6. DOI: 10.1016/0006-291x(77)90950-0. View

18.

Larsen T, Furst E . Microrheology of the liquid-solid transition during gelation. Phys Rev Lett. 2008; 100(14):146001. DOI: 10.1103/PhysRevLett.100.146001. View

19.

Malm A, Harrison A, Waigh T . Optical coherence tomography velocimetry of colloidal suspensions. Soft Matter. 2014; 10(41):8210-5. DOI: 10.1039/c4sm01111b. View

20.

Gong N, Ma A, Zhang L, Luo X, Zhang Y, Xu M . Site-specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity. Br J Pharmacol. 2011; 163(2):399-412. PMC: 3087140. DOI: 10.1111/j.1476-5381.2011.01227.x. View