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Dissecting the molecular basis of high viscosity of monospecific and bispecific IgG antibodies

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Article: 1692764 | Received 05 Aug 2019, Accepted 11 Nov 2019, Published online: 28 Nov 2019

References

  • The Antibody Society. List of approved antibodies. [cited 2019 Nov 19]. https://www.antibodysociety.org/resources/approved-antibodies/.
  • Carter PJ, Lazar GA. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat Rev Drug Discov. 2018;17:197–11.
  • Viola M, Sequeira J, Seiça R, Veiga F, Serra J, Santos AC, Ribeiro AJ. Subcutaneous delivery of monoclonal antibodies: how do we get there? J Control Release. 2018;286:301–14.
  • Jin JF, Zhu LL, Chen M, Xu HM, Wang HF, Feng XQ, Zhu XP, Zhou Q. The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection. Patient Prefer Adher. 2015;9:923–42.
  • Xu Y, Wang D, Mason B, Rossomando T, Li N, Liu D, Cheung JK, Xu W, Raghava S, Katiyar A, et al. Structure, heterogeneity and developability assessment of therapeutic antibodies. MAbs. 2019;11:239–64.
  • Shire SJ, Shahrokh Z, Liu J. Challenges in the development of high protein concentration formulations. J Pharm Sci. 2004;93:1390–402.
  • Hung JJ, Borwankar AU, Dear BJ, Truskett TM, Johnston KP. High concentration tangential flow ultrafiltration of stable monoclonal antibody solutions with low viscosities. J Membrane Sci. 2016;508:113–26.
  • Liu J, Nguyen MD, Andya JD, Shire SJ. Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution. J Pharm Sci. 2005;94:1928–40.
  • Yadav S, Liu J, Shire SJ, Kalonia DS. Specific interactions in high concentration antibody solutions resulting in high viscosity. J Pharm Sci. 2010;99:1152–68.
  • Yadav S, Shire SJ, Kalonia DS. Viscosity behavior of high-concentration monoclonal antibody solutions: correlation with interaction parameter and electroviscous effects. J Pharm Sci-Us. 2012;101:998–1011.
  • Du W, Klibanov AM. Hydrophobic salts markedly diminish viscosity of concentrated protein solutions. Biotechnol Bioeng. 2011;108:632–36.
  • He F, Woods CE, Litowski JR, Roschen LA, Gadgil HS, Razinkov VI, Kerwin BA. Effect of sugar molecules on the viscosity of high concentration monoclonal antibody solutions. Pharm Res-Dordr. 2011;28:1552–60.
  • Esfandiary R, Hayes DB, Parupudi A, Casas-Finet J, Bai S, Samra HS, Shah AU, Sathish HA. A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies. J Pharm Sci. 2013;102:62–72.
  • Esfandiary R, Parupudi A, Casas-Finet J, Gadre D, Sathish H. Mechanism of reversible self-association of a monoclonal antibody: role of electrostatic and hydrophobic interactions. J Pharm Sci. 2015;104:577–86.
  • Mason BD, Zhang L, Remmele RL Jr., Zhang J. Opalescence of an IgG2 monoclonal antibody solution as it relates to liquid-liquid phase separation. J Pharm Sci. 2011;100:4587–96.
  • Melander W, Horvath C. Salt effect on hydrophobic interactions in precipitation and chromatography of proteins: an interpretation of the lyotropic series. Arch Biochem Biophys. 1977;183:200–15.
  • Nishi H, Miyajima M, Nakagami H, Noda M, Uchiyama S, Fukui K. Phase separation of an IgG1 antibody solution under a low ionic strength condition. Pharm Res. 2010;27:1348–60.
  • Pindrus M, Shire SJ, Kelley RF, Demeule B, Wong R, Xu Y, Yadav S. Solubility challenges in high concentration monoclonal antibody formulations: relationship with amino acid sequence and intermolecular interactions. Mol Pharm. 2015;12:3896–907.
  • Yadav S, Sreedhara A, Kanai S, Liu J, Lien S, Lowman H, Kalonia DS, Shire SJ. Establishing a link between amino acid sequences and self-associating and viscoelastic behavior of two closely related monoclonal antibodies. Pharm Res-Dordr. 2011;28:1750–64.
  • Yadav S, Shire SJ, Kalonia DS. Factors affecting the viscosity in high concentration solutions of different monoclonal antibodies. J Pharm Sci. 2010;99:4812–29.
  • Chari R, Jerath K, Badkar AV, Kalonia DS. Long- and short-range electrostatic interactions affect the rheology of highly concentrated antibody solutions. Pharm Res-Dordr. 2009;26:2607–18.
  • Chow CK, Allan BW, Chai Q, Atwell S, Lu J. Therapeutic antibody engineering to improve viscosity and phase separation guided by crystal structure. Mol Pharm. 2016;13:915–23.
  • Shan L, Mody N, Sormani P, Rosenthal KL, Damschroder MM, Esfandiary R. Developability assessment of engineered monoclonal antibody variants with a complex self-association behavior using complementary analytical and in silico tools. Mol Pharm. 2018;15:5697–710.
  • Geng SB, Wittekind M, Vigil A, Tessier PM. Measurements of monoclonal antibody self-association are correlated with complex biophysical properties. Mol Pharm. 2016;13:1636–45.
  • Geoghegan JC, Fleming R, Damschroder M, Bishop SM, Sathish HA, Esfandiary R. Mitigation of reversible self-association and viscosity in a human IgG1 monoclonal antibody by rational, structure-guided Fv engineering. MAbs. 2016;8:941–50.
  • Buck PM, Chaudhri A, Kumar S, Singh SK. Highly viscous antibody solutions are a consequence of network formation caused by domain-domain electrostatic complementarities: insights from coarse-grained simulations. Mol Pharm. 2015;12:127–39.
  • Chennamsetty N, Voynov V, Kayser V, Helk B, Trout BL. Design of therapeutic proteins with enhanced stability. Proc Natl Acad Sci U S A. 2009;106:11937–42.
  • Nichols P, Li L, Kumar S, Buck PM, Singh SK, Goswami S, Balthazor B, Conley TR, Sek D, Allen MJ. Rational design of viscosity reducing mutants of a monoclonal antibody: hydrophobic versus electrostatic inter-molecular interactions. MAbs. 2015;7:212–30.
  • Spiess C, Zhai Q, Carter PJ. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol Immunol. 2015;67:95–106.
  • Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs. 2017;9:182–212.
  • Labrijn AF, Janmaat ML, Reichert JM, Parren P. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.
  • Woldeyes MA, Josephson LL, Leiske DL, Galush WJ, Roberts CJ, Furst EM. Viscosities and protein interactions of bispecific antibodies and their monospecific mixtures. Mol Pharm. 2018;15:4745–55.
  • Inoue N, Takai E, Arakawa T, Shiraki K. Specific decrease in solution viscosity of antibodies by arginine for therapeutic formulations. Mol Pharm. 2014;11:1889–96.
  • Atwell S, Ridgway JB, Wells JA, Carter P. Stable heterodimers from remodeling the domain interface of a homodimer using a phage display library. J Mol Biol. 1997;270:26–35.
  • Spiess C, Bevers J 3rd, Jackman J, Chiang N, Nakamura G, Dillon M, Liu H, Molina P, Elliott JM, Shatz W, et al. Development of a human IgG4 bispecific antibody for dual targeting of interleukin-4 (IL-4) and interleukin-13 (IL-13) cytokines. J Biol Chem. 2013;288:26583–93.
  • Spiess C, Merchant M, Huang A, Zheng Z, Yang NY, Peng J, Ellerman D, Shatz W, Reilly D, Yansura DG, et al. Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies. Nat Biotechnol. 2013;31:753–58.
  • Stubenrauch K, Wessels U, Regula JT, Kettenberger H, Schleypen J, Kohnert U. Impact of molecular processing in the hinge region of therapeutic IgG4 antibodies on disposition profiles in cynomolgus monkeys. Drug Metab Dispos. 2010;38:84–91.
  • Labrijn AF, Buijsse AO, van den Bremer ET, Verwilligen AY, Bleeker WK, Thorpe SJ, Killestein J, Polman CH, Aalberse RC, Schuurman J, et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol. 2009;27:767–71.
  • Kanai S, Liu J, Patapoff TW, Shire SJ. Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab-Fab interaction that impacts solution viscosity. J Pharm Sci. 2008;97:4219–27.
  • Ultsch M, Bevers J, Nakamura G, Vandlen R, Kelley RF, Wu LC, Eigenbrot C. Structural basis of signaling blockade by anti-IL-13 antibody Lebrikizumab. J Mol Biol. 2013;425:1330–39.
  • Peng K, Wang Y, Siradze K, Erickson R, Fischer SK, Staton TL. Measurement of IL-17AA and IL-17FF as pharmacodynamic biomarkers to demonstrate target engagement in the phase I study of MCAF5352A. Aaps J. 2019;21:9.
  • Kabat EA, Wu TT, Perry HM, Gottesman KS, Foeller C. Sequences of proteins of immunological interest. Bethesda (MD): NIH; 1991.
  • Traxlmayr MW, Kiefer JD, Srinivas RR, Lobner E, Tisdale AW, Mehta NK, Yang NJ, Tidor B, Wittrup KD. Strong enrichment of aromatic residues in binding sites from a charge-neutralized hyperthermostable Sso7d scaffold library. J Biol Chem. 2016;291:22496–508.
  • Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, Wong T, Chiang V, Luis E, Estevez A, et al. Molecular basis for negative regulation of the glucagon receptor. Proc Natl Acad Sci U S A. 2012;109:14393–98.
  • Molecular Operating Environment (MOE) 2013.08. Chemical Computing Group ULC, 1010 Sherbooke St. West, suite 910, Montreal, QC, Canada, H3A 2R7. 2018., 2018.
  • Tomar DS, Kumar S, Singh SK, Goswami S, Li L. Molecular basis of high viscosity in concentrated antibody solutions: strategies for high concentration drug product development. Mabs. 2016;8:216–28.
  • Locke KW, Maneval DC, LaBarre MJ. ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20. Drug Deliv. 2019;26:98–106.
  • Yelvington BJ. Subcutaneous Rituximab in follicular lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma. J Adv Pract Oncol. 2018;9:530–34.
  • Dent S, Ammendolea C, Christofides A, Edwards S, Incekol D, Pourmirza B, Kfoury S, Poirier B. A multidisciplinary perspective on the subcutaneous administration of trastuzumab in HER2-positive breast cancer. Curr Oncol. 2019;26:e70–e80.
  • Kastelic M, Dill KA, Kalyuzhnyi YV, Vlachy V. Controlling the viscosities of antibody solutions through control of their binding sites. J Mol Liq. 2018;270:234–42.
  • Arora J, Hickey JM, Majumdar R, Esfandiary R, Bishop SM, Samra HS, Middaugh CR, Weis DD, Volkin DB. Hydrogen exchange mass spectrometry reveals protein interfaces and distant dynamic coupling effects during the reversible self-association of an IgG1 monoclonal antibody. MAbs. 2015;7:525–39.
  • Arora J, Hu Y, Esfandiary R, Sathish HA, Bishop SM, Joshi SB, Middaugh CR, Volkin DB, Weis DD. Charge-mediated Fab-Fc interactions in an IgG1 antibody induce reversible self-association, cluster formation, and elevated viscosity. MAbs. 2016;8:1561–74.
  • Sudrik C, Cloutier T, Pham P, Samra HS, Trout BL. Preferential interactions of trehalose, L-arginine.HCl and sodium chloride with therapeutically relevant IgG1 monoclonal antibodies. MAbs. 2017;9:1155–68.
  • Dougherty DA. A computational study of cation-pi interactions vs salt bridges in aqueous media: implications for protein engineering. Peptides for the New Millennium. 2000;550–52.
  • McGaughey GB, Gagné M, Rappé AK. pi-stacking interactions alive and well in proteins. J Biol Chem. 1998;273:15458–63.
  • Gallivan JP, Dougherty DA. A computational study of cation-pi interactions vs salt bridges in aqueous media: implications for protein engineering. J Am Chem Soc. 2000;122:870–74.
  • Mecozzi S, West AP Jr., Dougherty DA. Cation-pi interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guide. Proc Natl Acad Sci U S A. 1996;93:10566–71.
  • Kennedy PJ, Oliveira C, Granja PL, Sarmento B. Monoclonal antibodies: technologies for early discovery and engineering. Crit Rev Biotechnol. 2018;38:394–408.
  • Li B, Fouts AE, Stengel K, Luan P, Dillon M, Liang WC, Feierbach B, Kelley RF, Hötzel I. In vitro affinity maturation of a natural human antibody overcomes a barrier to in vivo affinity maturation. MAbs. 2014;6:437–45.
  • Weber CA, Mehta PJ, Ardito M, Moise L, Martin B, De Groot AS. T cell epitope: friend or foe? Immunogenicity of biologics in context. Adv Drug Deliv Rev. 2009;61:965–76.
  • Quarmby V, Phung QT, Lill JR. MAPPs for the identification of immunogenic hotspots of biotherapeutics; an overview of the technology and its application to the biopharmaceutical arena. Expert Rev Proteomics. 2018;15:733–48.
  • Haberger M, Bomans K, Diepold K, Hook M, Gassner J, Schlothauer T, Zwick A, Spick C, Kepert JF, Hienz B, et al. Assessment of chemical modifications of sites in the CDRs of recombinant antibodies Susceptibility vs. functionality of critical quality attributes. Mabs. 2014;6:327–39.
  • DiCara DM, Andersen N, Chan R, Ernst JA, Ayalon G, Lazar GA, Agard NJ, Hilderbrand A, Hotzel I. High-throughput screening of antibody variants for chemical stability: identification of deamidation-resistant mutants. Mabs. 2018;10:1073–83.
  • Yang XY, Xu W, Dukleska S, Benchaar S, Mengisen S, Antochshuk V, Cheung J, Mann L, Babadjanova Z, Rowand J, et al. Developability studies before initiation of process development Improving manufacturability of monoclonal antibodies. Mabs. 2013;5:787–94.
  • Josephson LL, Galush WJ, Furst EM. Parallel temperature-dependent microrheological measurements in a microfluidic chip. Biomicrofluidics. 2016;10:043503.
  • Fukuda M, Watanabe A, Hayasaka A, Muraoka M, Hori Y, Yamazaki T, Imaeda Y, Koga A. Small-scale screening method for low-viscosity antibody solutions using small-angle X-ray scattering. Eur J Pharm Biopharm. 2017;112:132–37.
  • Tomar DS, Singh SK, Li L, Broulidakis MP, Kumar S. In Silico Prediction of Diffusion Interaction Parameter (kD), a Key Indicator of Antibody Solution Behaviors. Pharm Res. 2018;35:193.
  • Zhu K, Day T, Warshaviak D, Murrett C, Friesner R, Pearlman D. Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction. Proteins. 2014;82:1646–55.
  • Simmons LC, Reilly D, Klimowski L, Raju TS, Meng G, Sims P, Hong K, Shields RL, Damico LA, Rancatore P, et al. Expression of full-length immunoglobulins in Escherichia coli: rapid and efficient production of aglycosylated antibodies. J Immunol Methods. 2002;263:133–47.
  • Eaton DL, Wood WI, Eaton D, Hass PE, Hollingshead P, Wion K, Mather J, Lawn RM, Vehar GA, Gorman C. Construction and characterization of an active factor VIII variant lacking the central one-third of the molecule. Biochem. 1986;25:8343–47.
  • Polson AG, Yu SF, Elkins K, Zheng B, Clark S, Ingle GS, Slaga DS, Giere L, Du C, Tan C, et al. Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma. Blood. 2007;110:616–23.
  • Beard H, Cholleti A, Pearlman D, Sherman W, Loving KA. Applying physics-based scoring to calculate free energies of binding for single amino acid mutations in protein-protein complexes. PLoS One. 2013;8:e82849.
  • Bos AB, Luan P, Duque JN, Reilly D, Harms PD, Wong AW. Optimization and automation of an end-to-end high throughput microscale transient protein production process. Biotechnol Bioeng. 2015;112:1832–42.