Predicting deamidation and isomerization sites in therapeutic antibodies using structure-based in silico approaches

References

• Lu R-M, Hwang Y-C, Liu I-J, Lee C-C, Tsai H-Z, Li H-J, Wu H-C. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27(1):1. doi:10.1186/s12929-019-0592-z.
   PubMed Web of Science ®Google Scholar
• DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20–12. doi:10.1016/j.jhealeco.2016.01.012.
   PubMed Web of Science ®Google Scholar
• Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32(1):40–51. doi:10.1038/nbt.2786.
   PubMed Web of Science ®Google Scholar
• Bailly M, Mieczkowski C, Juan V, Metwally E, Tomazela D, Baker J, Uchida M, Kofman E, Raoufi F, Motlagh S. et al. Predicting antibody developability profiles through early stage discovery screening. Mabs-austin. 2020;12(1):1743053. doi:10.1080/19420862.2020.1743053.
   PubMed Web of Science ®Google Scholar
• Jarasch A, Koll H, Regula JT, Bader M, Papadimitriou A, Kettenberger H. Developability assessment during the selection of novel therapeutic antibodies. J Pharm Sci. 2015;104(6):1885–98. doi:10.1002/jps.24430.
   PubMed Web of Science ®Google Scholar
• Harris RJ, Kabakoff B, Macchi FD, Shen FJ, Kwong M, Andya JD, Shire SJ, Bjork N, Totpal K, Chen AB. Identification of multiple sources of charge heterogeneity in a recombinant antibody. J Chromatogr B Biomed Sci Appl. 2001;2001(2):233–45. doi:10.1016/s0378-4347(00)00548-x.
   Google Scholar
• Yan B, Steen S, Hambly D, Valliere-Douglass J, Vanden Bos T, Smallwood S, Yates Z, Arroll T, Han Y, Gadgil H. et al. Succinimide formation at asn 55 in the complementarity determining region of a recombinant monoclonal antibody IgG1 heavy chain. J Pharm Sci. 2009;98(10):3509–21. doi:10.1002/jps.21655.
   PubMed Web of Science ®Google Scholar
• Gervais D. Protein deamidation in biopharmaceutical manufacture: understanding, control and impact. J Chem Technol Biot. 2016;91(3):569–75. doi:10.1002/jctb.4850.
   Web of Science ®Google Scholar
• Alam ME, Barnett GV, Slaney TR, Starr CG, Das TK, Tessier PM. Deamidation can compromise antibody colloidal stability and enhance aggregation in a pH-dependent manner. Mol Pharm. 2019;16(5):1939–49. doi:10.1021/acs.molpharmaceut.8b01311.
   PubMedGoogle Scholar
• Lu X, Nobrega RP, Lynaugh H, Jain T, Barlow K, Boland T, Sivasubramanian A, Vásquez M, Xu Y. Deamidation and isomerization liability analysis of 131 clinical-stage antibodies. Mabs-austin. 2018;11(1):1–13. doi:10.1080/19420862.2018.1548233.
   PubMed Web of Science ®Google Scholar
• Liu YD, van Enk JZ, Flynn GC. Human antibody fc deamidation in vivo. Biologicals. 2009;37(5):313–22. doi:10.1016/j.biologicals.2009.06.001.
   PubMed Web of Science ®Google Scholar
• Yang N, Tang Q, Hu P, Lewis MJ. Use of in vitro systems to model in vivo degradation of therapeutic monoclonal antibodies. Anal Chem. 2018;90(13):7896–902. doi:10.1021/acs.analchem.8b00183.
   PubMed Web of Science ®Google Scholar
• Capasso S, Kirby AJ, Salvadori S, Sica F, Zagari A. Kinetics and mechanism of the reversible lsomerization of aspartic acid residues in tetrapeptides. J Chem Soc Perkin Trans. 1995;2(3):437. doi:10.1039/p29950000437.
   Google Scholar
• Konuklar FAS, Aviyente V. Modelling the hydrolysis of succinimide: formation of aspartate and reversible isomerization of aspartic acid via succinimide. Org Biomol Chem. 2003;1(13):2290–97. doi:10.1039/b211936f.
   PubMed Web of Science ®Google Scholar
• Geiger T, Deamidation CS. Isomerization, and racemization at Asparaginyl and aspartyl residues in peptides. J Biol Chem. 1987;262(15):785–94. doi:10.1016/S0021-9258(19)75855-4.
   PubMedGoogle Scholar
• Aswad DW, Paranandi MV, Schurter BT. Isoaspartate in peptides and proteins: formation, significance, and analysis. J Pharm Biomed Anal. 2000;21(6):1129–36. doi:10.1016/s0731-7085(99)00230-7.
   PubMed Web of Science ®Google Scholar
• Wakankar AA, Borchardt RT, Eigenbrot C, Shia S, Wang YJ, Shire SJ, Liu JL. Aspartate isomerization in the complementarity-determining regions of two closely related monoclonal antibodies. Biochemistry. 2007;46(6):1534–44. doi:10.1021/bi061500t.
   PubMed Web of Science ®Google Scholar
• Sreedhara A, Cordoba A, Zhu Q, Kwong J, Liu J. Characterization of the isomerization products of aspartate residues at two different sites in a monoclonal antibody. Pharm Res. 2012;29(1):187–97. doi:10.1007/s11095-011-0534-2.
   PubMed Web of Science ®Google Scholar
• Sharma VK, Patapoff TW, Kabakoff B, Pai S, Hilario E, Zhang B, Li C, Borisov O, Kelley RF, Chorny I. et al. In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability. Proc Natl Acad Sci U S A. 2014;111(52):18601–06. doi:10.1073/pnas.1421779112.
   PubMed Web of Science ®Google Scholar
• Sydow JF, Lipsmeier F, Larraillet V, Hilger M, Mautz B, Mølhøj M, Kuentzer J, Klostermann S, Schoch J, Voelger HR. et al. Structure-based prediction of asparagine and aspartate degradation sites in antibody variable regions. PloS One. 2014;9(6):e100736. doi:10.1371/journal.pone.0100736.
   PubMed Web of Science ®Google Scholar
• Láng A, Jákli I, Enyedi KN, Mező G, Menyhárd DK, Perczel A. Off-pathway 3D-structure provides protection against spontaneous Asn/Asp isomerization: shielding proteins achilles heel. Q Rev Biophys. 2020;53:e2. doi:10.1017/s003358351900009x.
   PubMed Web of Science ®Google Scholar
• Ince HH, Konuklar FAS, Ugur I, Ozcan ÖA, Sayadi M, Feig M, Aviyente V. Role of the n+1 amino acid residue on the deamidation of asparagine in pentapeptides. Molecular Physics. 2015;113(23):3839–48. doi:10.1080/00268976.2015.1068394.
   Web of Science ®Google Scholar
• Phillips JJ, Buchanan A, Andrews J, Chodorge M, Sridharan S, Mitchell L, Burmeister N, Kippen AD, Vaughan TJ, Higazi DR. et al. Rate of Asparagine Deamidation in a monoclonal antibody correlating with hydrogen exchange rate at adjacent downstream residues. Anal Chem. 2017;89(4):2361–68. doi:10.1021/acs.analchem.6b04158.
   PubMed Web of Science ®Google Scholar
• DiCara DM, Andersen N, Chan R, Ernst JA, Ayalon G, Lazar GA, Agard NJ, Hilderbrand A, Hötzel I. High-throughput screening of antibody variants for chemical stability: identification of deamidation-resistant mutants. Mabs-austin. 2018;10(7):1–11. doi:10.1080/19420862.2018.1504726.
   PubMed Web of Science ®Google Scholar
• Clarke S. Propensity for spontaneous succinimide formation from aspartyl and asparaginyl residues in cellular proteins. Int J Pept Protein Res. 1987;30(6):808–21. doi:10.1111/j.1399-3011.1987.tb03390.x.
   PubMedGoogle Scholar
• Robinson NE, Robinson AB. Prediction of protein deamidation rates from primary and three-dimensional structure. Proc Natl Acad Sci U S A. 2001;98(8):4367–72. doi:10.1073/pnas.071066498.
   PubMed Web of Science ®Google Scholar
• Stephenson RC, Clarke S. Succinimide formation from Aspartyl and asparaginyl peptides as a model for the spontaneous degradation of proteins. J Biol Chem. 1989;264(11):6164–70. doi:10.1016/s0021-9258(18)83327-0.
   PubMed Web of Science ®Google Scholar
• Wright HT, Urry DW. Nonenzymatic deamidation of asparaginyl and glutaminyl residues in proteins. Crit Rev Biochem Mol Biol. 1991;26(1):1–52. doi:10.3109/10409239109081719.
   PubMed Web of Science ®Google Scholar
• Lorenzo JR, Alonso LG, Sánchez IE, Lisacek F. Prediction of spontaneous protein deamidation from sequence-derived secondary structure and intrinsic disorder. PloS One. 2015;10(12):e0145186. doi:10.1371/journal.pone.0145186.
   PubMed Web of Science ®Google Scholar
• Jia L, Sun Y, de Brevern AG. Protein asparagine deamidation prediction based on structures with machine learning methods. PloS One. 2017;12(7):e0181347. doi:10.1371/journal.pone.0181347.
   PubMed Web of Science ®Google Scholar
• Plotnikov NV, Singh SK, Rouse JC, Kumar S. Quantifying the risks of asparagine deamidation and aspartate isomerization in biopharmaceuticals by computing reaction free-energy surfaces. J Phys Chem B. 2017;121(4):719–30. doi:10.1021/acs.jpcb.6b11614.
   PubMed Web of Science ®Google Scholar
• Yan Q, Huang M, Lewis MJ, Hu P. Structure based prediction of asparagine deamidation propensity in monoclonal antibodies. Mabs-austin. 2018;10(6):901–12. doi:10.1080/19420862.2018.1478646.
   PubMed Web of Science ®Google Scholar
• Brennan TV, Clarke S. Spontaneous degradation of polypeptides at aspartyl and asparaginyl residues: effects of the solvent dielectric. Protein Sci. 1993;2(3):331–38. doi:10.1002/pro.5560020305.
   PubMed Web of Science ®Google Scholar
• Brennan TV, Clarke S. Effect of adjacent histidine and cysteine residues on the spontaneous degradation of asparaginyl- and aspartyl-containing peptides. Int J Pept Protein Res. 1995;45(6):547–53. doi:10.1111/j.1399-3011.1995.tb01318.x.
   PubMedGoogle Scholar
• Labute P. LowModeMD–implicit low-mode velocity filtering applied to conformational search of macrocycles and protein loops. J Chem Inf Model. 2010;50(5):792–800. doi:10.1021/ci900508k.
   PubMed Web of Science ®Google Scholar
• Martin KP, Grimaldi P, Grempler R, Hansel S, Kumar S. Trends in industrialization of biotherapeutics: a survey of product characteristics of 89 antibody-based biotherapeutics. Mabs-austin. 2023;15(1):2191301. doi:10.1080/19420862.2023.2191301.
   PubMed Web of Science ®Google Scholar
• (Molecular Operating Environment (MOE), 2022.02), (Chemical Computing Group ULC, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7). 2022.
   Google Scholar
• Labute P. Binary QSAR: a new method for the determination of quantitative structure activity relationships. Pac Symp Biocomput. 1999;444–55. doi:10.1142/9789814447300_0044.
   PubMedGoogle Scholar
• Baptista AM, Teixeira VH, Soares CM. Constant- p H molecular dynamics using stochastic titration. J Chem Phys. 2002;117(9):4184–200. doi:10.1063/1.1497164.
   Web of Science ®Google Scholar
• Labute P. Protonate3D: assignment of ionization states and hydrogen coordinates to macromolecular structures. Proteins. 2009;75(1):187–205. doi:10.1002/prot.22234.
   PubMed Web of Science ®Google Scholar
• Labute P. The generalized born/volume integral implicit solvent model: estimation of the free energy of hydration using London dispersion instead of atomic surface area. J Comput Chem. 2008;29(10):1693–98. doi:10.1002/jcc.20933.
   PubMed Web of Science ®Google Scholar
• Kosky AA, Razzaq UO, Treuheit MJ, Brems DN. The effects of alpha-helix on the stability of asn residues: deamidation rates in peptides of varying helicity. Protein Sci. 1999;8(11):2519–23. doi:10.1110/ps.8.11.2519.
   PubMed Web of Science ®Google Scholar
• Irudayanathan FJ, Zarzar J, Lin J, Izadi S. Deciphering deamidation and isomerization in therapeutic proteins: effect of neighboring residue. Mabs-austin. 2022;14(1):2143006. doi:10.1080/19420862.2022.2143006.
   PubMed Web of Science ®Google Scholar
• Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–8, 27–8. doi:10.1016/0263-7855(96)00018-5.
   Google Scholar
• Phillips JC, Hardy DJ, Maia JDC, Stone JE, Ribeiro JV, Bernardi RC, Buch R, Fiorin G, Hénin J, Jiang W. et al. Scalable molecular dynamics on CPU and GPU architectures with NAMD. J Chem Phys. 2020;153(4):44130. doi:10.1063/5.0014475.
   PubMed Web of Science ®Google Scholar
• Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot BL, Grubmüller H, MacKerell AD. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods. 2017;14(1):71–73. doi:10.1038/nmeth.4067.
   PubMed Web of Science ®Google Scholar
• Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79(2):926–35. doi:10.1063/1.445869.
   Web of Science ®Google Scholar
• Darden T, York D, Pedersen L. Particle mesh Ewald: an N ⋅log(N) method for Ewald sums in large systems. J Chem Phys. 1993;98(12):10089–92. doi:10.1063/1.464397.
   Web of Science ®Google Scholar
• Ryckaert J-P, Ciccotti G, Berendsen HJ. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys. 1977;23(3):327–41. doi:10.1016/0021-9991(77)90098-5.
   Web of Science ®Google Scholar
• Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys. 1994;101(5):4177–89. doi:10.1063/1.467468.
   Web of Science ®Google Scholar
• Licari G, Martin KP, Crames M, Mozdzierz J, Marlow MS, Karow-Zwick AR, Kumar S, Bauer J. Embedding dynamics in intrinsic physicochemical profiles of market-stage antibody-based biotherapeutics. Mol Pharm. 2023;20(2):1096–111. doi:10.1021/acs.molpharmaceut.2c00838.
   PubMedGoogle Scholar