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Reduced elimination of IgG antibodies by engineering the variable region
Abstract
Fc engineering to increase the binding affinity of IgG antibodies to FcRn has been reported to reduce the elimination of IgG antibodies. Herein, we present a novel non-FcRn-dependent approach to reduce the elimination of IgG antibodies. Pharmacokinetic studies conducted in normal mice of various humanized IgG4 antibodies, which had identical constant regions but different variable region sequences, revealed that an antibody with a lower isoelectric point (pI) has a longer half-life. These antibodies exhibited comparable binding affinity to FcRn, and with the antibodies with lower pIs, a longer half-life was also observed in beta2-microglobulin knockout mice, suggesting that differences in the pharmacokinetics were due to a non-FcRn-dependent mechanism. On the basis of our findings, we attempted to engineer the pharmacokinetic properties of a humanized anti-IL6 receptor IgG1 antibody. Selected substitutions in the variable region, without substitution in the Fc region, lowered the pI but did not reduce the biological activity and showed a significant reduction in the clearance of the antibody in cynomolgus monkey. These results suggest that lowering the pI by engineering the variable region could reduce the elimination of IgG antibodies and could provide an alternative to Fc engineering of IgG antibodies.
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“Igawa et al. showed that lowering the total pI by 1–2 units resulted in longer half‐lives and slower elimination rates.41”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [41]
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Antibody Structure and Function: The Basis for Engineering Therapeutics
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“Consistent with this explanation, engineering IgG variable regions to remove patches of positive charge (without greatly altering protein pI) has also been used to reduce non-specific binding and improve PK [455].”
Kitazawa, T., Igawa, T., Sampei, Z., Muto, A., Kojima, T., Soeda, T., Yoshihashi, K., Okuyama-Nishida, Y., Saito, H., Tsunoda, H., et al. (2012) · Nature Medicine · doi:10.1038/nm.2942 · Cited by 520
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“Evidence has been presented that deliberately modifying the pI of an antibody by approximately one pI unit or more can give noticeable differences in the pharmacokinetics (PK) of an intact mAb.(29,30) Most studies of antibody charge modifications have involved intravenous (IV) administration; in contrast, there is lit…”
BackgroundEffects of Charge on Antibody Tissue Distribution and Pharmacokinetics
Boswell, C. A., Tesar, D. B., Mukhyala, K., Theil, F.-P., Fielder, P. J., & Khawli, L. A. (2010) · Bioconjugate Chemistry · doi:10.1021/bc100261d · Cited by 398
Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins
Liming, L. (2017) · Protein & Cell · doi:10.1007/s13238-017-0408-4 · Cited by 407
“Therefore, more sophisticated mechanistic models are needed for the TMDD analysis.”
BackgroundMethodInfluentialSampei, Z., Igawa, T., Soeda, T., Okuyama-Nishida, Y., Moriyama, C., Wakabayashi, T., Tanaka, E., Muto, A., Kojima, T., Kitazawa, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057479 · Cited by 342
“Clearance of hBS106 (67 mL/day/kg) was unexpectedly larger than the clearance of human IgG4 antibody reported in mice after subcutaneous injection (3–20 mL/day/kg) [29].”
BackgroundSelf-citationTutorial on monoclonal antibody pharmacokinetics and its considerations in early development
Ovacik, M., & Lin, K. (2018) · Clinical and Translational Science · doi:10.1111/cts.12567 · Cited by 299
Current progress in innovative engineered antibodies
Strohl, W. R. (2017) · Protein & Cell · doi:10.1007/s13238-017-0457-8 · Cited by 296
“…hexameric antibodies with high C1q binding and concomitant CDC effector function (Cook et al., 2016; de Jong et al., 2016), pH-dependent binding (Igawa et al., 2010a; Chaparro-Rogers et al., 2012; Devanaboyina et al., 2013) and sweeping antibodies (Igawa et al., 2013) that improve upon the…”
BackgroundInfluentialUchida, N., Sambe, T., Yoneyama, K., Fukazawa, N., Kawanishi, T., Kobayashi, S., & Shima, M. (2015) · Blood · doi:10.1182/blood-2015-06-650226 · Cited by 262
“The apparent extended half-life of ACE910 compared with other humanized antibodies (12-20 days)(26)might be a consequence of a reduced isoelectric point resulting from the amino acid–substituting antibody engineering technology applied.(16,27) The currentfindings suggest that target-mediated drugdisposition is negligi…”
Sharma, V. K., Patapoff, T. W., Kabakoff, B., Pai, S., Hilario, E., Zhang, B., Li, C., Borisov, O., Kelley, R. F., Chorny, I., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1421779112 · Cited by 256
“A few studies have shown such differences to be correlated to pI or specific mutations in the sequence (15, 16); however, no clear trend is reported.”
BackgroundA strategy for risk mitigation of antibodies with fast clearance
Hötzel, I., Theil, F.-P., Bernstein, L. J., Prabhu, S., Deng, R., Quintana, L., Lutman, J., Sibia, R., Chan, P., Bumbaca, D., et al. (2012) · mAbs · doi:10.4161/mabs.22189 · Cited by 245
“Igawa et al.(23) have previously shown that clearance of a human IgG1 antibody in cynomolgus monkeys can be reduced through changes in the variable domain that result in a lower pI.”
BackgroundPharmacokinetics and toxicology of therapeutic proteins: Advances and challenges
Vugmeyster, Y. (2012) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v3.i4.73 · Cited by 252
Dostálek, M., Gardner, I. B., Gurbaxani, B. M., Rose, R. H., & Chetty, M. (2013) · Clinical Pharmacokinetics · doi:10.1007/s40262-012-0027-4 · Cited by 236
Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics
Schoch, A., Kettenberger, H., Mundigl, O., Winter, G., Engert, J., Heinrich, J., & Emrich, T. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408766112 · Cited by 202
“(36) observed that IgG4 antibodies with lower isoelectric point (pI) values due to engineering in the variable region have a lower rate of fluid-phase pinocytosis and in turn a reduced elimination rate.”
BackgroundAbdiche, Y. N., Yeung, Y. A., Chaparro-Riggers, J., Barman, I., Strop, P., Chin, S. M., Pham, A., Bolton, G., McDonough, D., Lindquist, K., et al. (2015) · mAbs · doi:10.1080/19420862.2015.1008353 · Cited by 203
“hIgG1 25 737 (82) 16 332 (87) 12 72 (12) 17 68 (7) 14 hIgG1 37 998 (174) 6 372 (17) 4 164 (23) 8 135 (29) 8 hIgG2 25 540 (86) 10 250 (85) 5 63 (10) 8 53 (15) 8 hIgG2 37 768 (66) 6 333 (7) 4 147 (7) 4 93 (3) 4 hIgG3 25 585 (60) 5 188, 213 2 230 (34) 3 313 (109) 3 hIgG3 37 898 (64) 4 387 (22) 3 353, 328 2 357, 366 2 hIg…”
Wang, W., Lü, P., Fang, Y., Hamuro, L., Pittman, T. J., Carr, B. I., Hochman, J. H., & Prueksaritanont, T. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.111.039453 · Cited by 171
“In a recent study, Igawa et al. (2010) also suggested a potential role of isoelectric point in mAb PK.”
BackgroundA single molecular descriptor to predict solution behavior of therapeutic antibodies
Kingsbury, J. S., Saini, A., Auclair, S. M., Fu, L., Lantz, M. M., Halloran, K. T., Calero‐Rubio, C., Schwenger, W. J., Airiau, C. Y., Zhang, J., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb0372 · Cited by 158
Rabia, L. A., Desai, A. A., Jhajj, H. S., & Tessier, P. M. (2018) · Biochemical Engineering Journal · doi:10.1016/j.bej.2018.06.003 · Cited by 159
“the numbers of charged, hydrophobic and hydrophilic residues in CDRs [26, 27, 39, 41, 42, 44, 68–70] as well as the net charge of the variable regions [46, 47, 49].”
BackgroundZheng, Y., Tesar, D. B., Benincosa, L., Birnböck, H., Boswell, C. A., Bumbaca, D., Cowan, K. J., Danilenko, D. M., Daugherty, A. L., Fielder, P. J., et al. (2012) · mAbs · doi:10.4161/mabs.4.2.19387 · Cited by 149
Zhao, H., Atkinson, J. E., Gulesserian, S., Zeng, Z., Nater, J., Ou, J. W., Yang, P., Morrison, K. J. M., Coleman, J. D., Malik, F., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3202 · Cited by 144
“Since similar mutations have been shown to extend the half-life of antibodies (31), the mouse PK of AGS16C3F(K16D) and wild type, AGS-16C3F were compared but exposures were shown to”
BackgroundDatta‐Mannan, A., Thangaraju, A., Leung, D., Tang, Y., Witcher, D. R., Lu, J., & Wroblewski, V. J. (2015) · mAbs · doi:10.1080/19420862.2015.1016696 · Cited by 144
“2 across studies) through engineering either the variable region or the mAb framework, respectively, slows IgG clearance via a non-FcRn dependent mechanism.(9,11) These studies suggest reducing the overall net positive molecular charge improves mAb PK via decreased non-specific cellular interactions that, in part, may…”
BackgroundInfluentialEngineering the variable region of therapeutic IgG antibodies
Igawa, T., Tsunoda, H., Kuramochi, T., Sampei, Z., Ishii, S., & Hattori, K. (2011) · mAbs · doi:10.4161/mabs.3.3.15234 · Cited by 140
Self-citationMimoto, F., Katada, H., Kadono, S., Igawa, T., Kuramochi, T., Muraoka, M., Wada, Y., Haraya, K., Miyazaki, T., & Hattori, K. (2013) · Protein Engineering Design and Selection · doi:10.1093/protein/gzt022 · Cited by 127
“The interaction of soluble hFcRn was monitored as described previously (Igawa et al., 2010).”
MethodSelf-citationDeng, R., Jin, F., Prabhu, S., & Iyer, S. (2012) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2012.643868 · Cited by 126
Li, B., Tesar, D. B., Boswell, C. A., Cahaya, H. S., Wong, A., Zhang, J., Meng, Y. G., Eigenbrot, C. W., Pantua, H., Diao, J., et al. (2014) · mAbs · doi:10.4161/mabs.29809 · Cited by 122
“A dependence of clearance determined in mice on antibody pI was previously observed for a series of humanized IgG4, k isotype antibodies.(17) Igawa et al.”
BackgroundDobson, C., Devine, P. W. A., Phillips, J. J., Higazi, D. R., Lloyd, C., Popovic, B., Arnold, J., Buchanan, A. G., Lewis, A. R., Goodman, J., et al. (2016) · Scientific Reports · doi:10.1038/srep38644 · Cited by 117
Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics
Bumbaca, D., Boswell, C. A., Fielder, P. J., & Khawli, L. A. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9369-y · Cited by 119
Akbar, R., Bashour, H., Rawat, P., Robert, P. A., Smorodina, E., Cotet, T., Karlsen, K. F., Frank, R., Mehta, B. B., Vu, M. H., et al. (2022) · mAbs · doi:10.1080/19420862.2021.2008790 · Cited by 121
“255 These findings align with the previously reported impact of pI and PSR measures on mAbs PK. 22,264,272 In summary, the half-life of IgG mAbs can be tailored via the optimization of numerous physicochemical parameters, including FcRn affinity, thermal stability, pI, and PSR. ML and the increasing availability of mA…”
BackgroundResultPharmacokinetic properties of IgG and various Fc fusion proteins in mice
Unverdorben, F., Richter, F., Hutt, M., Seifert, O., Malinge, P., Fischer, N., & Kontermann, R. E. (2015) · mAbs · doi:10.1080/19420862.2015.1113360 · Cited by 117
“For example, a comparison of IgG4 antibodies with variable domains of different isoelectric points showed that molecules with a lower isoelectric point had a longer halflife.(23) A recent study confirmed this finding for antibodies with identical Fc regions but different Fab arms, which was attributed to differences i…”
BackgroundMechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides
Datta‐Mannan, A. (2019) · Drug Metabolism and Disposition · doi:10.1124/dmd.119.086488 · Cited by 113
“agnostic to chemical modification and transformations or alterations in FcRn interactions (Hong et al., 1999; Boswell et al., 2010; Igawa et al., 2010; Khawli et al., 2010).”
BackgroundCharacterization and screening of IgG binding to the neonatal Fc receptor
Neuber, T., Frese, K., Jaehrling, J., Jäger, S., Daubert, D., Felderer, K., Linnemann, M., Höhne, A., Kaden, S., Kölln, J., et al. (2014) · mAbs · doi:10.4161/mabs.28744 · Cited by 114
“For instance, for binding of an IgG1 to hFcRn, apparent K D values from 6 to 2500 nM have been reported.(9,14,19,23,25,27,35-37) This makes a literature-based comparison of reported affinities very challenging and hampers interpretation of results.”
BackgroundPoulin, P., Kenny, J. R., Hop, C. E. C. A., & Haddad, S. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22792 · Cited by 109
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Molecular engineering of antibodies for therapeutic and diagnostic purposes
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pH-dependent Binding Engineering Reveals an FcRn Affinity Threshold That Governs IgG Recycling
Borrok, M. J., Wu, Y., Beyaz, N., Yu, X., Oganesyan, V., Dall’Acqua, W. F., & Tsui, P. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.603712 · Cited by 111
“In this regard, we do envision that extremely long half-lives of Fc-containingmolecules could be achieved by combining FcRn binding engineering with FcRn-independent half-life-extending technologies, such as pI optimization (39) and pH-dependent antigen binding engineering (40, 41).”
BackgroundChen, Y., & Balthasar, J. P. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9395-9 · Cited by 105
“Even in cases where target-mediated elimination is unlikely, literature data has shown that antibodies with identical constant regions and similar FcRn binding may display different disposition kinetics (46,47).”
BackgroundAffinity Maturation Enhances Antibody Specificity but Compromises Conformational Stability
Shehata, L., Maurer, D. P., Wec, A. Z., Lilov, A., Champney, E. R., Sun, T., Archambault, K., Burnina, I., Lynaugh, H., Zhi, X., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.056 · Cited by 108
The multiple facets of FcRn in immunity
Stapleton, N. M., Einarsdottir, H., Stemerding, A. M., & Vidarsson, G. (2015) · Immunological Reviews · doi:10.1111/imr.12331 · Cited by 107
New BBB Model Reveals That IL-6 Blockade Suppressed the BBB Disorder, Preventing Onset of NMOSD
Takeshita, Y., Fujikawa, S., Serizawa, K., Fujisawa, M., Matsuo, K., Nemoto, J., Shimizu, F., Sano, Y., Tomizawa-Shinohara, H., Miyake, S., et al. (2021) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000001076 · Cited by 105
“The constant and variable regions of satralizumab are engineered to have pHdependent binding to IL-6 receptors, increased affinity to the neonatal Fc receptor, and a lower isoelectric point to extend the elimination half-life of the drug in plasma.(24,25) Importantly, it is reported that satralizumab showed beneficial…”
BackgroundPutnam, W. S., Prabhu, S., Zheng, Y., Subramanyam, M., & Wang, Y. (2010) · Trends in biotechnology · doi:10.1016/j.tibtech.2010.07.001 · Cited by 103
Igawa, T., Haraya, K., & Hattori, K. (2016) · Immunological Reviews · doi:10.1111/imr.12392 · Cited by 100
“The second technology is to engineer the variable region to lower the isoelectric point of the antibody in order to reduce the non-specific cellular uptake of the antibody (96).”
BackgroundSelf-citationAvery, L. B., Wade, J. M., Wang, M., Tam, A. S. P., King, A. C., Piche‐Nicholas, N., Kavosi, M. S., Penn, S., Cirelli, D. J., Kurz, J. C., et al. (2017) · mAbs · doi:10.1080/19420862.2017.1417718 · Cited by 99
“dramatically improved through engineering efforts to remove or reposition positive charges or counterbalance them with negative charges.(6,12,13,21,22) The availability of high-throughput in vitro assays capable of identifying these properties in mAbs would facilitate the early identification and de-selection of poten…”
BackgroundIgG Charge: Practical and Biological Implications
Yang, D., Kroe‐Barrett, R., Singh, S., & Laue, T. M. (2019) · Antibodies · doi:10.3390/antib8010024 · Cited by 98
“For example, neonatal Fc receptor (FcRn)-independent clearance rates are lower for mAbs with lower pI values than those with higher pI values [16–18], presumably due to decreased nonspecific cell surface binding [16,17,19,20].”
BackgroundA human endothelial cell-based recycling assay for screening of FcRn targeted molecules
Grevys, A., Nilsen, J., Sand, K. M. K., Daba, M. B., Øynebråten, I., Bern, M., McAdam, M. B., Foss, S., Schlothauer, T., Michaelsen, T. E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03061-x · Cited by 98
Kelly, R. L., Sun, T., Jain, T. S., Caffry, I., Yu, Y., Cao, Y., Lynaugh, H., Brown, M. E., Vásquez, M., Wittrup, K. D., et al. (2015) · mAbs · doi:10.1080/19420862.2015.1043503 · Cited by 90
Khuat, T. T., Bassett, R., Otte, E. A., Grevis-James, A., & Gabryś, B. (2024) · Computers & Chemical Engineering · doi:10.1016/j.compchemeng.2024.108585 · Cited by 102
Targeting FcRn for the modulation of antibody dynamics
Ward, E. S., Devanaboyina, S. C., & Ober, R. J. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.02.007 · Cited by 89
Glassman, P. M., & Balthasar, J. P. (2018) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2018.11.002 · Cited by 86
“It has been reported by several groups that changes in antibody charge (defined by molecular or variable domain isoelectric point) can lead to changes in tissue distribution and clearance of mAbs, potentially through altered electrostatic interactions with the glycocalyx decorating the surface of endothelial cells [35…”
BackgroundDatta‐Mannan, A., Lu, J., Witcher, D. R., Leung, D., Tang, Y., & Wroblewski, V. J. (2015) · mAbs · doi:10.1080/19420862.2015.1075109 · Cited by 89
“to charge repulsion with the negatively charged extracellular membrane, 6,7,31,35,36 or 2) decreased lysosomal degradation rates.(7,37) We postulated the reduced clearance of charge balanced mAbs is likely a consequence of both of these mechanisms, but to variable degrees as discussed elsewhere.”
BackgroundHarnessing the potential of machine learning for advancing “Quality by Design” in biomanufacturing
Walsh, I., Myint, M. K., Nguyen‐Khuong, T., Ho, Y. S., Ng, S. K., & Lakshmanan, M. (2022) · mAbs · doi:10.1080/19420862.2021.2013593 · Cited by 86
“2 6 The biopharmaceutical product quality is also extremely sensitive to changes in the underlying biomanufacturing operating conditions and raw materials.”
BackgroundSelecting and engineering monoclonal antibodies with drug-like specificity
Starr, C. G., & Tessier, P. M. (2019) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2019.01.008 · Cited by 81
Bumbaca Yadav, D., Sharma, V. K., Boswell, C. A., Hotzel, I., Tesar, D., Shang, Y., Ying, Y., Fischer, S. K., Grogan, J. L., Chiang, E. Y., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.692434 · Cited by 82
“(23) also were not able to see a clear correlation between s.”
BackgroundNet charge of antibody complementarity-determining regions is a key predictor of specificity
Rabia, L. A., Zhang, Y., Ludwig, S. D., Julian, M. C., & Tessier, P. M. (2018) · Protein Engineering Design and Selection · doi:10.1093/protein/gzz002 · Cited by 81
Non-specificity as the sticky problem in therapeutic antibody development
Ausserwöger, H., Schneider, M. M., Herling, T. W., Arosio, P., Invernizzi, G., Knowles, T. P. J., & Lorenzen, N. (2022) · Nature Reviews Chemistry · doi:10.1038/s41570-022-00438-x · Cited by 82
(2018) · doi:10.1080/19420862.2017.1389355 · Cited by 80
“We believe that this format helped us draw correlations between the in vitro affinity of IgG molecules to FcRn and IgG CL.”
ResultInfluentialCunningham, O., Scott, M., Zhou, Z. S., & Finlay, W. J. J. (2021) · mAbs · doi:10.1080/19420862.2021.1999195 · Cited by 77
“5.(17) Mouse pK studies with these closely related variants demonstrated that clearance rate was directly correlated with increasing pI of the variable domain.”
BackgroundAvoiding antibody aggregation during processing: Establishing hold times
Joshi, V. S., Shivach, T., Kumar, V., Yadav, N., & Rathore, A. S. (2014) · Biotechnology Journal · doi:10.1002/biot.201400052 · Cited by 77
“It has been demonstrated that intentionally modifying the pI of an antibody by approximately one pH unit can lead to significant differences in the pharmacokinetics of an intact Mab [19, 20].”
BackgroundPoulin, P., Burczynski, F. J., & Haddad, S. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24571 · Cited by 74
ADME of Biologics—What Have We Learned from Small Molecules?
Prueksaritanont, T., & Tang, C. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9353-6 · Cited by 75
“It is noteworthy that in vitro FcRn binding properties have been used extensively to aid in Fc engineering of mAbs with varying Fc sequences (Fc mutants) for their optimal t1/2 potential in humans, and that for these Fc mutants, there is a good correlation between FcRn binding affinities (primarily at acidic pH) and m…”
BackgroundZhang, L., Patapoff, T. W., Farnan, D., et al. (2012) · Journal of Chromatography A · doi:10.1016/j.chroma.2012.11.060 · Cited by 71
pH-dependent antigen-binding antibodies as a novel therapeutic modality
Igawa, T., Mimoto, F., & Hattori, K. (2014) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2014.08.003 · Cited by 70
Self-citationHeparin chromatography as an in vitro predictor for antibody clearance rate through pinocytosis
Kraft, T. E., Richter, W. F., Emrich, T., Knaupp, A., Schuster, M., Wolfert, A., & Kettenberger, H. (2019) · mAbs · doi:10.1080/19420862.2019.1683432 · Cited by 68
Datta‐Mannan, A., Estwick, S. A., Zhou, C., Choi, H., Douglass, N. E., Witcher, D. R., Lu, J., Beidler, C. B., & Millican, R. L. (2020) · mAbs · doi:10.1080/19420862.2020.1770028 · Cited by 67
“2 across studies) slows IgG clearance.(25,26)”
Martin, K., Grimaldi, C. M., Grempler, R., Hansel, S. B., & Kumar, S. (2023) · mAbs · doi:10.1080/19420862.2023.2191301 · Cited by 67
Reduction of Nonspecificity Motifs in Synthetic Antibody Libraries
Kelly, R. L., Le, D., Zhao, J., & Wittrup, K. D. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.11.008 · Cited by 67
Industrial bioprocessing perspectives on managing therapeutic protein charge variant profiles
Chung, S., Tian, J., Tan, Z., Chen, J., Lee, J., Borys, M., & Li, Z. J. (2018) · Biotechnology and Bioengineering · doi:10.1002/bit.26587 · Cited by 66
“…(PK) (Hötzel et al., 2012; Li et al., 2014), many reports have observed decreased tissue retention andwhole body clearance for acidic species and increased tissue retention and blood clearance for basic species (Boswell et al., 2010; Igawa et al., 2010; Schoch et al., 2015; Yadav et al., 2015).”
BackgroundChung, S., Nguyen, V., Lin, Y. L., Lafrance‐Vanasse, J., Scales, S. J., Lin, K., Deng, R., Williams, K., Sperinde, G. V., Li, J. J., et al. (2019) · mAbs · doi:10.1080/19420862.2019.1605270 · Cited by 70
Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies
Ishii‐Watabe, A., & Kuwabara, T. (2018) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2018.11.004 · Cited by 67
Blueprint for antibody biologics developability
Mieczkowski, C., Zhang, X., Lee, D., Nguyen, K., Lv, W., Wang, Y., Zhang, Y., Way, J., & Gries, J. (2023) · mAbs · doi:10.1080/19420862.2023.2185924 · Cited by 65
“Excessively high pIs have been associated with poor non-FcRn-dependent PK and bioavailability outcomes,(65) and further reducing the pI through selective engineering of the variable framework or CDR regions improved half-life in certain cases.(17,65,66) Similarly, excessive variable domain charge has correlated to fas…”
BackgroundPoulin, P., Hop, C. E. C. A., Ho, Q., Halladay, J. S., Haddad, S., & Kenny, J. R. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23288 · Cited by 64
Influence of Charge, Hydrophobicity, and Size on Vitreous Pharmacokinetics of Large Molecules
Crowell, S. R., Wang, K., Famili, A., Shatz-Binder, W., Loyet, K. M., Chang, V., Liu, Y., Prabhu, S., Kamath, A. V., & Kelley, R. F. (2019) · Translational Vision Science & Technology · doi:10.1167/tvst.8.6.1 · Cited by 62
“8–10 For large molecules, such as monoclonal antibodies (Mabs) or antibody fragments (Fabs), the impact of size on systemic clearance rates typically is considered primarily with respect to the ‘‘renal filtration cut off’’ wherein no or very limited renal clearance occurs for molecules larger than…”
Congdon, E. E., Lin, Y., Rajamohamedsait, H. B., Shamir, D. B., Krishnaswamy, S., Rajamohamedsait, W. J., Rasool, S., González‐Calle, V., Levenga, J., Gu, J., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0126-z · Cited by 64
“Such differences in uptake are well known in other immunotherapy fields and may be related to antibody charge [18, 19].”
BackgroundEffect of variable domain charge on in vitro and in vivo disposition of monoclonal antibodies
Liu, S., Verma, A., Kettenberger, H., Richter, W. F., & Shah, D. K. (2021) · mAbs · doi:10.1080/19420862.2021.1993769 · Cited by 61
“What makes the later mechanism less generalizable is the fact that the effect of charge on PK could be observed in both wild-type (WT) and FcRn knockout mice.(9,17) Therefore, it is important to clarify if the lower systemic exposure of positively charged antibodies mainly originates from electrostatic interactions wi…”
BackgroundRecombinant antibodies: Engineering and production in yeast and bacterial hosts
Jeong, K. J., Jang, S. H., & Velmurugan, N. (2010) · Biotechnology Journal · doi:10.1002/biot.201000381 · Cited by 67
“[11] modified the variable region instead of Fc region, which led to reduced pI values in variable region and a significant reduction in the clearance of the antibody.”
BackgroundDatta‐Mannan, A., Chow, C.-K., Dickinson, C. D., Driver, D. A., Lu, J., Witcher, D. R., & Wroblewski, V. J. (2012) · Drug Metabolism and Disposition · doi:10.1124/dmd.112.045864 · Cited by 61
Makowski, E. K., Wu, L., Gupta, P., & Tessier, P. M. (2021) · mAbs · doi:10.1080/19420862.2021.1895540 · Cited by 63
Optimization of therapeutic antibodies
Wang, B., Kankanamalage, S. G., Dong, J., & Liu, Y. (2021) · Antibody Therapeutics · doi:10.1093/abt/tbab003 · Cited by 62
“[36] demonstrated that lowering the pI of an antibody successfully improved its half-life, suggesting that it is a plausible way to reduce nonspecific clearance of antibodies.”
BackgroundCongdon, E. E., Chukwu, J. E., Shamir, D. B., Deng, J., Ujla, D., Sait, H. B. R., Neubert, T. A., Kong, X., & Sigurdsson, E. M. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.03.033 · Cited by 56
“Isoelectric point (IEP), the pH at which a molecule carries no charge, is one of these.”
BackgroundInfluentialAntibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody
Sampei, Z., Haraya, K., Tachibana, T., Fukuzawa, T., Shida-Kawazoe, M., Gan, S. W., Shimizu, Y., Ruike, Y., Feng, S., Kuramochi, T., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0209509 · Cited by 57
Self-citationFerl, G. Z., Theil, F., & Wong, H. (2016) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1994 · Cited by 54
Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life
Grevys, A., Frick, R., Mester, S., Flem-Karlsen, K., Nilsen, J., Foss, S., Sand, K. M. K., Emrich, T., Fischer, J. A. A., Greiff, V., et al. (2022) · iScience · doi:10.1016/j.isci.2022.103746 · Cited by 51
“For instance, the surface of cells is negatively charged, and high pI may facilitate cellular uptake and transport to lysosomes for degradation (Igawa et al., 2010b).”
InfluentialGrinshpun, B., Thorsteinson, N., Pereira, J. N., Rippmann, F., Nannemann, D., Sood, V. D., & Fomekong Nanfack, Y. (2021) · mAbs · doi:10.1080/19420862.2021.1932230 · Cited by 52
“strongly influence the rate of linear clearance in humans, in line with previous observations.(10,13,41) We were able to determine threshold values that displayed reasonably good performance in identifying antibodies with normal clearance and especially at excluding antibodies with fast clearance (Figure 7).”
BackgroundMethodResultUnderstanding the in vivo fate of radioimmunoconjugates for nuclear imaging
Vivier, D., Sharma, S. K., & Zeglis, B. M. (2018) · Journal of Labelled Compounds and Radiopharmaceuticals · doi:10.1002/jlcr.3628 · Cited by 57
Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies
Leipold, D. D., & Prabhu, S. (2018) · Clinical and Translational Science · doi:10.1111/cts.12597 · Cited by 56
“Charged amino acids within the complex IgG structure are not only crucial determinants of protein–protein interactions of IgG necessary for biological activity but also determinants of PK.(29,30) On the same lines, the overall charge of the mAb as measured by the isoelectric point (pI) has also been shown to influence…”
BackgroundInfluentialMonnet, C., Jorieux, S., Souyris, N., Zaki, O., Jacquet, A., Fournier, N., Crozet, F., de Romeuf, C., Bouayadi, K., Urbain, R., et al. (2014) · mAbs · doi:10.4161/mabs.27854 · Cited by 54
“2), a parameter that has been shown to negatively affect half-life and clearance.(45) In this set-up, all IgG variants displayed substantial serum half-life increase with ratios (half-life variant/WT) between 1.”
BackgroundBolduc, O. R., Lambert-Lanteigne, P., Colin, D. Y., Zhao, S. S., Proulx, C., Boeglin, D. R., Lubell, W. D., Pelletier, J. N., Féthière, J., Ong, H., et al. (2011) · The Analyst · doi:10.1039/c1an15235a · Cited by 53
Datta‐Mannan, A., Croy, J. E., Schirtzinger, L., Torgerson, S., Breyer, M. D., & Wroblewski, V. J. (2016) · mAbs · doi:10.1080/19420862.2016.1178435 · Cited by 51
“Clearance mechanisms related to FcRn binding, antigen interaction and charge have been characterized and are becoming better understood.(13,15,16,25,26,29) However, directed modulation of these for improved molecular properties is still in its early stages, and the broad translatability of these mechanisms is still be…”
BackgroundTarget-independent variable region mediated effects on antibody clearance can be FcRn independent
Kelly, R. L., Yu, Y., Sun, T., Caffry, I., Lynaugh, H., Brown, M. E., Jain, T. S., Xu, Y., & Wittrup, K. D. (2016) · mAbs · doi:10.1080/19420862.2016.1208330 · Cited by 49
“These results are also consistent with a similar study using the IgG4 isotype, in which a higher pI led to a shortened half-life and higher clearance rates regardless of presence of FcRn.(15) Studies on larger sets of antibodies suggest that the correlation between pI and clearance rates is not generalizable;(24,25) h…”
ResultInfluentialPoulin, P., & Haddad, S. (2013) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23502 · Cited by 54
Gurbaxani, B. M., Dostálek, M., & Gardner, I. B. (2013) · Molecular Immunology · doi:10.1016/j.molimm.2013.05.008 · Cited by 51
Jensen, P. F., Schoch, A., Larraillet, V., Hilger, M., Schlothauer, T., Emrich, T., & Rand, K. D. (2017) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m116.064675 · Cited by 50
“This may explain some of the current discrepancies in the literature on the role of the Fab in FcRn interaction as Fab arm mobility has been limited by interaction with antigen or Fab specific antibodies in some of the used in vitro assays (7, 10).”
Physicochemical Rules for Identifying Monoclonal Antibodies with Drug-like Specificity
Zhang, Y., Wu, L., Gupta, P., Desai, A. A., Smith, M. D., Rabia, L. A., Ludwig, S. D., & Tessier, P. M. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.0c00257 · Cited by 46
Maruyama, S. R., Garcia, G. R., Teixeira, F. R., et al. (2017) · Parasites & Vectors · doi:10.1186/s13071-017-2136-2 · Cited by 47
“Those results suggest that salivary antigen-specific IgG exhibit varied half-lives, whereby several factors could influence their degradation and clearance as: the subclass [48], amino acid composition of Fab regions determined by specificity [73] and patterns of glycosylation [74, 75].”
BackgroundGupta, P., Makowski, E. K., Kumar, S., Zhang, Y., Scheer, J. M., & Tessier, P. M. (2022) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00373 · Cited by 45
Pharmacokinetic de-risking tools for selection of monoclonal antibody lead candidates
Dostalek, M., Prueksaritanont, T., & Kelley, R. F. (2017) · mAbs · doi:10.1080/19420862.2017.1323160 · Cited by 45
“Some of these examples clearly demonstrate that there are cases when cynomolgus monkey failed to predict human pharmacokinetics correctly, due to either under- or over-prediction.(9,13)”
BackgroundA novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life
Souders, C. A., Nelson, S., Wang, Y., Crowley, A. R., Klempner, M. S., & Thomas, W. D. (2015) · mAbs · doi:10.1080/19420862.2015.1054585 · Cited by 45
“Aside from target-mediated clearance, which contributes to non-linear PK profiles and has limited opportunity for modulation,(14-16) the properties affecting linear and non-linear kinetics may include charge variation, nonspecific binding, size, delivery route, immunogenicity, post-translational modifications, hydroph…”
BackgroundFinch, D. K., Sleeman, M. A., Moisan, J., Ferraro, F., Botterell, S., Campbell, J., Cochrane, D., Cruwys, S., England, E., Lane, S., et al. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.06.031 · Cited by 44
Haraya, K., Tachibana, T., & Nezu, J. (2017) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2017.05.002 · Cited by 43
Self-citation
Metadata
- Authors
- Igawa, T., Tsunoda, H., Tachibana, T., Maeda, A., Mimoto, F., Moriyama, C., Nanami, M., Sekimori, Y., Nabuchi, Y., Aso, Y., & Hattori, K.
- Affiliations
- Chugai Pharmaceutical Co., Ltd. (Japan) (JP)
- Venue
- Protein Engineering Design and Selection
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-02-15
- Volume
- 23
- Issue
- 5
- Pages
- 385-392
- ISSN
- 0269-2139 (ISSN-L)
- 1741-0126
- 1741-0134
- OpenAlex
- W2104198642
- Cited by
- 265
- References
- 44
- Citations by year
- 2026: 12 · 2025: 8 · 2024: 15 · 2023: 21 · 2022: 20 · 2021: 22 · 2020: 14 · 2019: 19 · 2018: 25 · 2017: 22 · 2016: 12 · 2015: 22 · 2014: 12 · 2013: 12 · 2012: 17
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Protein Engineering Design and Selection (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Keywords
- antibody half-life, isoelectric point, humanized monoclonal antibody, IgG4 antibodies, pharmacokinetics, Macaca fascicularis, antibody clearance
- MeSH terms
- Animals, Antibodies, Monoclonal, Cricetulus, Genetic Engineering, Half-Life, Cricetinae, Humans, Immunoglobulin G, Immunoglobulin Variable Region, Isoelectric Point, Receptors, Fc, Protein Engineering, Histocompatibility Antigens Class I, CHO Cells, Mice
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