Reduced elimination of IgG antibodies by engineering the variable region

Igawa, T.; Tsunoda, H.; Tachibana, T.; Maeda, A.; Mimoto, F.; Moriyama, C.; Nanami, M.; Sekimori, Y.; Nabuchi, Y.; Aso, Y.; Hattori, K.

doi:10.1093/protein/gzq009

Cited by 265Monoclonal and Polyclonal Antibodies ResearchProtein purification and stabilityBiosimilars and Bioanalytical Methods

Reduced elimination of IgG antibodies by engineering the variable region

Igawa, T., Tsunoda, H., Tachibana, T., Maeda, A., Mimoto, F., Moriyama, C., Nanami, M., Sekimori, Y. +3 more·2010·Protein Engineering Design and Selection

DOI 10.1093/protein/gzq009

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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.
“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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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 · see citing works
Progress and challenges for the machine learning-based design of fit-for-purpose monoclonal antibodies
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 117 · see citing works
“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…”
BackgroundResult
Pharmacokinetic 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 114 · see citing works
“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…”
Background
Mechanisms 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 110 · see citing works
“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).”
Background
Characterization 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 109 · see citing works
“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.”
Background
In Vitro–In Vivo Extrapolation of Clearance: Modeling Hepatic Metabolic Clearance of Highly Bound Drugs and Comparative Assessment with Existing Calculation Methods
Poulin, P., Kenny, J. R., Hop, C. E. C. A., & Haddad, S. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22792 · Cited by 109 · see citing works
Targeting FcRn to Generate Antibody-Based Therapeutics
Ward, E. S., & Ober, R. J. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.07.007 · Cited by 109 · see citing works
Molecular engineering of antibodies for therapeutic and diagnostic purposes
Ducancel, F., & Muller, B. H. (2012) · mAbs · doi:10.4161/mabs.20776 · Cited by 108 · see citing works
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 107 · see citing works
“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).”
Background
Evaluation of a Catenary PBPK Model for Predicting the In Vivo Disposition of mAbs Engineered for High-Affinity Binding to FcRn
Chen, Y., & Balthasar, J. P. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9395-9 · Cited by 105 · see citing works
“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).”
Background
Affinity 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 104 · see citing works
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 103 · see citing works
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 103 · see citing works
“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…”
Background
Pharmacokinetic, pharmacodynamic and immunogenicity comparability assessment strategies for monoclonal antibodies
Putnam, W. S., Prabhu, S., Zheng, Y., Subramanyam, M., & Wang, Y. (2010) · Trends in biotechnology · doi:10.1016/j.tibtech.2010.07.001 · Cited by 101 · see citing works
Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation
Igawa, T., Haraya, K., & Hattori, K. (2016) · Immunological Reviews · doi:10.1111/imr.12392 · Cited by 99 · see citing works
“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-citation
Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics
Avery, 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 97 · see citing works
“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…”
Background
IgG Charge: Practical and Biological Implications
Yang, D., Kroe‐Barrett, R., Singh, S., & Laue, T. M. (2019) · Antibodies · doi:10.3390/antib8010024 · Cited by 98 · see citing works
“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].”
Background
A 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 · see citing works
High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice
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 · see citing works
Applications of machine learning in antibody discovery, process development, manufacturing and formulation: Current trends, challenges, and opportunities
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 98 · see citing works
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 87 · see citing works
Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development
Glassman, P. M., & Balthasar, J. P. (2018) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2018.11.002 · Cited by 86 · see citing works
“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…”
Background
The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies
Datta‐Mannan, A., Lu, J., Witcher, D. R., Leung, D., Tang, Y., & Wroblewski, V. J. (2015) · mAbs · doi:10.1080/19420862.2015.1075109 · Cited by 85 · see citing works
“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.”
Background
Harnessing 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 84 · see citing works
“2 6 The biopharmaceutical product quality is also extremely sensitive to changes in the underlying biomanufacturing operating conditions and raw materials.”
Background
Selecting 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 · see citing works
Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics
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 · see citing works
“(23) also were not able to see a clear correlation between s.”
Background
Net 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 · see citing works
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 80 · see citing works
Untitled work
(2018) · doi:10.1080/19420862.2017.1389355 · Cited by 80 · see citing works
“We believe that this format helped us draw correlations between the in vitro affinity of IgG molecules to FcRn and IgG CL.”
ResultInfluential
Polyreactivity and polyspecificity in therapeutic antibody development: risk factors for failure in preclinical and clinical development campaigns
Cunningham, O., Scott, M. J., Zhou, Z., & Finlay, W. J. J. (2021) · mAbs · doi:10.1080/19420862.2021.1999195 · Cited by 72 · see citing works
“5.(17) Mouse pK studies with these closely related variants demonstrated that clearance rate was directly correlated with increasing pI of the variable domain.”
Background
Avoiding antibody aggregation during processing: Establishing hold times
Joshi, V. S., Shivach, T., Kumar, V., et al. (2014) · Biotechnology Journal · doi:10.1002/biot.201400052 · Cited by 77 · see citing works
“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].”
Background
The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro -to- In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research
Poulin, P., Burczynski, F. J., & Haddad, S. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24571 · Cited by 74 · see citing works
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 74 · see citing works
“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…”
Background
Improving pH gradient cation-exchange chromatography of monoclonal antibodies by controlling ionic strength
Zhang, L., Patapoff, T. W., Farnan, D., et al. (2012) · Journal of Chromatography A · doi:10.1016/j.chroma.2012.11.060 · Cited by 71 · see citing works
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 68 · see citing works
Self-citation
Heparin 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 · see citing works
Influence of physiochemical properties on the subcutaneous absorption and bioavailability of monoclonal antibodies
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 · see citing works
“2 across studies) slows IgG clearance.(25,26)”
Trends in industrialization of biotherapeutics: a survey of product characteristics of 89 antibody-based biotherapeutics
Martin, K., Grimaldi, C. M., Grempler, R., Hansel, S. B., & Kumar, S. (2023) · mAbs · doi:10.1080/19420862.2023.2191301 · Cited by 67 · see citing works
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 · see citing works
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 · see citing works
“…(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).”
Background
Anin vitroFcRn- dependent transcytosis assay as a screening tool for predictive assessment of nonspecific clearance of antibody therapeutics in humans
Chung, 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 65 · see citing works
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 64 · see citing works
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 · see citing works
“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…”
Background
Comparative Assessment of In Vitro–In Vivo Extrapolation Methods used for Predicting Hepatic Metabolic Clearance of Drugs
Poulin, 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 · see citing works
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 · see citing works
“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…”
Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy
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 63 · see citing works
“Such differences in uptake are well known in other immunotherapy fields and may be related to antibody charge [18, 19].”
Background
Effect 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 · see citing works
“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…”
Background
Recombinant 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 62 · see citing works
“[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.”
Background
FcRn Affinity-Pharmacokinetic Relationship of Five Human IgG4 Antibodies Engineered for Improved In Vitro FcRn Binding Properties in Cynomolgus Monkeys
Datta‐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 · see citing works
Discovery-stage identification of drug-like antibodies using emerging experimental and computational methods
Makowski, E. K., Wu, L., Gupta, P., & Tessier, P. M. (2021) · mAbs · doi:10.1080/19420862.2021.1895540 · Cited by 60 · see citing works
Optimization of therapeutic antibodies
Wang, B., Kankanamalage, S. G., Dong, J., & Liu, Y. (2021) · Antibody Therapeutics · doi:10.1093/abt/tbab003 · Cited by 58 · see citing works
“[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.”
Background
Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy
Congdon, 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 55 · see citing works
“Isoelectric point (IEP), the pH at which a molecule carries no charge, is one of these.”
BackgroundInfluential
Antibody 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 · see citing works
Self-citation
Physiologically based pharmacokinetic models of small molecules and therapeutic antibodies: a mini‐review on fundamental concepts and applications
Ferl, G. Z., Theil, F., & Wong, H. (2016) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1994 · Cited by 54 · see citing works
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 · see citing works
“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).”
Influential
Identifying biophysical assays and <i>in silico</i> properties that enrich for slow clearance in clinical-stage therapeutic antibodies
Grinshpun, 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 · see citing works
“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).”
BackgroundMethodResult
Understanding 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 53 · see citing works
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 54 · see citing works
“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…”
BackgroundInfluential
Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody
Monnet, 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 51 · see citing works
“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.”
Background
Modified peptide monolayer binding His-tagged biomolecules for small ligand screening with SPR biosensors
Bolduc, O. R., Lambert-Lanteigne, P., Colin, D. Y., et al. (2011) · The Analyst · doi:10.1039/c1an15235a · Cited by 51 · see citing works
Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys
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 · see citing works
“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…”
Background
Target-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 51 · see citing works
“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…”
ResultInfluential
Toward a new paradigm for the efficient in vitro–in vivo extrapolation of metabolic clearance in humans from hepatocyte data
Poulin, P., & Haddad, S. (2013) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23502 · Cited by 54 · see citing works
Are endosomal trafficking parameters better targets for improving mAb pharmacokinetics than FcRn binding affinity?
Gurbaxani, B. M., Dostálek, M., & Gardner, I. B. (2013) · Molecular Immunology · doi:10.1016/j.molimm.2013.05.008 · Cited by 50 · see citing works
A Two-pronged Binding Mechanism of IgG to the Neonatal Fc Receptor Controls Complex Stability and IgG Serum Half-life
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 49 · see citing works
“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 · see citing works
Mining a differential sialotranscriptome of Rhipicephalus microplus guides antigen discovery to formulate a vaccine that reduces tick infestations
Maruyama, S. R., Garcia, G. R., Teixeira, F. R., et al. (2017) · Parasites & Vectors · doi:10.1186/s13071-017-2136-2 · Cited by 47 · see citing works
“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].”
Background
Antibodies with Weakly Basic Isoelectric Points Minimize Trade-offs between Formulation and Physiological Colloidal Properties
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Self-citation

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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)
ORCID: Igawa, T.
Tsunoda, H.
Tachibana, T.
Maeda, A.
Mimoto, F.
Hattori, K.
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
DOI: 10.1093/protein/gzq009
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: Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › 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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Reduced elimination of IgG antibodies by engineering the variable region

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