Volume 9 Issue 1
Jan.  2018
Turn off MathJax
Article Contents
Liming Liu. Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins[J]. Protein&Cell, 2018, 9(1): 15-32. doi: 10.1007/s13238-017-0408-4
Citation: Liming Liu. Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins[J]. Protein&Cell, 2018, 9(1): 15-32. doi: 10.1007/s13238-017-0408-4

Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins

doi: 10.1007/s13238-017-0408-4
  • Received Date: 2017-02-20
  • Rev Recd Date: 2017-03-23
  • There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1-2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life. Most mAbs display target mediated drug disposition (TMDD), which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody (ADA) response and off-target binding, which require careful consideration during the discovery stage. mAbs are primarily absorbed through the lymphatics via convection and can be conveniently administered by the subcutaneous (sc) route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be reasonably estimated using cynomolgus monkey data and allometric scaling methods.
  • loading
  • [1]
    Abuqayyas L, Zhang X, Balthasar JP (2013) Application of knockout mouse models to investigate the influence of FcgammaR on the pharmacokinetics and anti-platelet effects of MWReg30, a monoclonal anti-GPⅡb antibody. Int J Pharm 444:185-192
    Alt N, Zhang TY, Motchnik P, Taticek R, Quarmby V, Schlothauer T, Beck H, Emrich T, Harris RJ (2016) Determination of critical quality attributes for monoclonal antibodies using quality by design principles. Biologicals 44:291-305
    Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA (2007) The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol 25:21-50
    Ashwell G, Harford J (1982) Carbohydrate-specific receptors of the liver. Annu Rev Biochem 51:531-554
    Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang M, Allison DE, Lu D, Zhang Y, Joshi A, Dresser MJ (2012) A guide to rational dosing of monoclonal antibodies. Clin Pharmacokinet 51:119-135
    Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ (2011) Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 305:1460-1468
    Bertolotti-Ciarlet A, Wang W, Lownes R, Pristatsky P, Fang Y, McKelvey T, Li Y, Li Y, Drummond J, Prueksaritanont T, Vlasak J (2009) Impact of methionine oxidation on the binding of human IgG1 to Fc Rn and Fc gamma receptors. Mol Immunol 46:1878-1882
    Bittner B, Richter WF, Hourcade-Potelleret F, McIntyre C, Herting F, Zepeda ML, Schmidt J (2012) Development of a subcutaneous formulation for trastuzumab-nonclinical and clinical bridging approach to the approved intravenous dosing regimen.Arzneimittelforschung 62:401-409
    Bookbinder LH, Hofer A, Haller MF, Zepeda ML, Keller GA, Lim JE, Edgington TS, Shepard HM, Patton JS, Frost GI (2006) A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Control Release 114:230-241
    Boswell CA, Tesar DB, Mukhyala K, Theil FP, Fielder PJ, Khawli LA (2010) Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjug Chem 21:2153-2163
    Brambell FW (1966) The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet 2:1087-1093
    Brambell FW, Hemmings WA, Morris IG (1964) A theoretical model of gamma-globulin catabolism. Nature 203:1352-1354
    Brenner MC, Krzyzanski W, Chou JZ, Signore PE, Fung CK, Guzman D, Li D, Zhang W, Olsen DR, Nguyen VT, Koo CW, Sternlicht MD, Lipson KE (2016) FG-3019, a human monoclonal antibody recognizing connective tissue growth factor, is subject to target-mediated drug disposition. Pharm Res 33:1833-1849
    Bumbaca D, Wong A, Drake E, Reyes AE, Lin BC, Stephan JP, Desnoyers L, Shen BQ, Dennis MS (2011) Highly specific offtarget binding identified and eliminated during the humanization of an antibody against FGF receptor 4. MAbs 3:376-386
    Bumbaca D, Boswell CA, Fielder PJ, Khawli LA (2012) Physiochemical and biochemical factors influencing the pharmacokinetics of antibody therapeutics. AAPS J 14:554-558
    Bumbaca YD, Sharma VK, Boswell CA, Hotzel I, Tesar D, Shang Y, Ying Y, Fischer SK, Grogan JL, Chiang EY, Urban K, Ulufatu S, Khawli LA, Prabhu S, Joseph S, Kelley RF (2015) Evaluating the use of antibody variable region (Fv) charge as a risk assessment tool for predicting typical cynomolgus monkey pharmacokinetics. J Biol Chem 290:29732-29741
    Challa DK, Bussmeyer U, Khan T, Montoyo HP, Bansal P, Ober RJ, Ward ES (2013) Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis. MAbs 5:655-659
    Chen X, Liu YD, Flynn GC (2009) The effect of Fc glycan forms on human IgG2 antibody clearance in humans. Glycobiology 19:240-249
    Chirmule N, Jawa V, Meibohm B (2012) Immunogenicity to therapeutic proteins:impact on PK/PD and efficacy. AAPS J 14:296-302
    Clarke S, Gebbie C, Sweeney C, Olszewksi N, Smith J. A phase I, pharmacokinetic (PK) and preliminary efficacy assessment of ALD518, a humanized anti-IL-6 antibody, in patients with advanced cancer. 2009 ASCO poster. 2009. Ref Type:Abstract Daëron C (2014) Fc receptors as adaptive immunoreceptors. Curr Top Microbiol Immunol 382:131-164
    Danilov SM, Gavrilyuk VD, Franke FE, Pauls K, Harshaw DW, McDonald TD, Miletich DJ, Muzykantov VR (2001) Lung uptake of antibodies to endothelial antigens:key determinants of vascular immunotargeting. Am J Physiol Lung Cell Mol Physiol 280:L1335-L1347
    Datta-Mannan A, Wroblewski VJ (2014) Application of FcRn binding assays to guide mAb development. Drug Metab Dispos 42:1867-1872
    Datta-Mannan A, Witcher DR, Tang Y, Watkins J, Jiang W, Wroblewski VJ (2007a) Humanized IgG1 variants with differential binding properties to the neonatal Fc receptor:relationship to pharmacokinetics in mice and primates. Drug Metab Dispos 35:86-94
    Datta-Mannan A, Witcher DR, Tang Y, Watkins J, Wroblewski VJ (2007b) Monoclonal antibody clearance. Impact of modulating the interaction of IgG with the neonatal Fc receptor. J Biol Chem 282:1709-1717
    Datta-Mannan A, Chow CK, Dickinson C, Driver D, Lu J, Witcher DR, Wroblewski VJ (2012a) FcRn affinity-pharmacokinetic relationship of five human IgG4 antibodies engineered for improved in vitro FcRn binding properties in cynomolgus monkeys. Drug Metab Dispos 40:1545-1555
    Datta-Mannan A, Witcher DR, Lu J, Wroblewski VJ (2012b) Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys. MAbs 4:267-273
    Datta-Mannan A, Croy JE, Schirtzinger L, Torgerson S, Breyer M, Wroblewski VJ (2016) Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys. MAbs 8:969-982
    Deng R, Loyet KM, Lien S, Iyer S, DeForge LE, Theil FP, Lowman HB, Fielder PJ, Prabhu S (2010) Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-{alpha} antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab Dispos 38:600-605
    Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S (2011) Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data:what have we learned? MAbs 3:61-66
    Dirks NL, Meibohm B (2010) Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49:633-659
    Dong JQ, Salinger DH, Endres CJ, Gibbs JP, Hsu CP, Stouch BJ, Hurh E, Gibbs MA (2011) Quantitative prediction of human pharmacokinetics for monoclonal antibodies:retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet 50:131-142
    Dua P, Hawkins E, van der Graaf PH (2015) A tutorial on targetmediated drug disposition (TMDD) models. CPT Pharmacomet Syst Pharmacol 4:324-337
    Ecker DM, Jones SD, Levine HL (2015) The therapeutic monoclonal antibody market. MAbs 7:9-14
    Elvin JG, Couston RG, van der Walle CF (2013) Therapeutic antibodies:market considerations, disease targets and bioprocessing. Int J Pharm 440:83-98
    EMEA (2007) Guideline on requirements for first-in-man clinical trials for potential high-risk medicinal products. Ref Type:Pamphlet Fasanmade AA, Adedokun OJ, Olson A, Strauss R, Davis HM (2010) Serum albumin concentration:a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther 48:297-308
    Feyen O, Lueking A, Kowald A, Stephan C, Meyer HE, Gobel U, Niehues T (2008) Off-target activity of TNF-alpha inhibitors characterized by protein biochips. Anal Bioanal Chem 391:1713-1720
    Fujimori K, Covell DG, Fletcher JE, Weinstein JN (1990) A modeling analysis of monoclonal antibody percolation through tumors:a binding-site barrier. J Nucl Med 31:1191-1198
    Gao X, Ji JA, Veeravalli K, Wang YJ, Zhang T, Mcgreevy W, Zheng K, Kelley RF, Laird MW, Liu J, Cromwell M (2015) Effect of individual Fc methionine oxidation on FcRn binding:Met252 oxidation impairs FcRn binding more profoundly than Met428 oxidation. J Pharm Sci 104:368-377
    Ghetie V, Ward ES (1997) FcRn:the MHC class I-related receptor that is more than an IgG transporter. Immunol Today 18:592-598
    Gibiansky L, Gibiansky E, Kakkar T, Ma P (2008) Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn 35:573-591
    Gilliland LK, Walsh LA, Frewin MR, Wise MP, Tone M, Hale G, Kioussis D, Waldmann H (1999) Elimination of the immunogenicity of therapeutic antibodies. J Immunol 162:3663-3671
    Glatt DM, Beckford Vera DR, Parrott MC, Luft JC, Benhabbour SR, Mumper RJ (2016) The interplay of antigen affinity, internalization, and pharmacokinetics on CD44-positive tumor targeting of monoclonal antibodies. Mol Pharm 13:1894-1903
    Goetze AM, Liu YD, Zhang Z, Shah B, Lee E, Bondarenko PV, Flynn GC (2011) High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology 21:949-959
    Grimm HP (2009) Gaining insights into the consequences of targetmediated drug disposition of monoclonal antibodies using quasisteady-state approximations. J Pharmacokinet Pharmacodyn 36:407-420
    Harding FA, Stickler MM, Razo J, DuBridge RB (2010) The immunogenicity of humanized and fully human antibodies:residual immunogenicity resides in the CDR regions. MAbs 2:256-265
    Hinton PR, Johlfs MG, Xiong JM, Hanestad K, Ong KC, Bullock C, Keller S, Tang MT, Tso JY, Vasquez M, Tsurushita N (2004) Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem 279:6213-6216
    Hinton PR, Xiong JM, Johlfs MG, Tang MT, Keller S, Tsurushita N (2006) An engineered human IgG1 antibody with longer serum half-life. J Immunol 176:346-356
    Hotzel I, Theil FP, Bernstein LJ, Prabhu S, Deng R, Quintana L, Lutman J, Sibia R, Chan P, Bumbaca D, Fielder P, Carter PJ, Kelley RF (2012) A strategy for risk mitigation of antibodies with fast clearance. MAbs 4:753-760
    Huang Q, Riviere JE (2014) The application of allometric scaling principles to predict pharmacokinetic parameters across species. Expert Opin Drug Metab Toxicol 10:1241-1253
    Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi Y, Shimaoka S, Moriyama C, Watanabe T, Takubo R, Doi Y, Wakabayashi T, Hayasaka A, Kadono S, Miyazaki T, Haraya K, Sekimori Y, Kojima T, Nabuchi Y, Aso Y, Kawabe Y, Hattori K (2010a) Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol 28:1203-1207
    Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C, Nanami M, Sekimori Y, Nabuchi Y, Aso Y, Hattori K (2010b) Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel 23:385-392
    Igawa T, Maeda A, Haraya K, Tachibana T, Iwayanagi Y, Mimoto F, Higuchi Y, Ishii S, Tamba S, Hironiwa N, Nagano K, Wakabayashi T, Tsunoda H, Hattori K (2013) Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PLoS ONE 8:e63236
    Igawa T, Haraya K, Hattori K (2016) Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation. Immunol Rev 270:132-151
    Jackisch C, Muller V, Maintz C, Hell S, Ataseven B (2014) Subcutaneous administration of monoclonal antibodies in oncology. Geburtshilfe Frauenheilkd 74:343-349
    James LC, Roversi P, Tawfik DS (2003) Antibody multispecificity mediated by conformational diversity. Science 299:1362-1367
    Jefferis R (2009a) Glycosylation as a strategy to improve antibodybased therapeutics. Nat Rev Drug Discov 8:226-234
    Jefferis R (2009b) Recombinant antibody therapeutics:the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci 30:356-362
    Jefferis R, Lund J (2002) Interaction sites on human IgG-Fc for FcgammaR:current models. Immunol Lett 82:57-65
    Jones AJ, Papac DI, Chin EH, Keck R, Baughman SA, Lin YS, Kneer J, Battersby JE (2007) Selective clearance of glycoforms of a complex glycoprotein pharmaceutical caused by terminal Nacetylglucosamine is similar in humans and cynomolgus monkeys. Glycobiology 17:529-540
    Junghans RP (1997) Finally! The Brambell receptor (FcRB). Mediator of transmission of immunity and protection from catabolism for IgG. Immunol Res 16:29-57
    Kairemo KJ, Lappalainen AK, Kaapa E, Laitinen OM, Hyytinen T, Karonen SL, Gronblad M (2001) In vivo detection of intervertebral disk injury using a radiolabeled monoclonal antibody against keratan sulfate. J Nucl Med 42:476-482
    Kanda Y, Yamada T, Mori K, Okazaki A, Inoue M, Kitajima-Miyama K, Kuni-Kamochi R, Nakano R, Yano K, Kakita S, Shitara K, Satoh M (2007) Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different Nlinked Fc oligosaccharides:the high-mannose, hybrid, and complex types. Glycobiology 17:104-118
    Keck R, Nayak N, Lerner L, Raju S, Ma S, Schreitmueller T, Chamow S, Moorhouse K, Kotts C, Jones A (2008) Characterization of a complex glycoprotein whose variable metabolic clearance in humans is dependent on terminal N-acetylglucosamine content. Biologicals 36:49-60
    Kelley M, Ahene AB, Gorovits B, Kamerud J, King LE, McIntosh T, Yang J (2013) Theoretical considerations and practical approaches to address the effect of anti-drug antibody (ADA) on quantification of biotherapeutics in circulation. AAPS J 15:646-658
    Kelly RL, Sun T, Jain T, Caffry I, Yu Y, Cao Y, Lynaugh H, Brown M, Vasquez M, Wittrup KD, Xu Y (2015) High throughput crossinteraction measures for human IgG1 antibodies correlate with clearance rates in mice. MAbs 7:770-777
    Khawli LA, Goswami S, Hutchinson R, Kwong ZW, Yang J, Wang X, Yao Z, Sreedhara A, Cano T, Tesar D, Nijem I, Allison DE, Wong PY, Kao YH, Quan C, Joshi A, Harris RJ, Motchnik P (2010) Charge variants in IgG1:isolation, characterization, in vitro binding properties and pharmacokinetics in rats. MAbs 2:613-624
    Kijanka G, Ipcho S, Baars S, Chen H, Hadley K, Beveridge A, Gould E, Murphy D (2009) Rapid characterization of binding specificity and cross-reactivity of antibodies using recombinant human protein arrays. J Immunol Methods 340:132-137
    Kim JK, Tsen MF, Ghetie V, Ward ES (1994a) Catabolism of the murine IgG1 molecule:evidence that both CH2-CH3 domain interfaces are required for persistence of IgG1 in the circulation of mice. Scand J Immunol 40:457-465
    Kim JK, Tsen MF, Ghetie V, Ward ES (1994b) Localization of the site of the murine IgG1 molecule that is involved in binding to the murine intestinal Fc receptor. Eur J Immunol 24:2429-2434
    Kobayashi H, Le N, Kim IS, Kim MK, Pie JE, Drumm D, Paik DS, Waldmann TA, Paik CH, Carrasquillo JA (1999) The pharmacokinetic characteristics of glycolated humanized anti-Tac Fabs are determined by their isoelectric points. Cancer Res 59:422-430
    Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495-497
    Lee HJ, Pardridge WM (2003) Monoclonal antibody radiopharmaceuticals:cationization, pegylation, radiometal chelation, pharmacokinetics, and tumor imaging. Bioconjug Chem 14:546-553
    Li B, Tesar D, Boswell CA, Cahaya HS, Wong A, Zhang J, Meng YG, Eigenbrot C, Pantua H, Diao J, Kapadia SB, Deng R, Kelley RF (2014) Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge. MAbs 6:1255-1264
    Ling J, Zhou H, Jiao Q, Davis HM (2009) Interspecies scaling of therapeutic monoclonal antibodies:initial look. J Clin Pharmacol 49:1382-1402
    Liu L (2015) Antibody glycosylation and its impact on the pharmacokinetics and pharmacodynamics of monoclonal antibodies and Fc-fusion proteins. J Pharm Sci 104:1866-1884
    Liu L, Garcia AM, Santoro H, Zhang Y, McDonnell K, Dumont J, Bitonti A (2007) Amelioration of experimental autoimmune myasthenia gravis in rats by neonatal FcR blockade. J Immunol 178:5390-5398
    Liu L, Stadheim A, Hamuro L, Pittman T, Wang W, Zha D, Hochman J, Prueksaritanont T (2011) Pharmacokinetics of IgG1 monoclonal antibodies produced in humanized Pichia pastoris with specific glycoforms:a comparative study with CHO produced materials. Biologicals 39:205-210
    Liu L, Gomathinayagam S, Hamuro L, Prueksaritanont T, Wang W, Stadheim TA, Hamilton SR (2013) The impact of glycosylation on the pharmacokinetics of a TNFR2:Fc fusion protein expressed in glycoengineered Pichia pastoris. Pharm Res 30:803-812
    Lobo ED, Hansen RJ, Balthasar JP (2004) Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 93:2645-2668
    Lueking A, Beator J, Patz E, Mullner S, Mehes G, Amersdorfer P (2008) Determination and validation of off-target activities of antiCD44 variant 6 antibodies using protein biochips and tissue microarrays. Biotechniques 45:i-v Luu KT, Kraynov E, Kuang B, Vicini P, Zhong WZ (2013) Modeling, simulation, and translation framework for the preclinical development of monoclonal antibodies. AAPS J 15:551-558
    Mager DE (2006) Target-mediated drug disposition and dynamics. Biochem Pharmacol 72:1-10
    Mager DE, Jusko WJ (2001) General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn 28:507-532
    Mao CP, Brovarney MR, Dabbagh K, Birnbock HF, Richter WF, Del Nagro CJ (2013) Subcutaneous versus intravenous administration of rituximab:pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys. PLoS ONE 8:e80533
    Mi Y, Lin A, Fiete D, Steirer L, Baenziger JU (2014) Modulation of mannose and asialoglycoprotein receptor expression determines glycoprotein hormone half-life at critical points in the reproductive cycle. J Biol Chem 289:12157-12167
    Mould DR, Sweeney KR (2007) The pharmacokinetics and pharmacodynamics of monoclonal antibodies-mechanistic modeling applied to drug development. Curr Opin Drug Discov Dev 10:84-96
    Mullamitha SA, Ton NC, Parker GJ, Jackson A, Julyan PJ, Roberts C, Buonaccorsi GA, Watson Y, Davies K, Cheung S, Hope L, Valle JW, Radford JA, Lawrance J, Saunders MP, Munteanu MC, Nakada MT, Nemeth JA, Davis HM, Jiao Q, Prabhakar U, Lang Z, Corringham RE, Beckman RA, Jayson GC (2007) Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors. Clin Cancer Res 13:2128-2135
    Muller PY, Milton M, Lloyd P, Sims J, Brennan FR (2009) The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies. Curr Opin Biotechnol 20:722-729
    Ng CM, Stefanich E, Anand BS, Fielder PJ, Vaickus L (2006) Pharmacokinetics/pharmacodynamics of nondepleting anti-CD4 monoclonal antibody (TRX1) in healthy human volunteers. Pharm Res 23:95-103
    Nisen M (2015) The best selling prescription drugs in the world last year. Quartz. Ref Type:Newspaper Nose M, Wigzell H (1983) Biological significance of carbohydrate chains on monoclonal antibodies. Proc Natl Acad Sci USA 80:6632-6636
    Notkins AL (2004) Polyreactivity of antibody molecules. Trends Immunol 25:174-179
    Oitate M, Masubuchi N, Ito T, Yabe Y, Karibe T, Aoki T, Murayama N, Kurihara A, Okudaira N, Izumi T (2011) Prediction of human pharmacokinetics of therapeutic monoclonal antibodies from simple allometry of monkey data. Drug Metab Pharmacokinet 26:423-430
    Olafsen T (2012) Fc engineering:serum half-life modulation through FcRn binding. Methods Mol Biol 907:537-556
    Olafsen T, Kenanova VE, Wu AM (2006) Tunable pharmacokinetics:modifying the in vivo half-life of antibodies by directed mutagenesis of the Fc fragment. Nat Protoc 1:2048-2060
    Onda M, Kreitman RJ, Vasmatzis G, Lee B, Pastan I (1999) Reduction of the nonspecific animal toxicity of anti-Tac(Fv)-PE38 by mutations in the framework regions of the Fv which lower the isoelectric point. J Immunol 163:6072-6077
    Pan H, Chen K, Chu L, Kinderman F, Apostol I, Huang G (2009) Methionine oxidation in human IgG2 Fc decreases binding affinities to protein A and FcRn. Protein Sci 18:424-433
    Patel DA, Puig-Canto A, Challa DK, Perez MH, Ober RJ, Ward ES (2011) Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. J Immunol 187:1015-1022
    Pennica D, Lam VT, Weber RF, Kohr WJ, Basa LJ, Spellman MW, Ashkenazi A, Shire SJ, Goeddel DV (1993) Biochemical characterization of the extracellular domain of the 75-kilodalton tumor necrosis factor receptor. Biochemistry 32:3131-3138
    Richter WF, Jacobsen B (2014) Subcutaneous absorption of biotherapeutics:knowns and unknowns. Drug Metab Dispos 42:1881-1889
    Richter WF, Gallati H, Schiller CD (1999) Animal pharmacokinetics of the tumor necrosis factor receptor-immunoglobulin fusion protein lenercept and their extrapolation to humans. Drug Metab Dispos 27:21-25
    Richter WF, Bhansali SG, Morris ME (2012) Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J 14:559-570
    Robbie GJ, Criste R, Dall'Acqua WF, Jensen K, Patel NK, Losonsky GA, Griffin MP (2013) A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother 57:6147-6153
    Roche Media Release (2013) Herceptin SC formulation approval. Roche Media Release. Ref Type:Newspaper Roche Media Release (2016) MABTHERA SC formulation EU approval. Roche Media Release. Ref Type:Newspaper Roopenian DC, Akilesh S (2007) FcRn:the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715-725
    Rudnick SI, Lou J, Shaller CC, Tang Y, Klein-Szanto AJ, Weiner LM, Marks JD, Adams GP (2011) Influence of affinity and antigen internalization on the uptake and penetration of anti-HER2 antibodies in solid tumors. Cancer Res 71:2250-2259
    Saber H, Gudi R, Manning M, Wearne E, Leighton JK (2016) An FDA oncology analysis of immune activating products and firstin-human dose selection. Regul Toxicol Pharmacol 81:448-456
    Sachs UJ, Socher I, Braeunlich CG, Kroll H, Bein G, Santoso S (2006) A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor alpha-chain promoter. Immunology 119:83-89
    Salar A, Avivi I, Bittner B, Bouabdallah R, Brewster M, Catalani O, Follows G, Haynes A, Hourcade-Potelleret F, Janikova A, Larouche JF, McIntyre C, Pedersen M, Pereira J, Sayyed P, Shpilberg O, Tumyan G (2014) Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma:results from a two-stage, phase IB study. J Clin Oncol 32:1782-1791
    Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, Wakabayashi T, Tanaka E, Muto A, Kojima T, Kitazawa T, Yoshihashi K, Harada A, Funaki M, Haraya K, Tachibana T, Suzuki S, Esaki K, Nabuchi Y, Hattori K (2013) Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VⅢ cofactor activity. PLoS ONE 8:e57479
    Schoch A, Kettenberger H, Mundigl O, Winter G, Engert J, Heinrich J, Emrich T (2015) Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. Proc Natl Acad Sci USA 112:5997-6002
    Shah DK, Betts AM (2013) Antibody biodistribution coefficients:inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human. MAbs 5:297-305
    Shpilberg O, Jackisch C (2013) Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase. Br J Cancer 109:1556-1561
    Simister NE, Mostov KE (1989) An Fc receptor structurally related to MHC class I antigens. Nature 337:184-187
    Somerfield J, Hill-Cawthorne GA, Lin A, Zandi MS, McCarthy C, Jones JL, Willcox M, Shaw D, Thompson SA, Compston AS, Hale G, Waldmann H, Coles AJ (2010) A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 185:763-768
    Stefanich EG, Ren S, Danilenko DM, Lim A, Song A, Iyer S, Fielder PJ (2008) Evidence for an asialoglycoprotein receptor on nonparenchymal cells for O-linked glycoproteins. J Pharmacol Exp Ther 327:308-315
    Swiercz R, Chiguru S, Tahmasbi A, Ramezani SM, Hao G, Challa DK, Lewis MA, Kulkarni PV, Sun X, Ober RJ, Mason RP, Ward ES (2014) Use of Fc-engineered antibodies as clearing agents to increase contrast during PET. J Nucl Med 55:1204-1207
    Tao MH, Morrison SL (1989) Studies of aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and effector functions mediated by the human IgG constant region. J Immunol 143:2595-2601
    Ternant D, Arnoult C, Pugniere M, Dhommee C, Drocourt D, Perouzel E, Passot C, Baroukh N, Mulleman D, Tiraby G, Watier H, Paintaud G, Gouilleux-Gruart V (2016) IgG1 allotypes influence the pharmacokinetics of therapeutic monoclonal antibodies through FcRn binding. J Immunol 196:607-613
    Tsuchida D, Yamazaki K, Akashi S (2016) Comprehensive characterization of relationship between higher-order structure and FcRn binding affinity of stress-exposed monoclonal antibodies. Pharm Res 33:994-1002
    UK Expert Scientific Group (2006) Expert Scientific Group on Phase I Clinical Trials. Ref Type:Pamphlet Vaccaro C, Zhou J, Ober RJ, Ward ES (2005) Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol 23:1283-1288
    van Meer PJ, Kooijman M, Brinks V, Gispen-de Wied CC, Silva-Lima B, Moors EH, Schellekens H (2013) Immunogenicity of mAbs in non-human primates during nonclinical safety assessment. MAbs 5:810-816
    Vugmeyster Y, Szklut P, Wensel D, Ross J, Xu X, Awwad M, Gill D, Tchistiakov L, Warner G (2011) Complex pharmacokinetics of a humanized antibody against human amyloid beta peptide, antiabeta Ab2, in nonclinical species. Pharm Res 28:1696-1706
    Wang W, Prueksaritanont T (2010) Prediction of human clearance of therapeutic proteins:simple allometric scaling method revisited. Biopharm Drug Dispos 31:253-263
    Wang W, Wang EQ, Balthasar JP (2008) Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 84:548-558
    Wang DD, Zhang S, Zhao H, Men AY, Parivar K (2009) Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 49:1012-1024
    Wang W, Lu P, Fang Y, Hamuro L, Pittman T, Carr B, Hochman J, Prueksaritanont T (2011a) Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. Drug Metab Dispos 39:1469-1477
    Wang W, Vlasak J, Li Y, Pristatsky P, Fang Y, Pittman T, Roman J, Wang Y, Prueksaritanont T, Ionescu R (2011b) Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies. Mol Immunol 48:860-866
    Wang W, Chen N, Shen X, Cunningham P, Fauty S, Michel K, Wang B, Hong X, Adreani C, Nunes CN, Johnson CV, Yin KC, Groff M, Zou Y, Liu L, Hamuro L, Prueksaritanont T (2012) Lymphatic transport and catabolism of therapeutic proteins after subcutaneous administration to rats and dogs. Drug Metab Dispos 40:952-962
    Wang J, Iyer S, Fielder PJ, Davis JD, Deng R (2016) Projecting human pharmacokinetics of monoclonal antibodies from nonclinical data:comparative evaluation of prediction approaches in early drug development. Biopharm Drug Dispos 37:51-65
    Wittrup KD, Thurber GM, Schmidt MM, Rhoden JJ (2012) Practical theoretic guidance for the design of tumor-targeting agents. Methods Enzymol 503:255-268
    Wright A, Morrison SL (1994) Effect of altered CH2-associated carbohydrate structure on the functional properties and in vivo fate of chimeric mouse-human immunoglobulin G1. J Exp Med 180:1087-1096
    Wright A, Sato Y, Okada T, Chang K, Endo T, Morrison S (2000) In vivo trafficking and catabolism of IgG1 antibodies with Fc associated carbohydrates of differing structure. Glycobiology 10:1347-1355
    Wu H, Pfarr DS, Johnson S, Brewah YA, Woods RM, Patel NK, White WI, Young JF, Kiener PA (2007) Development of motavizumab, an ultra-potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract. J Mol Biol 368:652-665
    Wynne C, Harvey V, Schwabe C, Waaka D, McIntyre C, Bittner B (2013) Comparison of subcutaneous and intravenous administration of trastuzumab:a Phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer. J Clin Pharmacol. doi: 10.1177/0091270012436560
    Yeung YA, Leabman MK, Marvin JS, Qiu J, Adams CW, Lien S, Starovasnik MA, Lowman HB (2009) Engineering human IgG1 affinity to human neonatal Fc receptor:impact of affinity improvement on pharmacokinetics in primates. J Immunol 182:7663-7671
    Yeung YA, Wu X, Reyes AE, Vernes JM, Lien S, Lowe J, Maia M, Forrest WF, Meng YG, Damico LA, Ferrara N, Lowman HB (2010) A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life. Cancer Res 70:3269-3277
    Yu M, Brown D, Reed C, Chung S, Lutman J, Stefanich E, Wong A, Stephan JP, Bayer R (2012) Production, characterization, and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans. MAbs 4:475-487
    Zahnd C, Kawe M, Stumpp MT, de Pasquale C, Tamaskovic R, Nagy-Davidescu G, Dreier B, Schibli R, Binz HK, Waibel R, Pluckthun A (2010) Efficient tumor targeting with high-affinity designed ankyrin repeat proteins:effects of affinity and molecular size. Cancer Res 70:1595-1605
    Zheng Y, Tesar DB, Benincosa L, Birnbock H, Boswell CA, Bumbaca D, Cowan KJ, Danilenko DM, Daugherty AL, Fielder PJ, Grimm HP, Joshi A, Justies N, Kolaitis G, Lewin-Koh N, Li J, McVay S, O'Mahony J, Otteneder M, Pantze M, Putnam WS, Qiu ZJ, Ruppel J, Singer T, Stauch O, Theil FP, Visich J, Yang J, Ying Y, Khawli LA, Richter WF (2012) Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration. MAbs 4:243-255
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (1218) PDF downloads(8122) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint