The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies

References

• Presta LG. Molecular engineering and design of therapeutic antibodies. Curr Opin Immunol 2008; 20:460-70; PMID:18656541; http://dx.doi.org/10.1016/j.coi.2008.06.012
   PubMed Web of Science ®Google Scholar
• Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7:715-25; PMID:17703228; http://dx.doi.org/10.1038/nri2155
   PubMed Web of Science ®Google Scholar
• Buss NA, Henderson SJ, McFarlane M, Shenton JM, de Haan L. Monoclonal antibody therapeutics: history and future. Curr Opin Pharmacol 2012; 12:615-22; PMID:22920732; http://dx.doi.org/10.1016/j.coph.2012.08.001
   PubMed Web of Science ®Google Scholar
• Datta-Mannan A, Wroblewski VJ. Application of FcRn binding assays to guide mab development. Drug Metab Dispos 2014; 42:1867-72; PMID:25024401; http://dx.doi.org/10.1124/dmd.114.059089
   PubMedGoogle Scholar
• Schoch A, Kettenberger H, Mundigl O, Winter G, Engert J, Heinrich J, Emrich T. Charge-mediated influence of the antibody variable domain on FcRn-dependent pharmacokinetics. Proc Natl Acad Sci U S A 2015; 112(19):5997-6002.
   PubMed Web of Science ®Google Scholar
• Datta-Mannan A, Thangaraju A, Leung D, Tang Y, Witcher DR, Lu J, Wroblewski VJ. Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics. mAbs 2015; 7:483-93; PMID:25695748; http://dx.doi.org/10.1080/19420862.2015.1016696
   PubMed Web of Science ®Google Scholar
• Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C, Nanami M, Sekimori Y, Nabuchi Y, Aso Y, et al. Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel 2010; 23:385-92; PMID:20159773; http://dx.doi.org/10.1093/protein/gzq009
   PubMed Web of Science ®Google Scholar
• Li B, Tesar D, Boswell CA, Cahaya HS, Wong A, Zhang J, Meng YG, Eigenbrot C, Pantua H, Diao J, et al. Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge. mAbs 2014; 6:1255-64; PMID:25517310; http://dx.doi.org/10.4161/mabs.29809
   PubMed Web of Science ®Google Scholar
• Wang W, Vlasak J, Li Y, Pristatsky P, Fang Y, Pittman T, Roman J, Wang Y, Prueksaritanont T, Ionescu R. Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies. Mol Immunol 2011; 48:860-6; PMID:21256596; http://dx.doi.org/10.1016/j.molimm.2010.12.009
   PubMed Web of Science ®Google Scholar
• Dall'Acqua WF, Kiener PA, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem 2006; 281:23514-24; PMID:16793771; http://dx.doi.org/10.1074/jbc.M604292200
   PubMed Web of Science ®Google Scholar
• Dall'Acqua WF, Woods RM, Ward ES, Palaszynski SR, Patel NK, Brewah YA, Wu H, Kiener PA, Langermann S. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J Immunol 2002; 169:5171-80; http://dx.doi.org/10.4049/jimmunol.169.9.5171
   PubMed Web of Science ®Google Scholar
• Datta-Mannan A, Chow CK, Dickinson C, Driver D, Lu J, Witcher DR, Wroblewski VJ. FcRn affinity-pharmacokinetic relationship of five human IgG4 antibodies engineered for improved in vitro FcRn binding properties in cynomolgus monkeys. Drug Metab Dispos 2012; 40:1545-55; PMID:22584253; http://dx.doi.org/10.1124/dmd.112.045864
   PubMed Web of Science ®Google Scholar
• Datta-Mannan A, Witcher DR, Lu J, Wroblewski VJ. Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys. mAbs 2012; 4:267-73; PMID:22377715; http://dx.doi.org/10.4161/mabs.4.2.19364
   PubMed Web of Science ®Google Scholar
• Datta-Mannan A, Witcher DR, Tang Y, Watkins J, Jiang W, Wroblewski VJ. Humanized IgG1 variants with differential binding properties to the neonatal Fc receptor: relationship to pharmacokinetics in mice and primates. Drug Metab Dispos 2007; 35:86-94; PMID:17050651; http://dx.doi.org/10.1124/dmd.106.011734
   PubMed Web of Science ®Google Scholar
• Datta-Mannan A, Witcher DR, Tang Y, Watkins J, Wroblewski VJ. Monoclonal antibody clearance. Impact of modulating the interaction of IgG with the neonatal Fc receptor. J Biol Chem 2007; 282:1709-17; PMID:17135257; http://dx.doi.org/10.1074/jbc.M607161200
   PubMed Web of Science ®Google Scholar
• Deng R, Loyet KM, Lien S, Iyer S, DeForge LE, Theil F-P, Lowman HB, Fielder PJ, Prabhu S. Pharmacokinetics of Humanized Monoclonal Anti-Tumor Necrosis Factor-α Antibody and Its Neonatal Fc Receptor Variants in Mice and Cynomolgus Monkeys. Drug Metab Dispos 2010; 38:600-5; PMID:20071453; http://dx.doi.org/10.1124/dmd.109.031310
   PubMed Web of Science ®Google Scholar
• Hinton PR, Johlfs MG, Xiong JM, Hanestad K, Ong KC, Bullock C, Keller S, Tang MT, Tso JY, Vásquez M, et al. Engineered Human IgG Antibodies with Longer Serum Half-lives in Primates. J Biol Chem 2004; 279:6213-6; PMID:14699147; http://dx.doi.org/10.1074/jbc.C300470200
   PubMed Web of Science ®Google Scholar
• Hinton PR, Xiong JM, Johlfs MG, Tang MT, Keller S, Tsurushita N. An engineered human IgG1 antibody with longer serum half-life. J Immunol 2006; 176:346-56; http://dx.doi.org/10.4049/jimmunol.176.1.346
   PubMed Web of Science ®Google Scholar
• Yeung YA, Leabman MK, Marvin JS, Qiu J, Adams CW, Lien S, Starovasnik MA, Lowman HB. Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol 2009; 182:7663-71; http://dx.doi.org/10.4049/jimmunol.0804182
   PubMed Web of Science ®Google Scholar
• Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, Yamaguchi T. Importance of Neonatal FcR in Regulating the Serum Half-Life of Therapeutic Proteins Containing the Fc Domain of Human IgG1: A Comparative Study of the Affinity of Monoclonal Antibodies and Fc-Fusion Proteins to Human Neonatal FcR. J Immunol 2010; 184:1968-76; PMID:20083659; http://dx.doi.org/10.4049/jimmunol.0903296
   PubMed Web of Science ®Google Scholar
• Wang W, Lu P, Fang Y, Hamuro L, Pittman T, Carr B, Hochman J, Prueksaritanont T. Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. Drug Metab Dispos 2011; 39:1469-77; PMID:21610128; http://dx.doi.org/10.1124/dmd.111.039453
   PubMed Web of Science ®Google Scholar
• Zheng Y, Scheerens H, Davis JC, Deng R, Fischer SK, Woods C, Fielder PJ, Stefanich EG. Translational pharmacokinetics and pharmacodynamics of an FcRn-variant anti-CD4 monoclonal antibody from preclinical model to phase I study. Clin Pharmacol Ther 2011; 89:283-90; PMID:21191378; http://dx.doi.org/10.1038/clpt.2010.311
   PubMed Web of Science ®Google Scholar
• Chaparro-Riggers J, Liang H, DeVay RM, Bai L, Sutton JE, Chen W, Geng T, Lindquist K, Casas MG, Boustany LM, et al. Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. J Biol Chem 2012; 287:11090-7; PMID:22294692; http://dx.doi.org/10.1074/jbc.M111.319764
   PubMed Web of Science ®Google Scholar
• Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi Y, Shimaoka S, Moriyama C, Watanabe T, Takubo R, Doi Y, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol 2010; 28:1203-7; PMID:20953198; http://dx.doi.org/10.1038/nbt.1691
   PubMed Web of Science ®Google Scholar
• Igawa T, Mimoto F, Hattori K. pH-dependent antigen-binding antibodies as a novel therapeutic modality. Biochim Biophys Acta 2014; 1844:1943-50; PMID:25125373; http://dx.doi.org/10.1016/j.bbapap.2014.08.003
   PubMed Web of Science ®Google Scholar
• Igawa T, Maeda A, Haraya K, Tachibana T, Iwayanagi Y, Mimoto F, Higuchi Y, Ishii S, Tamba S, Hironiwa N, et al. Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PloS one 2013; 8:e63236; PMID:23667591; http://dx.doi.org/10.1371/journal.pone.0063236
   PubMed Web of Science ®Google Scholar
• Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IW, Sproule TJ, Lazar GA, Roopenian DC, Desjarlais JR. Enhanced antibody half-life improves in vivo activity. Nat Biotechnol 2010; 28:157-9; PMID:20081867; http://dx.doi.org/10.1038/nbt.1601
   PubMed Web of Science ®Google Scholar
• Gurbaxani B, Dela Cruz LL, Chintalacharuvu K, Morrison SL. Analysis of a family of antibodies with different half-lives in mice fails to find a correlation between affinity for FcRn and serum half-life. Mol Immunol 2006; 43:1462-73; PMID:16139891; http://dx.doi.org/10.1016/j.molimm.2005.07.032
   PubMed Web of Science ®Google Scholar
• Yeung YA, Wu X, Reyes AE, 2nd, Vernes JM, Lien S, Lowe J, Maia M, Forrest WF, Meng YG, Damico LA, et al. A therapeutic anti-VEGF antibody with increased potency independent of pharmacokinetic half-life. Cancer Res 2010; 70:3269-77; PMID:20354184; http://dx.doi.org/10.1158/0008-5472.CAN-09-4580
   PubMed Web of Science ®Google Scholar
• Khawli LA, Goswami S, Hutchinson R, Kwong ZW, Yang J, Wang X, Yao Z, Sreedhara A, Cano T, Tesar D, et al. Charge variants in IgG1: Isolation, characterization, in vitro binding properties and pharmacokinetics in rats. mAbs 2010; 2:613-24; PMID:20818176; http://dx.doi.org/10.4161/mabs.2.6.13333
   PubMed Web of Science ®Google Scholar
• Bumbaca D, Boswell CA, Fielder PJ, Khawli LA. Physiochemical and biochemical factors influencing the pharmacokinetics of antibody therapeutics. AAPS J 2012; 14:554-8; PMID:22610647; http://dx.doi.org/10.1208/s12248-012-9369-y
   PubMed Web of Science ®Google Scholar
• Sharma VK, Patapoff TW, Kabakoff B, Pai S, Hilario E, Zhang B, Li C, Borisov O, Kelley RF, Chorny I, et al. In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability. Proc Natl Acad Sci U S A 2014; 111:18601-6; PMID:25512516; http://dx.doi.org/10.1073/pnas.1421779112
   PubMed Web of Science ®Google Scholar
• Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. mAbs 2011; 3:422-30; PMID:22048693; http://dx.doi.org/10.4161/mabs.3.5.16983
   PubMed Web of Science ®Google Scholar
• Henne KR, Ason B, Howard M, Wang W, Sun J, Higbee J, Tang J, Matsuda KC, Xu R, Zhou L, et al. Anti-PCSK9 antibody pharmacokinetics and low-density lipoprotein-cholesterol pharmacodynamics in nonhuman primates are antigen affinity-dependent and exhibit limited sensitivity to neonatal Fc receptor-binding enhancement. J Pharmacol Exp Ther 2015; 353:119-31; PMID:25653417; http://dx.doi.org/10.1124/jpet.114.221242
   PubMed Web of Science ®Google Scholar
• Gurbaxani B, Dostalek M, Gardner I. Are endosomal trafficking parameters better targets for improving mAb pharmacokinetics than FcRn binding affinity? Mol Immunol 2013; 56:660-74; PMID:23917469; http://dx.doi.org/10.1016/j.molimm.2013.05.008
   PubMed Web of Science ®Google Scholar
• Hotzel I, Theil FP, Bernstein LJ, Prabhu S, Deng R, Quintana L, Lutman J, Sibia R, Chan P, Bumbaca D, et al. A strategy for risk mitigation of antibodies with fast clearance. mAbs 2012; 4:753-60; PMID:23778268; http://dx.doi.org/10.4161/mabs.22189
   PubMed Web of Science ®Google Scholar
• Li B, Tesar D, Boswell A, Cahaya H, Wong A, Zhang J, Gloria Meng Y, Eigenbrot C, Pantua H, Diao J, et al. Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge. mAbs 2014; 6:1255-64.
   PubMed Web of Science ®Google Scholar
• Stubenrauch K, Wessels U, Regula JT, Kettenberger H, Schleypen J, Kohnert U. Impact of molecular processing in the hinge region of therapeutic IgG4 antibodies on disposition profiles in cynomolgus monkeys. Drug Metab Dispos 2010; 38:84-91; PMID:19850673; http://dx.doi.org/10.1124/dmd.109.029751
   PubMed Web of Science ®Google Scholar