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Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics

  • Mini-Review
  • Theme: ADME of Therapeutic Proteins
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Abstract

Monoclonal antibodies are increasingly being developed to treat multiple disease areas, including those related to oncology, immunology, neurology, and ophthalmology. There are multiple factors, such as charge, size, neonatal Fc receptor (FcRn) binding affinity, target affinity and biology, immunoglobulin G (IgG) subclass, degree and type of glycosylation, injection route, and injection site, that could affect the pharmacokinetics (PK) of these large macromolecular therapeutics, which in turn could have ramifications on their efficacy and safety. This minireview examines how characteristics of the antibodies could be altered to change their PK profiles. For example, it was observed that a net charge modification of at least a 1-unit shift in isoelectric point altered antibody clearance. Antibodies with enhanced affinity for FcRn at pH 6.0 display longer serum half-lives and slower clearances than wild type. Antibody fragments have different clearance rates and tissue distribution profiles than full length antibodies. Fc glycosylation is perceived to have a minimal effect on PK while that of terminal high mannose remains unclear. More investigation is warranted to determine if injection route and/or site impacts PK. Nonetheless, a better understanding of the effects of all these variations may allow for the better design of antibody therapeutics.

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Abbreviations

Cyno:

Cynomolgus monkey

Fab:

Antigen binding fragment

Fc:

Fragment crystallizable

FcγR:

Fc gamma receptor

FcRn:

Neonatal Fc receptor

GlcNAc:

N-acetylglucosamine

HC:

Heavy chain

IgG:

Immunoglobulin G

LC:

Light chain

pI :

Isoelectric point

PK:

Pharmacokinetics

References

  1. Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies—mechanistic modeling applied to drug development. Curr Opin Drug Discov Dev. 2007;10(1):84–96.

    CAS  Google Scholar 

  2. Sarmay G, Lund J, Rozsnyay Z, Gergely J, Jefferis R. Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fc gamma receptor. Mol Immunol. 1992;29(5):633–9.

    Article  PubMed  CAS  Google Scholar 

  3. Correia IR. Stability of IgG isotypes in serum. mAbs. 2010;2(3):221–32.

    Article  PubMed  Google Scholar 

  4. Dong JQ, Salinger DH, Endres CJ, Gibbs JP, Hsu CP, Stouch BJ, et al. Quantitative prediction of human pharmacokinetics for monoclonal antibodies: retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet. 2011;50(2):131–42.

    Article  PubMed  CAS  Google Scholar 

  5. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58.

    Article  PubMed  CAS  Google Scholar 

  6. Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11(1–2):81–8.

    Article  PubMed  CAS  Google Scholar 

  7. Yeung YA, Leabman MK, Marvin JS, Qiu J, Adams CW, Lien S, et al. Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol. 2009;182(12):7663–71.

    Article  PubMed  CAS  Google Scholar 

  8. Deng R, Loyet KM, Lien S, Iyer S, DeForge LE, Theil FP, et al. Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-{alpha} antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab Dispos Biol Fate Chem. 2010;38(4):600–5.

    Article  PubMed  CAS  Google Scholar 

  9. Khawli LA, Biela B, Hu P, Epstein AL. Comparison of recombinant derivatives of chimeric TNT-3 antibody for the radioimaging of solid tumors. Hybridoma Hybridomics. 2003;22(1):1–9.

    Article  CAS  Google Scholar 

  10. Dennis MS, Jin H, Dugger D, Yang R, McFarland L, Ogasawara A, et al. Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent. Cancer Res. 2007;67(1):254–61.

    Article  PubMed  CAS  Google Scholar 

  11. Boswell CA, Tesar DB, Mukhyala K, Theil FP, Fielder PJ, Khawli LA. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjug Chem. 2010;21(12):2153–63.

    Article  PubMed  CAS  Google Scholar 

  12. Khawli LA, Goswami S, Hutchinson R, Kwong ZW, Yang J, Wang X, et al. Charge variants in IgG1: Isolation, characterization, in vitro binding properties and pharmacokinetics in rats. mAbs. 2010;2(6):613–24.

    Article  PubMed  Google Scholar 

  13. Tao MH, Morrison SL. 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. 1989;143(8):2595–601.

    PubMed  CAS  Google Scholar 

  14. Harris RJ. Heterogeneity of recombinant antibodies: linking structure to function. Dev Biol. 2005;122:117–27.

    CAS  Google Scholar 

  15. Goetze AM, Liu YD, Zhang Z, Shah B, Lee E, Bondarenko PV, et al. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology. 2011;21(7):949–59.

    Article  PubMed  CAS  Google Scholar 

  16. Barrett JS, Wagner JG, Fisher SJ, Wahl RL. Effect of intraperitoneal injection volume and antibody protein dose on the pharmacokinetics of intraperitoneally administered IgG2a kappa murine monoclonal antibody in the rat. Cancer Res. 1991;51(13):3434–44.

    PubMed  CAS  Google Scholar 

  17. Xu Z, Wang Q, Zhuang Y, Frederick B, Yan H, Bouman-Thio E, et al. Subcutaneous bioavailability of golimumab at 3 different injection sites in healthy subjects. J Clin Pharmacol. 2010;50(3):276–84.

    Article  PubMed  CAS  Google Scholar 

  18. Ternant D, Paintaud G. Pharmacokinetics and concentration–effect relationships of therapeutic monoclonal antibodies and fusion proteins. Expert Opin Biol Ther. 2005;5 Suppl 1:S37–47.

    Article  PubMed  CAS  Google Scholar 

  19. Andya JD, Hsu CC, Shire SJ. Mechanisms of aggregate formation and carbohydrate excipient stabilization of lyophilized humanized monoclonal antibody formulations. AAPS pharmSci. 2003;5(2):E10.

    Article  PubMed  Google Scholar 

  20. Jain RK. Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng. 1999;1:241–63.

    Article  PubMed  CAS  Google Scholar 

  21. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583–92.

    Article  PubMed  CAS  Google Scholar 

  22. Tabrizi M, Bornstein GG, Suria H. Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease. AAPS J. 2010;12(1):33–43.

    Article  PubMed  CAS  Google Scholar 

  23. Thurber GM, Schmidt MM, Wittrup KD. Factors determining antibody distribution in tumors. Trends Pharmacol Sci. 2008;29(2):57–61.

    PubMed  CAS  Google Scholar 

  24. Lee HJ, Pardridge WM. Monoclonal antibody radiopharmaceuticals: cationization, pegylation, radiometal chelation, pharmacokinetics, and tumor imaging. Bioconjug Chem. 2003;14(3):546–53.

    Article  PubMed  CAS  Google Scholar 

  25. Herve F, Ghinea N, Scherrmann JM. CNS delivery via adsorptive transcytosis. AAPS J. 2008;10(3):455–72.

    Article  PubMed  Google Scholar 

  26. Kobayashi H, Le N, Kim IS, Kim MK, Pie JE, Drumm D, et al. The pharmacokinetic characteristics of glycolated humanized anti-Tac Fabs are determined by their isoelectric points. Cancer Res. 1999;59(2):422–30.

    PubMed  CAS  Google Scholar 

  27. Khawli LA, Glasky MS, Alauddin MM, Epstein AL. Improved tumor localization and radioimaging with chemically modified monoclonal antibodies. Cancer Biother Radiopharm. 1996;11(3):203–15.

    Article  PubMed  CAS  Google Scholar 

  28. Zheng Y, Tesar DB, Benincosa L, Birnböck H, Boswell CA, Bumbaca D, et al. Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration. mAbs. 2012;4(2):0–1.

    Article  Google Scholar 

  29. Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C, et al. Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel PEDS. 2010;23(5):385–92.

    Article  CAS  Google Scholar 

  30. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25.

    Article  PubMed  CAS  Google Scholar 

  31. Zheng Y, Scheerens H, Davis Jr JC, Deng R, Fischer SK, Woods C, et al. Translational pharmacokinetics and pharmacodynamics of an FcRn-variant anti-CD4 monoclonal antibody from preclinical model to phase I study. Clin Pharmacol Ther. 2011;89(2):283–90.

    Article  PubMed  CAS  Google Scholar 

  32. Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313(5787):670–3.

    Article  PubMed  CAS  Google Scholar 

  33. Kanda Y, Yamada T, Mori K, Okazaki A, Inoue M, Kitajima-Miyama K, et al. Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology. 2007;17(1):104–18.

    Article  PubMed  CAS  Google Scholar 

  34. Deng R, Jin F, Prabhu S, Iyer S. Monoclonal antibodies: what are the pharmacokinetic and pharmacodynamic considerations for drug development? Expert Opin Drug Metab Toxicol. 2012;8(2):141–60.

    Article  PubMed  CAS  Google Scholar 

  35. Millward TA, Heitzmann M, Bill K, Langle U, Schumacher P, Forrer K. Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice. Biol J Int Assoc Biol Stand. 2008;36(1):41–7.

    CAS  Google Scholar 

  36. Wright A, Morrison SL. Effect of C2-associated carbohydrate structure on Ig effector function: studies with chimeric mouse-human IgG1 antibodies in glycosylation mutants of Chinese hamster ovary cells. J Immunol. 1998;160(7):3393–402.

    PubMed  CAS  Google Scholar 

  37. Wright A, Sato Y, Okada T, Chang K, Endo T, Morrison S. In vivo trafficking and catabolism of IgG1 antibodies with Fc associated carbohydrates of differing structure. Glycobiology. 2000;10(12):1347–55.

    Article  PubMed  CAS  Google Scholar 

  38. Sweetser MT, Woodworth J, Swan S, Ticho B. Results of a randomized open-label crossover study of the bioequivalence of subcutaneous versus intramuscular administration of alefacept. Dermatol Online J. 2006;12(3):1.

    PubMed  Google Scholar 

  39. Xu ZH, Wang QM, Zhuang YL, Frederick B, Yan H, Marini JC, et al. Bioavailability of golimumab, an anti-tumor necrosis factor-α human monoclonal antibody, administered subcutaneously at three different injection sites in healthy subjects. Clin Pharmacol Ther. 2009;85(S1):S24.

    Google Scholar 

  40. McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. Subcutaneous administration of biotherapeutics: current experience in animal models. Curr Opin Mol Ther. 2010;12(4):461–70.

    PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS

The authors would like to thank Frank-Peter Theil, Enzo Palma, Wendy Putnam, and Devin Tesar for helpful discussion.

Conflict of Interest Statement

All authors are employees of Genentech, Inc., a member of the Roche Group, and are Roche stockholders.

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Authors and Affiliations

  1. Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., 1 DNA Way MS #463A, South San Francisco, California, 94080, USA

    Daniela Bumbaca, C. Andrew Boswell, Paul J. Fielder & Leslie A. Khawli

Authors
  1. Daniela Bumbaca
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  2. C. Andrew Boswell
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  3. Paul J. Fielder
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  4. Leslie A. Khawli
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Corresponding author

Correspondence to Daniela Bumbaca.

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Guest Editors: Craig Svensson, Joseph Balthasar, and Frank-Peter Theil

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Bumbaca, D., Boswell, C.A., Fielder, P.J. et al. Physiochemical and Biochemical Factors Influencing the Pharmacokinetics of Antibody Therapeutics. AAPS J 14, 554–558 (2012). https://doi.org/10.1208/s12248-012-9369-y

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  • DOI: https://doi.org/10.1208/s12248-012-9369-y

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