Skip to main content

Advertisement

SpringerLink
Log in

Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer

  • Expert Review
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Antibody-drug conjugates (ADCs) are ushering in the next era of targeted therapy against cancer. An ADC for cancer therapy consists of a potent cytotoxic payload that is attached to a tumour-targeted antibody by a chemical linker, usually with an average drug-to-antibody ratio (DAR) of 3.5–4. The theory is to deliver potent cytotoxic payloads directly to tumour cells while sparing healthy cells. However, practical application has proven to be more difficult. At present there are only two ADCs approved for clinical use. Nevertheless, in the last decade there has been an explosion of options for ADC engineering to optimize target selection, Fc receptor interactions, linker, payload and more. Evaluation of these strategies requires an understanding of the mechanistic underpinnings of ADC pharmacokinetics. Development of ADCs for use in cancer further requires an understanding of tumour properties and kinetics within the tumour environment, and how the presence of cancer as a disease will impact distribution and elimination. Key pharmacokinetic considerations for the successful design and clinical application of ADCs in oncology are explored in this review, with a focus on the mechanistic determinants of distribution and elimination.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ADA:

Anti-drug antibody

ADC:

Antibody-drug conjugate

ADCC:

Antibody-dependent cell-mediated cytotoxicity

BBB:

Blood-brain barrier

DAR:

Drug-to-antibody ratio

DM1:

N2’-deacetyl-N2’-(3-mercapto-1-oxopropyl)-maytansine

DM4:

N2’-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansine

ECD:

Extracellular domain

EPR:

Enhanced permeability and retention

FcRn:

Neonatal Fc receptor

FcγR:

Fc-gamma receptor

IC50 :

Half maximal inhibitory concentration

IFP:

Interstitial fluid pressure

MMAE:

Monomethyl auristatin E

MMAF:

Monomethyl auristatin F

MPS:

Mononuclear phagocyte system

P-gp:

P-glycoprotein

PBPK:

Physiologically-based pharmacokinetic

TER:

Transcapillary escape rate

TMDD:

Target-mediated drug disposition

References

  1. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of Brentuximab Vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Diamantis N, Banerji U. Antibody-drug conjugates--an emerging class of cancer treatment. Br J Cancer. 2016;114(4):362–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kraeber-Bodere F, Bodet-Milin C, Rousseau C, Eugene T, Pallardy A, Frampas E, et al. Radioimmunoconjugates for the treatment of cancer. Semin Oncol. 2014;41(5):613–22.

    CAS  PubMed  Google Scholar 

  5. Han TH, Zhao B. Absorption, distribution, metabolism, and excretion considerations for the development of antibody-drug conjugates. Drug Metab Dispos Biol Fate Chem. 2014;42(11):1914–20.

    PubMed  Google Scholar 

  6. Garg A, Balthasar JP. Physiologically-based pharmacokinetic (PBPK) model to predict IgG tissue kinetics in wild-type and FcRn-knockout mice. J Pharmacokinet Pharmacodyn. 2007;34(5):687–709.

    CAS  PubMed  Google Scholar 

  7. Li H, Han TH, Hunder NN, Jang G, Zhao B. Population pharmacokinetics of Brentuximab Vedotin in patients with CD30-expressing hematologic malignancies. J Clin Pharmacol. 2017;57(9):1148–58.

    CAS  PubMed  Google Scholar 

  8. Lu D, Girish S, Gao Y, Wang B, Yi JH, Guardino E, et al. Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates. Cancer Chemother Pharmacol. 2014;74(2):399–410.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Deslandes A. Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human Phase 1 studies. mAbs. 2014;6(4):859–70.

    PubMed  PubMed Central  Google Scholar 

  10. Levy G. Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther. 1994;56(3):248–52.

    CAS  PubMed  Google Scholar 

  11. Shah DK, Betts AM. Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J Pharmacokinet Pharmacodyn. 2012;39(1):67–86.

    CAS  PubMed  Google Scholar 

  12. Khot A, Tibbitts J, Rock D, Shah DK. Development of a translational physiologically based pharmacokinetic model for antibody-drug conjugates: a case study with T-DM1. AAPS J. 2017. https://doi.org/10.1208/s12248-017-0131-3

    CAS  PubMed  Google Scholar 

  13. Kraynov E, Kamath AV, Walles M, Tarcsa E, Deslandes A, Iyer RA, et al. Current approaches for absorption, distribution, metabolism, and excretion characterization of antibody-Drug conjugates: an industry white paper. Drug Metab Dispos Biol Fate Chem. 2016;44(5):617–23.

    CAS  PubMed  Google Scholar 

  14. Gorovits B, Alley SC, Bilic S, Booth B, Kaur S, Oldfield P, et al. Bioanalysis of antibody–drug conjugates: american association of pharmaceutical scientists antibody–drug conjugate working group position paper. Bioanalysis. 2013;5(9):997–1006.

    CAS  PubMed  Google Scholar 

  15. Singh AP, Shah DK. Application of a PK-PD modeling and simulation-based strategy for clinical translation of antibody-drug conjugates: a case study with Trastuzumab Emtansine (T-DM1). AAPS J. 2017;19(4):1054–70.

    CAS  PubMed  Google Scholar 

  16. Poon KA, Flagella K, Beyer J, Tibbitts J, Kaur S, Saad O, et al. Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability. Toxicol Appl Pharmacol. 2013;273(2):298–313.

    CAS  PubMed  Google Scholar 

  17. Hock MB, Thudium KE, Carrasco-Triguero M, Schwabe NF. Immunogenicity of antibody drug conjugates: bioanalytical methods and monitoring strategy for a novel therapeutic modality. AAPS J. 2015;17(1):35–43.

    CAS  PubMed  Google Scholar 

  18. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315–37.

    CAS  PubMed  Google Scholar 

  19. Ritchie M, Tchistiakova L, Scott N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. mAbs. 2013;5(1):13–21.

    PubMed  PubMed Central  Google Scholar 

  20. Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated Drug Disposition. J Pharmacokinet Pharmacodyn. 2001;28(6):507–32.

    CAS  PubMed  Google Scholar 

  21. Fujimori K, Covell DG, Fletcher JE, Weinstein JN. A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J Nucl Med. 1990;31(7):1191–8.

    CAS  PubMed  Google Scholar 

  22. Peletier LA, Gabrielsson J. Dynamics of target-mediated drug disposition: characteristic profiles and parameter identification. J Pharmacokinet Pharmacodyn. 2012;39(5):429–51.

    PubMed  PubMed Central  Google Scholar 

  23. Giddabasappa A, Gupta VR, Norberg R, Gupta P, Spilker ME, Wentland J, et al. Biodistribution and targeting of anti-5T4 antibody-drug conjugate using fluorescence molecular tomography. Mol Cancer Ther. 2016;15(10):2530–40.

    CAS  PubMed  Google Scholar 

  24. Sun X, Ponte JF, Yoder NC, Laleau R, Coccia J, Lanieri L, et al. Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-maytansinoid conjugates. Bioconjug Chem. 2017;28(5):1371–81.

    CAS  PubMed  Google Scholar 

  25. Boswell CA, Mundo EE, Firestein R, Zhang C, Mao W, Gill H, et al. An integrated approach to identify normal tissue expression of targets for antibody-drug conjugates: case study of TENB2. Br J Pharmacol. 2013;168(2):445–57.

    CAS  PubMed  Google Scholar 

  26. Glassman PM, Balthasar JP. Physiologically-based pharmacokinetic modeling to predict the clinical pharmacokinetics of monoclonal antibodies. J Pharmacokinet Pharmacodyn. 2016;43(4):427–46.

    PubMed  Google Scholar 

  27. Reardon DA, Lassman AB, van den Bent M, Kumthekar P, Merrell R, Scott AM, et al. Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma. Neuro Oncol. 2016;19(7):965–75.

  28. Tolcher AW, Ochoa L, Hammond LA, Patnaik A, Edwards T, Takimoto C, et al. Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study. J Clin Oncol Official J Am Soc Clin Oncol. 2003;21(2):211–22.

    CAS  Google Scholar 

  29. Boswell CA, Mundo EE, Zhang C, Stainton SL, Yu SF, Lacap JA, et al. Differential effects of predosing on tumor and tissue uptake of an 111In-labeled anti-TENB2 antibody-drug conjugate. J Nuclear Med Official Publication, Soc Nuclear Med. 2012;53(9):1454–61.

    CAS  Google Scholar 

  30. Boswell CA, Bumbaca D, Fielder PJ, Khawli LA. Compartmental tissue distribution of antibody therapeutics: experimental approaches and interpretations. AAPS J. 2012;14(3):612–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Grimm HP. Gaining insights into the consequences of target-mediated drug disposition of monoclonal antibodies using quasi-steady-state approximations. J Pharmacokinet Pharmacodyn. 2009;36(5):407–20.

    CAS  PubMed  Google Scholar 

  32. Malik PRV, Hamadeh A, Phipps C, Edginton AN. Population PBPK modelling of trastuzumab: a framework for quantifying and predicting inter-individual variability. J Pharmacokinet Pharmacodyn. 2017;44(3):277–90.

    CAS  PubMed  Google Scholar 

  33. Williams SP, Ogasawara A, Tinianow JN, Flores JE, Kan D, Lau J, et al. ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. Oncotarget. 2016;7(18):25103–12.

    PubMed  PubMed Central  Google Scholar 

  34. Ingle GS, Chan P, Elliott JM, Chang WS, Koeppen H, Stephan JP, et al. High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate. Br J Haematol. 2008;140(1):46–58.

    CAS  PubMed  Google Scholar 

  35. Pincus SH, Song K, Maresh GA, Hamer DH, Dimitrov DS, Chen W, et al. Identification of human anti-HIV gp160 monoclonal antibodies that make effective immunotoxins. J Virol. 2017;91(3)

  36. Berger C, Madshus IH, Stang E. Cetuximab in combination with anti-human IgG antibodies efficiently down-regulates the EGF receptor by macropinocytosis. Exp Cell Res. 2012;318(20):2578–91.

    CAS  PubMed  Google Scholar 

  37. Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH. Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. Int J Cancer. 2005;116(3):359–67.

    CAS  PubMed  Google Scholar 

  38. Dello Sbarba P, Rovida E. Transmodulation of cell surface regulatory molecules via ectodomain shedding. Biol Chem. 2002;383(1):69–83.

    CAS  Google Scholar 

  39. Pak Y, Pastan I, Kreitman RJ, Lee B. Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model. PLoS One. 2014;9(10):e110716.

    PubMed  PubMed Central  Google Scholar 

  40. Weigle WO. Elimination of antigen-antibody complexes from sera of rabbits. J Immunol (Baltimore, Md : 1950). 1958;81(3):204–13.

    CAS  Google Scholar 

  41. Berson SA, Yalow RS. Quantitative aspects of the reaction between insulin and insulin-binding antibody. J Clin Invest. 1959;38:1996–2016.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Pool M, Kol A, Lub-de Hooge MN, Gerdes CA, de Jong S, de Vries EG, et al. Extracellular domain shedding influences specific tumor uptake and organ distribution of the EGFR PET tracer 89Zr-imgatuzumab. Oncotarget. 2016;7(42):68111–21.

  43. Bruno R, Washington CB, Lu JF, Lieberman G, Banken L, Klein P. Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother Pharmacol. 2005;56(4):361–9.

    CAS  PubMed  Google Scholar 

  44. Pastuskovas CV, Mallet W, Clark S, Kenrick M, Majidy M, Schweiger M, et al. Effect of immune complex formation on the distribution of a novel antibody to the ovarian tumor antigen CA125. Drug Metab Dispos Biol Fate Chem. 2010;38(12):2309–19.

    CAS  PubMed  Google Scholar 

  45. Ackerman ME, Pawlowski D, Wittrup KD. Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids. Mol Cancer Ther. 2008;7(7):2233–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Vasalou C, Helmlinger G, Gomes B. A mechanistic tumor penetration model to guide antibody drug conjugate design. PLoS One. 2015;10(3):e0118977.

    PubMed  PubMed Central  Google Scholar 

  47. Rudnick SI, Lou J, Shaller CC, Tang Y, Klein-Szanto AJ, Weiner LM, et al. Influence of affinity and antigen internalization on the uptake and penetration of anti-HER2 antibodies in solid tumors. Cancer Res. 2011;71(6):2250–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, et al. ABT-414, an antibody–drug conjugate targeting a tumor-selective EGFR epitope. Mol Cancer Ther. 2016;15(4):661.

    CAS  PubMed  Google Scholar 

  49. Bondza S, Stenberg J, Nestor M, Andersson K, Bjorkelund H. Conjugation effects on antibody-drug conjugates: evaluation of interaction kinetics in real time on living cells. Mol Pharm. 2014;11(11):4154–63.

    CAS  PubMed  Google Scholar 

  50. Glassman PM, Balthasar JP. Physiologically-based modeling to predict the clinical behavior of monoclonal antibodies directed against lymphocyte antigens. mAbs. 2017;9(2):297–306.

    CAS  PubMed  Google Scholar 

  51. Beum PV, Lindorfer MA, Beurskens F, Stukenberg PT, Lokhorst HM, Pawluczkowycz AW, et al. Complement activation on B lymphocytes opsonized with rituximab or Ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol. 2008;181(1):822–32.

    CAS  PubMed  Google Scholar 

  52. Wiig H, Swartz MA. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol Rev. 2012;92(3):1005–60.

    CAS  PubMed  Google Scholar 

  53. Sarin H. Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. J Angiogenes Res. 2010;2:14.

    PubMed  PubMed Central  Google Scholar 

  54. Hossler FE, Monson FC. Microvasculature of the rabbit urinary bladder. Anat Rec. 1995;243(4):438–48.

    CAS  PubMed  Google Scholar 

  55. Boswell CA, Mundo EE, Zhang C, Bumbaca D, Valle NR, Kozak KR, et al. Impact of drug conjugation on pharmacokinetics and tissue distribution of anti-STEAP1 antibody-drug conjugates in rats. Bioconjug Chem. 2011;22(10):1994–2004.

    CAS  PubMed  Google Scholar 

  56. Xie H, Audette C, Hoffee M, Lambert JM, Blattler WA. Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice. J Pharmacol Exp Ther. 2004;308(3):1073–82.

    CAS  PubMed  Google Scholar 

  57. Parving HH, Jensen HA, Westrup M. Increased transcapillary escape rate of albumin and IgG in essential hypertension. Scand J Clin Lab Invest. 1977;37(3):223–7.

    CAS  PubMed  Google Scholar 

  58. Parving HH, Ranek L, Lassen NA. Increased transcapillary escape rate of albumin in patients with cirrhosis of the liver. Scand J Clin Lab Invest. 1977;37(7):643–8.

    CAS  PubMed  Google Scholar 

  59. Parving HH. Increased microvascular permeability to plasma proteins in short- and long-term juvenile diabetics. Diabetes. 1976;25(2 SUPPL):884–9.

    CAS  PubMed  Google Scholar 

  60. Parving HH, Rossing N. Simultaneous determination of the transcapillary escape rate of albumin and IgG in normal and long-term juvenile diabetic subjects. Scand J Clin Lab Invest. 1973;32(3):239–44.

    CAS  PubMed  Google Scholar 

  61. Hesse B, Parving HH, Lund-Jacobsen H, Noer I. Transcapillary escape rate of albumin and right atrial pressure in chronic congestive heart failure before and after treatment. Circ Res. 1976;39(3):358–62.

    CAS  PubMed  Google Scholar 

  62. Parving HH, Worm AM, Rossing N. Plasma volume, intravascular albumin and its transcapillary escape rate in patients with extensive skin disease. Br J Dermatol. 1976;95(5):519–214.

    CAS  PubMed  Google Scholar 

  63. Fleck A, Hawker F, Wallace PI, Raines G, Trotter J, Ledingham IM, et al. Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury. Lancet. 1985;325(8432):781–4.

    Google Scholar 

  64. Ballmer PE, Ochsenbein AF, Schütz-Hofmann S. Transcapillary escape rate of albumin positively correlates with plasma albumin concentration in acute but not in chronic inflammatory disease. Metabolism. 1994;43(6):697–705.

    CAS  PubMed  Google Scholar 

  65. Pedersen LM, Terslev L, Sørensen PG, Stokholm KH. Urinary albumin excretion and transcapillary escape rate of albumin in malignancies. Med Oncol (Northwood, London, England). 2000;17(2):117–22.

    CAS  Google Scholar 

  66. Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633–59.

    CAS  PubMed  Google Scholar 

  67. Gupta M, Lorusso PM, Wang B, Yi JH, Burris HA 3rd, Beeram M, et al. Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. J Clin Pharmacol. 2012;52(5):691–703.

    CAS  PubMed  Google Scholar 

  68. Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis. 2008;11(2):109–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Centelles MN, Wright M, Gedroyc W, Thanou M. Focused ultrasound induced hyperthermia accelerates and increases the uptake of anti-HER-2 antibodies in a xenograft model. Pharmacol Res. 2016;114:144–51.

    CAS  PubMed  Google Scholar 

  70. Chacko AM, Li C, Pryma DA, Brem S, Coukos G, Muzykantov V. Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: crossing the blood-brain barrier divide. Expert Opin Drug Deliv. 2013;10(7):907–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Jadhav SB, Khaowroongrueng V, Fueth M, Otteneder MB, Richter W, Derendorf H. Tissue distribution of a therapeutic monoclonal antibody determined by large pore microdialysis. J Pharm Sci. 2017;106(9):2853–9.

    CAS  PubMed  Google Scholar 

  72. van Furth R, Cohn ZA, Hirsch JG, Humphrey JH, Spector WG, Langevoort HL. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ. 1972;46(6):845–52.

    PubMed  PubMed Central  Google Scholar 

  73. Harrison PT, Davis W, Norman JC, Hockaday AR, Allen JM. Binding of monomeric immunoglobulin G triggers Fc gamma RI-mediated endocytosis. J Biol Chem. 1994;269(39):24396–402.

    CAS  PubMed  Google Scholar 

  74. Richter WF, Jacobsen B. Subcutaneous absorption of biotherapeutics: knowns and unknowns. Drug Metab Dispos. 2014;42(11):1881–9.

    PubMed  Google Scholar 

  75. Richter WF, Bhansali SG, Morris ME. Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J. 2012;14(3):559–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Deng R, Meng YG, Hoyte K, Lutman J, Lu Y, Iyer S, et al. Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice. mAbs. 2012;4(1):101–9.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  79. McCarthy KM, Yoong Y, Simister NE. Bidirectional transcytosis of IgG by the rat neonatal fc receptor expressed in a rat kidney cell line: a system to study protein transport across epithelia. J Cell Sci. 2000;113(Pt 7):1277–85.

    CAS  PubMed  Google Scholar 

  80. Fuhrmann S, Kloft C, Huisinga W. Impact of altered endogenous IgG on unspecific mAb clearance. J Pharmacokinet Pharmacodyn. 2017;44(4):351–74.

    CAS  PubMed  Google Scholar 

  81. Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood–brain barrier. J Neurochem. 2002;81(1):203–6.

    CAS  PubMed  Google Scholar 

  82. Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J Neuroimmunol. 2001;114(1–2):168–72.

    CAS  PubMed  Google Scholar 

  83. Pardridge WM. Drug transport across the blood–brain barrier. J Cereb Blood Flow Metab. 2012;32(11):1959–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hamblett KJ, Le T, Rock BM, Rock DA, Siu S, Huard JN, et al. Altering antibody-drug conjugate binding to the neonatal fc receptor impacts efficacy and tolerability. Mol Pharm. 2016;13(7):2387–96.

    CAS  PubMed  Google Scholar 

  85. Acchione M, Kwon H, Jochheim CM, Atkins WM. Impact of linker and conjugation chemistry on antigen binding, Fc receptor binding and thermal stability of model antibody-drug conjugates. mAbs. 2012;4(3):362–72.

    PubMed  PubMed Central  Google Scholar 

  86. Brachet G, Respaud R, Arnoult C, Henriquet C, Dhommee C, Viaud-Massuard MC, et al. Increment in drug loading on an antibody-drug conjugate increases its binding to the human neonatal Fc receptor in vitro. Mol Pharm. 2016;13(4):1405–12.

    CAS  PubMed  Google Scholar 

  87. Gessner JE, Heiken H, Tamm A, Schmidt RE. The IgG Fc receptor family. Ann Hematol. 1998;76(6):231–48.

    CAS  PubMed  Google Scholar 

  88. Abuqayyas L, Balthasar JP. Application of knockout mouse models to investigate the influence of FcgammaR on the tissue distribution and elimination of 8C2, a murine IgG1 monoclonal antibody. Int J Pharm. 2012;439(1–2):8–16.

    CAS  PubMed  Google Scholar 

  89. Abuqayyas L, Zhang X, Balthasar JP. 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. 2013;444(1–2):185–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. mAbs. 2016;8(4):659–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(16):2698–704.

    CAS  Google Scholar 

  92. Uppal H, Doudement E, Mahapatra K, Darbonne WC, Bumbaca D, Shen B-Q, et al. Potential mechanisms for thrombocytopenia development with Trastuzumab Emtansine (T-DM1). Clin Cancer Res. 2015;21(1):123–33.

    CAS  PubMed  Google Scholar 

  93. Li F, Ulrich M, Jonas M, Stone IJ, Linares G, Zhang X, et al. Tumor associated macrophages can contribute to antitumor activity through FcgammaR-mediated processing of antibody-drug conjugates. Mol Cancer Ther. 2017;16(7):1347–54.

    CAS  PubMed  Google Scholar 

  94. Ko SY, Pegu A, Rudicell RS, Yang ZY, Joyce MG, Chen X, et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature. 2014;514(7524):642–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Grevys A, Bern M, Foss S, Bratlie DB, Moen A, Gunnarsen KS, et al. Fc engineering of human IgG1 for altered binding to the neonatal Fc receptor affects Fc effector functions. J Immunol (Baltimore, Md : 1950). 2015;194(11):5497–508.

    CAS  Google Scholar 

  96. Tolcher AW, Sugarman S, Gelmon KA, Cohen R, Saleh M, Isaacs C, et al. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 1999;17(2):478–84.

    CAS  Google Scholar 

  97. Comereski CR, Peden WM, Davidson TJ, Warner GL, Hirth RS, Frantz JD. BR96-doxorubicin conjugate (BMS-182248) versus doxorubicin: a comparative toxicity assessment in rats. Toxicol Pathol. 1994;22(5):473–88.

    CAS  PubMed  Google Scholar 

  98. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235–44.

    CAS  PubMed  Google Scholar 

  99. Sessa C, Weigang-Köhler K, Pagani O, Greim G, Mora O, De Pas T, et al. Phase I and pharmacological studies of the cryptophycin analogue LY355703 administered on a single intermittent or weekly schedule. Eur J Cancer. 2002;38(18):2388–96.

    CAS  PubMed  Google Scholar 

  100. Edelman MJ, Gandara DR, Hausner P, Israel V, Thornton D, DeSanto J, et al. Phase 2 study of cryptophycin 52 ( LY355703) in patients previously treated with platinum based chemotherapy for advanced non-small cell lung cancer. Lung Cancer. 2003;39(2):197–9.

    PubMed  Google Scholar 

  101. Verma VA, Pillow TH, DePalatis L, Li G, Phillips GL, Polson AG, et al. The cryptophycins as potent payloads for antibody drug conjugates. Bioorg Med Chem Lett. 2015;25(4):864–8.

    CAS  PubMed  Google Scholar 

  102. Ogitani Y, Abe Y, Iguchi T, Yamaguchi J, Terauchi T, Kitamura M, et al. Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology. Bioorg Med Chem Lett. 2016;26(20):5069–72.

    CAS  PubMed  Google Scholar 

  103. Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, Chari R, et al. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol Cancer Ther. 2010;9(10):2689–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Oroudjev E, Lopus M, Wilson L, Audette C, Provenzano C, Erickson H, et al. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther. 2010;9(10):2700–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Alley SC, Zhang X, Okeley NM, Anderson M, Law CL, Senter PD, et al. The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther. 2009;330(3):932–8.

    CAS  PubMed  Google Scholar 

  106. Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin DR, Sievers EL, et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16(3):888–97.

    CAS  Google Scholar 

  107. Mantaj J, Jackson PJM, Rahman KM, Thurston DE. From anthramycin to pyrrolobenzodiazepine (PBD)-containing antibody–drug conjugates (ADCs). Angewandte Chemie (International ed in English). 2017;56(2):462–88.

    CAS  Google Scholar 

  108. Erickson HK, Widdison WC, Mayo MF, Whiteman K, Audette C, Wilhelm SD, et al. Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates. Bioconjug Chem. 2010;21(1):84–92.

    CAS  PubMed  Google Scholar 

  109. Erickson HK, Lewis Phillips GD, Leipold DD, Provenzano CA, Mai E, Johnson HA, et al. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther. 2012;11(5):1133–42.

    CAS  PubMed  Google Scholar 

  110. Erickson HK, Lambert JM. ADME of antibody-maytansinoid conjugates. AAPS J. 2012;14(4):799–805.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer. 2002;2(10):750–63.

    CAS  PubMed  Google Scholar 

  112. Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66(8):4426–33.

    CAS  PubMed  Google Scholar 

  113. Kovtun YV, Audette CA, Ye Y, Xie H, Ruberti MF, Phinney SJ, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 2006;66(6):3214–21.

    CAS  PubMed  Google Scholar 

  114. Golfier S, Kopitz C, Kahnert A, Heisler I, Schatz CA, Stelte-Ludwig B, et al. Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther. 2014;13(6):1537–48.

    CAS  PubMed  Google Scholar 

  115. de Souza EG, Hara CC, Fagundes DL, de Queiroz AA, Morceli G, Calderon IM, et al. Maternal-foetal diabetes modifies neonatal fc receptor expression on human leucocytes. Scand J Immunol. 2016;84(4):237–44.

    PubMed  Google Scholar 

  116. Singh AP, Sharma S, Shah DK. Quantitative characterization of in vitro bystander effect of antibody-drug conjugates. J Pharmacokinet Pharmacodyn. 2016;43(6):567–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097–108.

    CAS  PubMed  Google Scholar 

  118. Kovtun YV, Audette CA, Mayo MF, Jones GE, Doherty H, Maloney EK, et al. Antibody-maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res. 2010;70(6):2528–37.

    CAS  PubMed  Google Scholar 

  119. Tang R, Cohen S, Perrot J-Y, Faussat A-M, Zuany-Amorim C, Marjanovic Z, et al. P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients. BMC Cancer. 2009;9:199.

    PubMed  PubMed Central  Google Scholar 

  120. Toppmeyer DL, Slapak CA, Croop J, Kufe DW. Role of P-glycoprotein in dolastatin 10 resistance. Biochem Pharmacol. 1994;48(3):609–12.

    CAS  PubMed  Google Scholar 

  121. Beeram M, Krop IE, Burris HA, Girish SR, Yu W, Lu MW, et al. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer. 2012;118(23):5733–40.

    CAS  PubMed  Google Scholar 

  122. Wang H, Rangan VS, Sung MC, Passmore D, Kempe T, Wang X, et al. Pharmacokinetic characterization of BMS-936561, an anti-CD70 antibody-drug conjugate, in preclinical animal species and prediction of its pharmacokinetics in humans. Biopharm Drug Dispos. 2016;37(2):93–106.

    PubMed  Google Scholar 

  123. Widdison W, Wilhelm S, Veale K, Costoplus J, Jones G, Audette C, et al. Metabolites of antibody-maytansinoid conjugates: characteristics and in vitro potencies. Mol Pharm. 2015;12(6):1762–73.

    CAS  PubMed  Google Scholar 

  124. Yurkovetskiy AV, Yin M, Bodyak N, Stevenson CA, Thomas JD, Hammond CE, et al. A polymer-based antibody-vinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res. 2015;75(16):3365–72.

    CAS  PubMed  Google Scholar 

  125. Behrens CR, Ha EH, Chinn LL, Bowers S, Probst G, Fitch-Bruhns M, et al. Antibody-drug conjugates (ADCs) derived from interchain cysteine cross-linking demonstrate improved homogeneity and other pharmacological properties over conventional heterogeneous ADCs. Mol Pharm. 2015;12(11):3986–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Hamblett KJ, Senter PD, Chace DF, Sun MMC, Lenox J, Cerveny CG, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody Drug conjugate. Clin Cancer Res. 2004;10(20):7063–70.

    CAS  PubMed  Google Scholar 

  127. Strop P, Delaria K, Foletti D, Witt JM, Hasa-Moreno A, Poulsen K, et al. Site-specific conjugation improves therapeutic index of antibody drug conjugates with high drug loading. Nat Biotechnol. 2015;33(7):694–6.

    CAS  PubMed  Google Scholar 

  128. Lyon RP, Bovee TD, Doronina SO, Burke PJ, Hunter JH, Neff-LaFord HD, et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotech. 2015;33(7):733–5.

    CAS  Google Scholar 

  129. Zhao RY, Wilhelm SD, Audette C, Jones G, Leece BA, Lazar AC, et al. Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates. J Med Chem. 2011;54(10):3606–23.

    CAS  PubMed  Google Scholar 

  130. Schumacher D, Hackenberger CP, Leonhardt H, Helma J. Current status: site-specific antibody drug conjugates. J Clin Immunol. 2016;36(Suppl 1):100–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Behrens CR, Liu B. Methods for site-specific drug conjugation to antibodies. mAbs. 2014;6(1):46–53.

    PubMed  Google Scholar 

  132. Chudasama V, Maruani A, Caddick S. Recent advances in the construction of antibody-drug conjugates. Nat Chem. 2016;8(2):114–9.

    CAS  PubMed  Google Scholar 

  133. Sochaj AM, Swiderska KW, Otlewski J. Current methods for the synthesis of homogeneous antibody-drug conjugates. Biotechnol Adv. 2015;33(6 Pt 1):775–84.

    CAS  PubMed  Google Scholar 

  134. Pillow TH, Tien J, Parsons-Reponte KL, Bhakta S, Li H, Staben LR, et al. Site-specific trastuzumab maytansinoid antibody-drug conjugates with improved therapeutic activity through linker and antibody engineering. J Med Chem. 2014;57(19):7890–9.

    CAS  PubMed  Google Scholar 

  135. Thompson P, Fleming R, Bezabeh B, Huang F, Mao S, Chen C, et al. Rational design, biophysical and biological characterization of site-specific antibody-tubulysin conjugates with improved stability, efficacy and pharmacokinetics. J Control Release Off J Control Release Soc. 2016;236:100–16.

    CAS  Google Scholar 

  136. Strop P, Tran TT, Dorywalska M, Delaria K, Dushin R, Wong OK, et al. RN927C, a site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther. 2016;15(11):2698–708.

    CAS  PubMed  Google Scholar 

  137. Shen BQ, Xu K, Liu L, Raab H, Bhakta S, Kenrick M, et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol. 2012;30(2):184–9.

    CAS  PubMed  Google Scholar 

  138. Strop P, Liu SH, Dorywalska M, Delaria K, Dushin RG, Tran TT, et al. Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol. 2013;20(2):161–7.

    CAS  PubMed  Google Scholar 

  139. Dorywalska M, Strop P, Melton-Witt JA, Hasa-Moreno A, Farias SE, Galindo Casas M, et al. Site-dependent degradation of a non-cleavable auristatin-based linker-payload in rodent plasma and its effect on ADC efficacy. PLoS One. 2015;10(7):e0132282.

    PubMed  PubMed Central  Google Scholar 

  140. Dorywalska M, Strop P, Melton-Witt JA, Hasa-Moreno A, Farias SE, Galindo Casas M, et al. Effect of attachment site on stability of cleavable antibody drug conjugates. Bioconjug Chem. 2015;26(4):650–9.

    CAS  PubMed  Google Scholar 

  141. Gikanga B, Adeniji NS, Patapoff TW, Chih HW, Yi L. Cathepsin B cleavage of vcMMAE-based antibody-drug conjugate is not drug location or monoclonal antibody carrier specific. Bioconjug Chem. 2016;27(4):1040–9.

    CAS  PubMed  Google Scholar 

  142. Bryant P, Pabst M, Badescu G, Bird M, McDowell W, Jamieson E, et al. In vitro and in vivo evaluation of cysteine rebridged trastuzumab-MMAE antibody drug conjugates with defined Drug-to-antibody ratios. Mol Pharm. 2015;12(6):1872–9.

    CAS  PubMed  Google Scholar 

  143. Maruani A, Smith ME, Miranda E, Chester KA, Chudasama V, Caddick S. A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy. Nat Commun. 2015;6:6645.

    CAS  PubMed  Google Scholar 

  144. Thurber GM, Dane WK. A mechanistic compartmental model for total antibody uptake in tumors. J Theor Biol. 2012;314:57–68.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  146. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.

    CAS  PubMed  Google Scholar 

  147. Baker JH, Lindquist KE, Huxham LA, Kyle AH, Sy JT, Minchinton AI. Direct visualization of heterogeneous extravascular distribution of trastuzumab in human epidermal growth factor receptor type 2 overexpressing xenografts. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(7):2171–9.

    CAS  Google Scholar 

  148. Jain RK, Baxter LT. Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. Cancer Res. 1988;48(24 Pt 1):7022–32.

    CAS  PubMed  Google Scholar 

  149. Dudley AC. Tumor endothelial cells. Cold Spring Harb Perspect Med. 2012;2(3):a006536.

    PubMed  PubMed Central  Google Scholar 

  150. Heine M, Freund B, Nielsen P, Jung C, Reimer R, Hohenberg H, et al. High interstitial fluid pressure is associated with low tumour penetration of diagnostic monoclonal antibodies applied for molecular imaging purposes. PLoS One. 2012;7(5):e36258.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Jain RK. Transport of molecules in the tumor interstitium: a review. Cancer Res. 1987;47(12):3039–51.

    CAS  PubMed  Google Scholar 

  152. Jain RK. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 1987;6(4):559–93.

    CAS  PubMed  Google Scholar 

  153. Heldin C-H, Rubin K, Pietras K, Ostman A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat Rev Cancer. 2004;4(10):806–13.

    CAS  PubMed  Google Scholar 

  154. Curti BD, Urba WJ, Alvord WG, Janik JE, Smith JW 2nd, Madara K, et al. Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment. Cancer Res. 1993;53(10 Suppl):2204–7.

    CAS  PubMed  Google Scholar 

  155. Roh HD, Boucher Y, Kalnicki S, Buchsbaum R, Bloomer WD, Jain RK. Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response. Cancer Res. 1991;51(24):6695–8.

    CAS  PubMed  Google Scholar 

  156. Milosevic M, Fyles A, Hedley D, Pintilie M, Levin W, Manchul L, et al. Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements. Cancer Res. 2001;61(17):6400–5.

    CAS  PubMed  Google Scholar 

  157. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science (New York, NY). 2005;307(5706):58.

    CAS  Google Scholar 

  158. Mohammadi M, Chen P. Effect of microvascular distribution and its density on interstitial fluid pressure in solid tumors: a computational model. Microvasc Res. 2015;101:26–32.

    CAS  PubMed  Google Scholar 

  159. Gremonprez F, Descamps B, Izmer A, Vanhove C, Vanhaecke F, De Wever O, et al. Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model. Oncotarget. 2015;6(30):29889–900.

    PubMed  PubMed Central  Google Scholar 

  160. O'Connor JP, Carano RA, Clamp AR, Ross J, Ho CC, Jackson A, et al. Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15(21):6674–82.

    CAS  Google Scholar 

  161. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci U S A. 1996;93(25):14765–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Yang AD, Bauer TW, Camp ER, Somcio R, Liu W, Fan F, et al. Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy. Cancer. 2005;103(8):1561–70.

    CAS  PubMed  Google Scholar 

  163. Arjaans M, Oude Munnink TH, Oosting SF, Terwisscha van Scheltinga AG, Gietema JA, Garbacik ET, et al. Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer Res. 2013;73(11):3347–55.

    CAS  PubMed  Google Scholar 

  164. Pastuskovas CV, Mundo EE, Williams SP, Nayak TK, Ho J, Ulufatu S, et al. Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model. Mol Cancer Ther. 2012;11(3):752–62.

    CAS  PubMed  Google Scholar 

  165. Abuqayyas L, Balthasar JP. Pharmacokinetic mAb-mAb interaction: anti-VEGF mAb decreases the distribution of anti-CEA mAb into colorectal tumor xenografts. AAPS J. 2012;14(3):445–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Rajkumar VS, Boxer G, Robson M, Muddle J, Papastavrou Y, Pedley RB. A comparative study of PDGFR inhibition with imatinib on radiolabeled antibody targeting and clearance in two pathologically distinct models of colon adenocarcinoma. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 2012;33(6):2019–29.

    CAS  Google Scholar 

  167. Baranowska-Kortylewicz J, Abe M, Pietras K, Kortylewicz ZP, Kurizaki T, Nearman J, et al. Effect of platelet-derived growth factor receptor-β inhibition with STI571 on Radioimmunotherapy. Cancer Res. 2005;65(17):7824–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Hofmann M, McCormack E, Mujic M, Rossberg M, Bernd A, Bereiter-Hahn J, et al. Increased plasma colloid osmotic pressure facilitates the uptake of therapeutic macromolecules in a xenograft tumor model. Neoplasia (New York, NY). 2009;11(8):812–22.

    CAS  Google Scholar 

  169. Baronzio G, Parmar G, Baronzio M. Overview of methods for overcoming hindrance to drug delivery to tumors, with special attention to tumor interstitial fluid. Front Oncol. 2015;5:165.

    PubMed  PubMed Central  Google Scholar 

  170. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12 Part 1):6387–92.

    CAS  PubMed  Google Scholar 

  171. Noguchi Y, Wu J, Duncan R, Strohalm J, Ulbrich K, Akaike T, et al. Early phase tumor accumulation of macromolecules: a great difference in clearance rate between tumor and normal tissues. Jpn J Cancer Res Gann. 1998;89(3):307–14.

    CAS  PubMed  Google Scholar 

  172. Maeda H. Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting. Proc Jpn Acad Ser B. 2012;88(3):53–71.

    CAS  Google Scholar 

  173. Nagamitsu A, Greish K, Maeda H. Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug SMANCS: cases of advanced solid tumors. Jpn J Clin Oncol. 2009;39(11):756–66.

    PubMed  Google Scholar 

  174. Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000;60(9):2497–503.

    CAS  PubMed  Google Scholar 

  175. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497(7451):633–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Ha KD, Bidlingmaier SM, Zhang Y, Su Y, Liu B. High-content analysis of antibody phage-display library selection outputs identifies tumor selective macropinocytosis-dependent rapidly internalizing antibodies. Mol Cell Proteomics : MCP. 2014;13(12):3320–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Hagan PL, Halpern SE, Dillman RO, Shawler DL, Johnson DE, Chen A, et al. Tumor size: effect on monoclonal antibody uptake in tumor models. J Nucl Med Off Publ Soc Nucl Med. 1986;27(3):422–7.

    CAS  Google Scholar 

  178. Pedley RB, Boden J, Keep PA, Harwood PJ, Green AJ, Rogers GT. Relationship between tumour size and uptake of radiolabelled anti-CEA in a colon tumour xenograft. Eur J Nucl Med. 1987;13(4):197–202.

    CAS  PubMed  Google Scholar 

  179. Williams LE, Duda RB, Proffitt RT, Beatty BG, Beatty JD, Wong JY, et al. Tumor uptake as a function of tumor mass: a mathematic model. J Nucl Med Off Publ Soc Nucl Med. 1988;29(1):103–9.

    CAS  Google Scholar 

  180. Kinuya S, Yokoyama K, Kawashima A, Izumo M, Sorita T, Obata T, et al. Radioimmunotherapy with 186Re-labeled monoclonal antibody to treat liver metastases of colon cancer cells in nude mice. Cancer Biother Radiopharm. 2002;17(6):681–7.

    CAS  PubMed  Google Scholar 

  181. Kinuya S, Li X-F, Yokoyama K, Mori H, Shiba K, Watanabe N, et al. Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy. Cancer Sci. 2003;94(7):650–4.

    CAS  PubMed  Google Scholar 

  182. Li X-F, Kinuya S, Yokoyama K, Koshida K, Mori H, Shiba K, et al. Benefits of combined radioimmunotherapy and anti-angiogenic therapy in a liver metastasis model of human colon cancer cells. Eur J Nucl Med Mol Imaging. 2002;29(12):1669–74.

    CAS  PubMed  Google Scholar 

  183. Dearling JL, Flynn AA, Qureshi U, Whiting S, Boxer GM, Green A, et al. Localization of radiolabeled anti-CEA antibody in subcutaneous and intrahepatic colorectal xenografts: influence of tumor size and location within host organ on antibody uptake. Nucl Med Biol. 2009;36(8):883–94.

    CAS  PubMed  Google Scholar 

  184. Muller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Science Transl Med. 2015;7(315):315ra188.

    Google Scholar 

Download references

Acknowledgments and Disclosures

Murray Cutler, for wisdom in manuscript preparation.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Waterloo, 10A Victoria St South, Kitchener, Ontario, N2G 1C5, Canada

    Paul Malik, Colin Phipps, Andrea Edginton & Jonathan Blay

  2. DMPK & Translational Modeling, Abbvie Inc., North Chicago, Illinois, 60064, USA

    Colin Phipps

Authors
  1. Paul Malik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Colin Phipps
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Edginton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan Blay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea Edginton.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Malik, P., Phipps, C., Edginton, A. et al. Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer. Pharm Res 34, 2579–2595 (2017). https://doi.org/10.1007/s11095-017-2259-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-017-2259-3

Keywords

Search

Navigation