Advertisement

Pharmaceutical Research

, Volume 32, Issue 11, pp 3577–3583 | Cite as

Internalization, Trafficking, Intracellular Processing and Actions of Antibody-Drug Conjugates

Expert Review

Abstract

Purpose

This review discusses the molecular mechanism involved in the targeting and delivery of antibody-drug conjugates (ADCs), the new class of biopharmaceuticals mainly designed for targeted cancer therapy.

Methods

this review goes over major progress in preclinical and clinical studies of ADCs, in the past 5 years.

Results

The pharmacokinetics and pharmacodynamics of ADCs involve multiple mechanisms, including internalization of ADCs by target cells, intracellular trafficking, release of conjugated drugs, and payload.

Conclusion

These mechanisms actually jointly determine the efficacy of ADCs. Therefore, the optimization of ADCs should take them as necessary rationales.

KEY WORDS

Antibody drug conjugate Internalization Recycling Trafficking Linker 

ABBREVIATIONS

ADC

Antibody-drug conjugates

ADCC

Antibody-dependent cellular cytotoxicity

CDC

Complement-dependent cytotoxicity

DM1

N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)- maytansine

EGFR

Epidermal growth factor receptor

FcRn

Neonatal Fc receptor

MMAE

Monomethyl auristatin E

MTD

Maximum tolerated doses

References

  1. 1.
    Goldmacher VS, Kovtun YV. Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells. Ther Deliv. 2011;2(3):397–416.CrossRefPubMedGoogle Scholar
  2. 2.
    Gelderman KA, Tomlinson S, Ross GD, Gorter A. Complement function in mAb-mediated cancer immunotherapy. Trends Immunol. 2004;25(3):158–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Dosio F, Brusa P, Cattel L. Immunotoxins and anticancer drug conjugate assemblies: the role of the linkage between components. Toxins (Basel). 2011;3(7):848–83.CrossRefGoogle Scholar
  4. 4.
    Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490–6.PubMedGoogle Scholar
  5. 5.
    Sievers EL. Antibody-targeted chemotherapy of acute myeloid leukemia using gemtuzumab ozogamicin (Mylotarg). Blood Cells Mol Dis. 2003;31(1):7–10.CrossRefPubMedGoogle Scholar
  6. 6.
    Walter RB, Raden BW, Kamikura DM, Cooper JA, Bernstein ID. Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood. 2005;105(3):1295–302.CrossRefPubMedGoogle Scholar
  7. 7.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Ohtani M, Numazaki M, Yajima Y, Fujita-Yamaguchi Y. Mechanisms of antibody-mediated insulin-like growth factor I receptor (IGF-IR) down-regulation in MCF-7 breast cancer cells. Biosci Trends. 2009;3(4):131–8.PubMedGoogle Scholar
  9. 9.
    Law CL, Cerveny CG, Gordon KA, Klussman K, Mixan BJ, Chace DF, et al. Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. Clin Cancer Res. 2004;10(23):7842–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Smith LM, Nesterova A, Alley SC, Torgov MY, Carter PJ. Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97. Mol Cancer Ther. 2006;5(6):1474–82.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    Thurber GM, Schmidt MM, Wittrup KD. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv Drug Deliv Rev. 2008;60(12):1421–34.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Xu S, Olenyuk BZ, Okamoto CT, Hamm-Alvarez SF. Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv Drug Deliv Rev. 2013;65(1):121–38.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Bhattacharya S, Roxbury D, Gong X, Mukhopadhyay D, Jagota A. DNA conjugated SWCNTs enter endothelial cells via Rac1 mediated macropinocytosis. Nano Lett. 2012;12(4):1826–30.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Muro S, Wiewrodt R, Thomas A, Koniaris L, Albelda SM, Muzykantov VR, et al. A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. J Cell Sci. 2003;116(Pt 8):1599–609.CrossRefPubMedGoogle Scholar
  19. 19.
    Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25.CrossRefPubMedGoogle Scholar
  20. 20.
    Ward ES, Martinez C, Vaccaro C, Zhou J, Tang Q, Ober RJ. From sorting endosomes to exocytosis: association of Rab4 and Rab11 GTPases with the Fc receptor, FcRn, during recycling. Mol Biol Cell. 2005;16(4):2028–38.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol. 2010;10(5):301–16.CrossRefPubMedGoogle Scholar
  22. 22.
    Ghetie V, Hubbard JG, Kim JK, Tsen MF, Lee Y, Ward ES. Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice. Eur J Immunol. 1996;26(3):690–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A. 1996;93(11):5512–6.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Israel EJ, Wilsker DF, Hayes KC, Schoenfeld D, Simister NE. Increased clearance of IgG in mice that lack beta 2-microglobulin: possible protective role of FcRn. Immunology. 1996;89(4):573–8.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Igawa T, Ishii S, Tachibana T, Maeda A, Higuchi Y, Shimaoka S, et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat Biotechnol. 2010;28(11):1203–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Petkova SB, Akilesh S, Sproule TJ, Christianson GJ, Al Khabbaz H, Brown AC, et al. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol. 2006;18(12):1759–69.CrossRefPubMedGoogle Scholar
  27. 27.
    Kenanova V, Olafsen T, Crow DM, Sundaresan G, Subbarayan M, Carter NH, et al. Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments. Cancer Res. 2005;65(2):622–31.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Stern M, Herrmann R. Overview of monoclonal antibodies in cancer therapy: present and promise. Crit Rev Oncol Hematol. 2005;54(1):11–29.CrossRefPubMedGoogle Scholar
  29. 29.
    Gerber HP, Kung-Sutherland M, Stone I, Morris-Tilden C, Miyamoto J, McCormick R, et al. Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas. Blood. 2009;113(18):4352–61.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefPubMedGoogle Scholar
  31. 31.
    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. 2010;16(3):888–97.CrossRefPubMedGoogle Scholar
  32. 32.
    Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL, et al. Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem. 2006;17(1):114–24.CrossRefPubMedGoogle Scholar
  33. 33.
    Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer. 2008;99(1):100–9.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778–84.CrossRefPubMedGoogle Scholar
  35. 35.
    Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102(4):1458–65.CrossRefPubMedGoogle Scholar
  36. 36.
    Dubowchik GM, Firestone RA, Padilla L, Willner D, Hofstead SJ, Mosure K, et al. Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity. Bioconjug Chem. 2002;13(4):855–69.CrossRefPubMedGoogle Scholar
  37. 37.
    Casi G, Neri D. Antibody-drug conjugates: basic concepts, examples and future perspectives. J Control Release. 2012;161(2):422–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154–69.CrossRefPubMedGoogle Scholar
  39. 39.
    Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23(9):1137–46.CrossRefPubMedGoogle Scholar
  40. 40.
    Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21(1):5–13.CrossRefPubMedGoogle Scholar
  41. 41.
    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.CrossRefPubMedGoogle Scholar
  42. 42.
    Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280–90.CrossRefPubMedGoogle Scholar
  43. 43.
    Sanderson RJ, Hering MA, James SF, Sun MM, Doronina SO, Siadak AW, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11(2 Pt 1):843–52.PubMedGoogle Scholar
  44. 44.
    Polson AG, Calemine-Fenaux J, Chan P, Chang W, Christensen E, Clark S, et al. Antibody-drug conjugates for the treatment of non-Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6):2358–64.CrossRefPubMedGoogle Scholar
  45. 45.
    Oflazoglu E, Stone IJ, Gordon K, Wood CG, Repasky EA, Grewal IS, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14(19):6171–80.CrossRefPubMedGoogle Scholar
  46. 46.
    Feld J, Barta SK, Schinke C, Braunschweig I, Zhou Y, Verma AK. Linked-in: design and efficacy of antibody drug conjugates in oncology. Oncotarget. 2013;4(3):397–412.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Flygare JA, Pillow TH, Aristoff P. Antibody-drug conjugates for the treatment of cancer. Chem Biol Drug Des. 2013;81(1):113–21.CrossRefPubMedGoogle Scholar
  48. 48.
    Iyer U, Kadambi VJ. Antibody drug conjugates - Trojan horses in the war on cancer. J Pharmacol Toxicol Methods. 2011;64(3):207–12.CrossRefPubMedGoogle Scholar
  49. 49.
    Hamblett KJ, Senter PD, Chace DF, Sun MM, 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.CrossRefPubMedGoogle Scholar
  50. 50.
    Tolcher AW. BR96-doxorubicin: been there, done that! J Clin Oncol. 2000;18(23):4000.PubMedGoogle Scholar
  51. 51.
    Hellstrom I, Hellstrom KE, Senter PD. Development and activities of the BR96-doxorubicin immunoconjugate. Methods Mol Biol. 2001;166:3–16.PubMedGoogle Scholar
  52. 52.
    Lin K, Tibbitts J. Pharmacokinetic considerations for antibody drug conjugates. Pharm Res. 2012;29(9):2354–66.CrossRefPubMedGoogle Scholar
  53. 53.
    Teicher BA, Chari RV. Antibody conjugate therapeutics: challenges and potential. Clin Cancer Res. 2011;17(20):6389–97.CrossRefPubMedGoogle Scholar
  54. 54.
    FitzGerald DJ, Wayne AS, Kreitman RJ, Pastan I. Treatment of hematologic malignancies with immunotoxins and antibody-drug conjugates. Cancer Res. 2011;71(20):6300–9.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Phillips DJ, Gibson MI. Redox-sensitive materials for drug delivery: targeting the correct intracellular environment, tuning release rates, and appropriate predictive systems. Antioxid Redox Signal. 2014;21(5):786–803.Google Scholar
  56. 56.
    Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93(11):2645–68.CrossRefPubMedGoogle Scholar
  57. 57.
    MacMillan KS, Boger DL. Fundamental relationships between structure, reactivity, and biological activity for the duocarmycins and CC-1065. J Med Chem. 2009;52(19):5771–80.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Thevanayagam L, Bell A, Chakraborty I, Sufi B, Gangwar S, Zang A, et al. Novel detection of DNA-alkylated adducts of antibody-drug conjugates with potentially unique preclinical and biomarker applications. Bioanalysis. 2013;5(9):1073–81.CrossRefPubMedGoogle Scholar
  59. 59.
    Chari RV, Martell BA, Gross JL, Cook SB, Shah SA, Blattler WA, et al. Immunoconjugates containing novel maytansinoids: promising anticancer drugs. Cancer Res. 1992;52(1):127–31.PubMedGoogle Scholar
  60. 60.
    Vaklavas C, Forero-Torres A. Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Ther Adv Hematol. 2012;3(4):209–25.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Burris HA. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer. Expert Opin Biol Ther. 2011;11(6):807–19.CrossRefPubMedGoogle Scholar
  62. 62.
    Yu B, Tai HC, Xue W, Lee LJ, Lee RJ. Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol. 2010;27(7):286–98.PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    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.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Scientific Development Manager, Discovery BiologyGenScript USA Inc.PiscatawayUSA

Personalised recommendations