Antibody Directed Delivery for Treatment of Cancer: Antibody Drug Conjugates and Immunotoxins

Part of the Cancer Drug Discovery and Development book series (CDD&D)


A major goal in the development of cancer therapeutics is to identify agents that will effectively eradicate tumors while having minimal effects on cells of normal tissues. Unfortunately, the majority of anticancer agents developed to date have substantial side effect profiles and a narrow therapeutic index. One means to improve the selectivity and efficacy of cancer therapy is by choosing therapeutic targets with altered levels of expression on malignant versus normal cells. Following the introduction of monoclonal antibody (MAb) technology by Kohler and Milstein (Nature 256:495–497, 1975), the potential to utilize the antigen-selectivity of MAbs to deliver toxic agents initiated an extensive effort to design antibody-targeted therapeutics. The clinical utility of MAb-based therapeutics was substantially improved by both the chimerization and humanization of murine MAbs, both of which substantially reduced immunogenicity and improved MAb half-life. The ability to obtain fully human MAbs from transgenic mice and by phage display has further enhanced the clinical potential of these approaches (Nat Rev Immunol 6:343–357, 2006; Expert Opin Investig Drugs 7:607–614, 1998; Nat Biotechnol 23:1117–1125, 2005). Monoclonal antibodies and fragments of MAbs have been used to effectively deliver radionuclides (Hosp Pract (Minneap) 38:82–93, 2010; Clin Cancer Res 17:6406–6416, 2011), cytokines (Integr Biol (Camb) 3:468–478, 2011; Int J Cancer 102:109–116, 2002), plant and bacterial toxins (FEBS J 278:4683–4700, 2011; Expert Opin Drug Deliv 8:605–621, 2011; Drug Discov Today 16:495–503, 2011), and a variety of cytotoxic drugs (Nat Biotechnol 21:778–784, 2003; Cancer Res 53:3336–3342, 1993; Expert Opin Investig Drugs 6:169–172, 1997; Science 261:212–215, 1993). Although simple in concept, the design of effective targeting agents has required substantial investigation and modification in the selection of MAbs and their targets, the types of linkers used, and the potency of the toxic agents that are delivered. This chapter focuses on MAb-directed delivery of plant and bacterial toxins (immunotoxins) and MAb-directed delivery of cytotoxic drugs (antibody–drug conjugates: ADCs).


Maximum Tolerate Dose Hodgkin Lymphoma Anaplastic Large Cell Lymphoma Gemtuzumab Ozogamicin Brentuximab Vedotin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497PubMedCrossRefGoogle Scholar
  2. 2.
    Carter PJ (2006) Potent antibody therapeutics by design. Nat Rev Immunol 6:343–357PubMedCrossRefGoogle Scholar
  3. 3.
    Jakobovits A (1998) The long-awaited magic bullets: therapeutic human monoclonal antibodies from transgenic mice. Expert Opin Investig Drugs 7:607–614PubMedCrossRefGoogle Scholar
  4. 4.
    Lonberg N (2005) Human antibodies from transgenic animals. Nat Biotechnol 23:1117–1125PubMedCrossRefGoogle Scholar
  5. 5.
    Goldenberg DM, Sharkey RM (2010) Radioactive antibodies: a historical review of selective targeting and treatment of cancer. Hosp Pract (Minneap) 38:82–93CrossRefGoogle Scholar
  6. 6.
    Steiner M, Neri D (2011) Antibody-radionuclide conjugates for cancer therapy: historical considerations and new trends. Clin Cancer Res 17:6406–6416PubMedCrossRefGoogle Scholar
  7. 7.
    Frey K, Zivanovic A, Schwager K, Neri D (2011) Antibody-based targeting of interferon-alpha to the tumor neovasculature: a critical evaluation. Integr Biol (Camb) 3:468–478CrossRefGoogle Scholar
  8. 8.
    Halin C, Niesner U, Villani ME, Zardi L, Neri D (2002) Tumor-targeting properties of antibody-­vascular endothelial growth factor fusion proteins. Int J Cancer 102:109–116PubMedCrossRefGoogle Scholar
  9. 9.
    Weldon JE, Pastan I (2011) A guide to taming a toxin—recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer. FEBS J 278:4683–4700PubMedCrossRefGoogle Scholar
  10. 10.
    Lorberboum-Galski H (2011) Human toxin-based recombinant immunotoxins/chimeric proteins as a drug delivery system for targeted treatment of human diseases. Expert Opin Drug Deliv 8:605–621PubMedCrossRefGoogle Scholar
  11. 11.
    Choudhary S, Mathew M, Verma RS (2011) Therapeutic potential of anticancer immunotoxins. Drug Discov Today 16:495–503PubMedCrossRefGoogle Scholar
  12. 12.
    Trail PA, Willner D, Lasch SJ, Henderson AJ, Hofstead S, Casazza AM et al (1993) Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 261:212–215PubMedCrossRefGoogle Scholar
  13. 13.
    Hinman LM, Hamann PR, Wallace R, Menendez AT, Durr FE, Upeslacis J (1993) Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics. Cancer Res 53:3336–3342PubMedGoogle Scholar
  14. 14.
    Liu C, Chari RV (1997) The development of antibody delivery systems to target cancer with highly potent maytansinoids. Expert Opin Investig Drugs 6:169–172PubMedCrossRefGoogle Scholar
  15. 15.
    Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF et al (2003) Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21:778–784PubMedCrossRefGoogle Scholar
  16. 16.
    Schindler J, Gajavelli S, Ravandi F, Shen Y, Parekh S, Braunchweig I et al (2011) A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia. Br J Haematol 154:471–476PubMedCrossRefGoogle Scholar
  17. 17.
    Blanc V, Bousseau A, Caron A, Carrez C, Lutz RJ, Lambert JM (2011) SAR3419: an ­anti-CD19-maytansinoid immunoconjugate for the treatment of B-cell malignancies. Clin Cancer Res 17:6448–6458PubMedCrossRefGoogle Scholar
  18. 18.
    Gerber HP, Senter PD, Grewal IS (2009) Antibody drug-conjugates targeting the tumor ­vasculature: current and future developments. MAbs 1:247–253PubMedCrossRefGoogle Scholar
  19. 19.
    Seon BK, Matsuno F, Haruta Y, Kondo M, Barcos M (1997) Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin. Clin Cancer Res 3:1031–1044PubMedGoogle Scholar
  20. 20.
    Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW et al (1995) Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res 1:1623–1634PubMedGoogle Scholar
  21. 21.
    Baccala A, Sercia L, Li J, Heston W, Zhou M (2007) Expression of prostate-specific membrane antigen in tumor-associated neovasculature of renal neoplasms. Urology 70:385–390PubMedCrossRefGoogle Scholar
  22. 22.
    Haffner MC, Kronberger IE, Ross JS, Sheehan CE, Zitt M, Muhlmann G et al (2009) Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers. Hum Pathol 40:1754–1761PubMedCrossRefGoogle Scholar
  23. 23.
    Henry MD, Wen S, Silva MD, Chandra S, Milton M, Worland PJ (2004) A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer. Cancer Res 64:7995–8001PubMedCrossRefGoogle Scholar
  24. 24.
    Galsky MD, Eisenberger M, Moore-Cooper S, Kelly WK, Slovin SF, DeLaCruz A et al (2008) Phase I trial of the prostate-specific membrane antigen-directed immunoconjugate MLN2704 in patients with progressive metastatic castration-resistant prostate cancer. J Clin Oncol 26:2147–2154PubMedCrossRefGoogle Scholar
  25. 25.
    Ma D, Hopf CE, Malewicz AD, Donovan GP, Senter PD, Goeckeler WF et al (2006) Potent antitumor activity of an auristatin-conjugated, fully human monoclonal antibody to prostate-specific membrane antigen. Clin Cancer Res 12:2591–2596PubMedCrossRefGoogle Scholar
  26. 26.
    Wang X, Ma D, Olson WC, Heston WD (2011) In vitro and in vivo responses of advanced prostate tumors to PSMA ADC, an auristatin-conjugated antibody to prostate-specific membrane antigen. Mol Cancer Ther 10:1728–1739PubMedCrossRefGoogle Scholar
  27. 27.
    Vitetta ES, Thorpe PE (1991) Immunotoxins containing ricin or its A chain. Semin Cell Biol 2:47–58PubMedGoogle Scholar
  28. 28.
    Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I (1989) A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature 339:394–397PubMedCrossRefGoogle Scholar
  29. 29.
    Brinkmann U, Reiter Y, Jung SH, Lee B, Pastan I (1993) A recombinant immunotoxin containing a disulfide-stabilized Fv fragment. Proc Natl Acad Sci USA 90:7538–7542PubMedCrossRefGoogle Scholar
  30. 30.
    Bolognesi A, Polito L, Tazzari PL, Lemoli RM, Lubelli C, Fogli M et al (2000) In vitro anti-tumour activity of anti-CD80 and anti-CD86 immunotoxins containing type 1 ribosome-inactivating proteins. Br J Haematol 110:351–361PubMedCrossRefGoogle Scholar
  31. 31.
    Rosenblum M (2004) Immunotoxins and toxin constructs in the treatment of leukemia and lymphoma. Adv Pharmacol 51:209–228PubMedCrossRefGoogle Scholar
  32. 32.
    Stirpe F (2004) Ribosome-inactivating proteins. Toxicon 44:371–383PubMedCrossRefGoogle Scholar
  33. 33.
    Kreitman RJ, Pastan I (2006) Immunotoxins in the treatment of hematologic malignancies. Curr Drug Targets 7:1301–1311PubMedCrossRefGoogle Scholar
  34. 34.
    Lambert JM, Goldmacher VS, Collinson AR, Nadler LM, Blattler WA (1991) An immunotoxin prepared with blocked ricin: a natural plant toxin adapted for therapeutic use. Cancer Res 51:6236–6242PubMedGoogle Scholar
  35. 35.
    Thorpe PE, Wallace PM, Knowles PP, Relf MG, Brown AN, Watson GJ et al (1988) Improved antitumor effects of immunotoxins prepared with deglycosylated ricin A-chain and hindered disulfide linkages. Cancer Res 48:6396–6403PubMedGoogle Scholar
  36. 36.
    Ghetie V, Vitetta ES (2001) Chemical construction of immunotoxins. Mol Biotechnol 18:251–268PubMedCrossRefGoogle Scholar
  37. 37.
    Ghetie V, Vitetta E (1994) Immunotoxins in the therapy of cancer: from bench to clinic. Pharmacol Ther 63:209–234PubMedCrossRefGoogle Scholar
  38. 38.
    Blakey DC, Watson GJ, Knowles PP, Thorpe PE (1987) Effect of chemical deglycosylation of ricin A chain on the in vivo fate and cytotoxic activity of an immunotoxin composed of ricin A chain and anti-Thy 1.1 antibody. Cancer Res 47:947–952PubMedGoogle Scholar
  39. 39.
    Winkler U, Gottstein C, Schon G, Kapp U, Wolf J, Hansmann ML et al (1994) Successful treatment of disseminated human Hodgkin’s disease in SCID mice with deglycosylated ricin A-chain immunotoxins. Blood 83:466–475PubMedGoogle Scholar
  40. 40.
    Schnell R, Borchmann P, Staak JO, Schindler J, Ghetie V, Vitetta ES et al (2003) Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin’s lymphoma. Ann Oncol 14:729–736PubMedCrossRefGoogle Scholar
  41. 41.
    Herrera L, Yarbrough S, Ghetie V, Aquino DB, Vitetta ES (2003) Treatment of SCID/human B cell precursor ALL with anti-CD19 and anti-CD22 immunotoxins. Leukemia 17:334–338PubMedCrossRefGoogle Scholar
  42. 42.
    Shapira A, Benhar I (2010) Toxin-based therapeutic approaches. Toxins (Basel) 2:2519–2583CrossRefGoogle Scholar
  43. 43.
    Dosio F, Brusa P, Cattel L (2011) Immunotoxins and anticancer drug conjugate assemblies: the role of the linkage between components. Toxins (Basel) 3:848–883CrossRefGoogle Scholar
  44. 44.
    Rosenblum MG, Barth S (2009) Development of novel, highly cytotoxic fusion constructs containing granzyme B: unique mechanisms and functions. Curr Pharm Des 15:2676–2692PubMedCrossRefGoogle Scholar
  45. 45.
    Liu Y, Cheung LH, Hittelman WN, Rosenblum MG (2003) Targeted delivery of human pro-apoptotic enzymes to tumor cells: in vitro studies describing a novel class of recombinant highly cytotoxic agents. Mol Cancer Ther 2:1341–1350PubMedGoogle Scholar
  46. 46.
    Mathew M, Verma RS (2009) Humanized immunotoxins: a new generation of immunotoxins for targeted cancer therapy. Cancer Sci 100:1359–1365PubMedCrossRefGoogle Scholar
  47. 47.
    Onda M, Beers R, Xiang L, Nagata S, Wang QC, Pastan I (2008) An immunotoxin with greatly reduced immunogenicity by identification and removal of B cell epitopes. Proc Natl Acad Sci USA 105:11311–11316PubMedCrossRefGoogle Scholar
  48. 48.
    Pastan I, Onda M, Weldon J, Fitzgerald D, Kreitman R (2011) Immunotoxins with decreased immunogenicity and improved activity. Leuk Lymphoma 52(Suppl 2):87–90PubMedCrossRefGoogle Scholar
  49. 49.
    Cizeau J, Grenkow DM, Brown JG, Entwistle J, MacDonald GC (2009) Engineering and biological characterization of VB6-845, an anti-EpCAM immunotoxin containing a T-cell epitope-depleted variant of the plant toxin bouganin. J Immunother 32:574–584PubMedCrossRefGoogle Scholar
  50. 50.
    Kreitman RJ, Hassan R, Fitzgerald DJ, Pastan I (2009) Phase I trial of continuous infusion anti-mesothelin recombinant immunotoxin SS1P. Clin Cancer Res 15:5274–5279PubMedCrossRefGoogle Scholar
  51. 51.
    Dubowchik GM, Walker MA (1999) Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs. Pharmacol Ther 83:67–123PubMedCrossRefGoogle Scholar
  52. 52.
    Trail PA, Bianchi AB (1999) Monoclonal antibody drug conjugates in the treatment of cancer. Curr Opin Immunol 11:584–588PubMedCrossRefGoogle Scholar
  53. 53.
    Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL et al (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812–1821PubMedCrossRefGoogle Scholar
  54. 54.
    Katz J, Janik JE, Younes A (2011) Brentuximab Vedotin (SGN-35). Clin Cancer Res 17:6428–6436PubMedCrossRefGoogle Scholar
  55. 55.
    DeFrancesco L (2011) Seattle Genetics rare cancer drug sails through accelerated approval. Nat Biotechnol 29:851–852PubMedCrossRefGoogle Scholar
  56. 56.
    Ikeda H, Hideshima T, Fulciniti M, Lutz RJ, Yasui H, Okawa Y et al (2009) The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin Cancer Res 15:4028–4037PubMedCrossRefGoogle Scholar
  57. 57.
    Jiang XR, Song A, Bergelson S, Arroll T, Parekh B, May K et al (2011) Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov 10:101–111PubMedCrossRefGoogle Scholar
  58. 58.
    Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX (2011) Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 128:347–356PubMedCrossRefGoogle Scholar
  59. 59.
    Smyth MJ, Pietersz GA, McKenzie IF (1987) The mode of action of methotrexate-monoclonal antibody conjugates. Immunol Cell Biol 65(Pt 2):189–200PubMedCrossRefGoogle Scholar
  60. 60.
    Ghose T, Ferrone S, Blair AH, Kralovec Y, Temponi M, Singh M et al (1991) Regression of human melanoma xenografts in nude mice injected with methotrexate linked to monoclonal antibody 225.28 to human high molecular weight-melanoma associated antigen. Cancer Immunol Immunother 34:90–96PubMedCrossRefGoogle Scholar
  61. 61.
    Elias DJ, Kline LE, Robbins BA, Johnson HC Jr, Pekny K, Benz M et al (1994) Monoclonal antibody KS1/4-methotrexate immunoconjugate studies in non-small cell lung carcinoma. Am J Respir Crit Care Med 150:1114–1122PubMedGoogle Scholar
  62. 62.
    Schrappe M, Bumol TF, Apelgren LD, Briggs SL, Koppel GA, Markowitz DD et al (1992) Long-term growth suppression of human glioma xenografts by chemoimmunoconjugates of 4-desacetylvinblastine-3-carboxyhydrazide and monoclonal antibody 9.2.27. Cancer Res 52:3838–3844PubMedGoogle Scholar
  63. 63.
    Petersen BH, DeHerdt SV, Schneck DW, Bumol TF (1991) The human immune response to KS1/4-desacetylvinblastine (LY256787) and KS1/4-desacetylvinblastine hydrazide (LY203728) in single and multiple dose clinical studies. Cancer Res 51:2286–2290PubMedGoogle Scholar
  64. 64.
    Yang HM, Reisfeld RA (1988) Doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude mice. Proc Natl Acad Sci USA 85:1189–1193PubMedCrossRefGoogle Scholar
  65. 65.
    Trail PA, King HD, Dubowchik GM (2003) Monoclonal antibody drug immunoconjugates for targeted treatment of cancer. Cancer Immunol Immunother 52:328–337PubMedGoogle Scholar
  66. 66.
    Shih LB, Goldenberg DM, Xuan H, Lu HW, Mattes MJ, Hall TC (1994) Internalization of an intact doxorubicin immunoconjugate. Cancer Immunol Immunother 38:92–98PubMedCrossRefGoogle Scholar
  67. 67.
    Trail PA, Willner D, Lasch SJ, Henderson AJ, Greenfield RS, King D et al (1992) Antigen-specific activity of carcinoma-reactive BR64-doxorubicin conjugates evaluated in vitro and in human tumor xenograft models. Cancer Res 52:5693–5700PubMedGoogle Scholar
  68. 68.
    King HD, Yurgaitis D, Willner D, Firestone RA, Yang MB, Lasch SJ et al (1999) Monoclonal antibody conjugates of doxorubicin prepared with branched linkers: a novel method for increasing the potency of doxorubicin immunoconjugates. Bioconjug Chem 10:279–288PubMedCrossRefGoogle Scholar
  69. 69.
    King HD, Dubowchik GM, Mastalerz H, Willner D, Hofstead SJ, Firestone RA et al (2002) Monoclonal antibody conjugates of doxorubicin prepared with branched peptide linkers: inhibition of aggregation by methoxytriethyleneglycol chains. J Med Chem 45:4336–4343PubMedCrossRefGoogle Scholar
  70. 70.
    Shih LB, Goldenberg DM, Xuan H, Lu H, Sharkey RM, Hall TC (1991) Anthracycline immunoconjugates prepared by a site-specific linkage via an amino-dextran intermediate carrier. Cancer Res 51:4192–4198PubMedGoogle Scholar
  71. 71.
    Saleh MN, LoBuglio AF, Trail PA (1998) Immunoconjugate therapy of solid tumors: studies with BR96-doxorubicin. In: Grossbard ML (ed) Monoclonal antibody-based therapy of cancer, Ith edn. Marcel Dekker, Inc., New York, pp 397–416Google Scholar
  72. 72.
    Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L et al (2001) Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7:1490–1496PubMedGoogle Scholar
  73. 73.
    Larson RA, Sievers EL, Stadtmauer EA, Lowenberg B, Estey EH, Dombret H et al (2005) Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 104:1442–1452PubMedCrossRefGoogle Scholar
  74. 74.
    Jurcic JG (2012) What happened to anti-CD33 therapy for acute myeloid leukemia? Curr Hematol Malig Rep 7:65–73PubMedCrossRefGoogle Scholar
  75. 75.
    DiJoseph JF, Dougher MM, Evans DY, Zhou BB, Damle NK (2011) Preclinical anti-tumor activity of antibody-targeted chemotherapy with CMC-544 (inotuzumab ozogamicin), a CD22-specific immunoconjugate of calicheamicin, compared with non-targeted combination chemotherapy with CVP or CHOP. Cancer Chemother Pharmacol 67:741–749PubMedCrossRefGoogle Scholar
  76. 76.
    Advani A, Coiffier B, Czuczman MS, Dreyling M, Foran J, Gine E et al (2010) Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol 28:2085–2093PubMedCrossRefGoogle Scholar
  77. 77.
    Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL et al (2006) Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem 17:114–124PubMedCrossRefGoogle Scholar
  78. 78.
    Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF et al (2003) cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 102:1458–1465PubMedCrossRefGoogle Scholar
  79. 79.
    Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, Kovtun Y et al (2006) Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem 49:4392–4408PubMedCrossRefGoogle Scholar
  80. 80.
    Oroudjev E, Lopus M, Wilson L, Audette C, Provenzano C, Erickson H et al (2010) Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol Cancer Ther 9:2700–2713PubMedCrossRefGoogle Scholar
  81. 81.
    Chari RV, Martell BA, Gross JL, Cook SB, Shah SA, Blattler WA et al (1992) Immunoconjugates containing novel maytansinoids: promising anticancer drugs. Cancer Res 52:127–131PubMedGoogle Scholar
  82. 82.
    Dubowchik GM, Firestone RA, Padilla L, Willner D, Hofstead SJ, Mosure K et al (2002) 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 13:855–869PubMedCrossRefGoogle Scholar
  83. 83.
    Doronina SO, Bovee TD, Meyer DW, Miyamoto JB, Anderson ME, Morris-Tilden CA et al (2008) Novel peptide linkers for highly potent antibody-auristatin conjugate. Bioconjug Chem 19:1960–1963PubMedCrossRefGoogle Scholar
  84. 84.
    Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin DR, Sievers EL et al (2010) Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res 16:888–897PubMedCrossRefGoogle Scholar
  85. 85.
    Jackson D, Gooya J, Mao S, Kinneer K, Xu L, Camara M et al (2008) A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. Cancer Res 68:9367–9374PubMedCrossRefGoogle Scholar
  86. 86.
    Oflazoglu E, Stone IJ, Gordon K, Wood CG, Repasky EA, Grewal IS et al (2008) Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res 14:6171–6180PubMedCrossRefGoogle Scholar
  87. 87.
    Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E et al (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1 an antibody-cytotoxic drug conjugate. Cancer Res 68:9280–9290PubMedCrossRefGoogle Scholar
  88. 88.
    Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W et al (2010) 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 28:2698–2704PubMedCrossRefGoogle Scholar
  89. 89.
    Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S et al (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398–405PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Regeneron Pharmaceuticals Inc.New YorkUSA

Personalised recommendations