Skip to main content
SpringerLink
Log in

Antibody Drug and Radionuclide Conjugates for GI Cancers

  • Chapter
  • First Online:
Immunotherapy for Gastrointestinal Cancer

Abstract

In the mid-1980’s, after it was found that patients rapidly developed neutralising antibodies to tumour-directed ‘therapeutic mouse antibodies’, the concept of using these mouse antibodies to deliver cytotoxic therapeutics emerged. However, success was limited. Anti-mouse antibodies developed even with a limited number of infusions of the antibody-drug conjugates, and often the cytotoxic agents were released in the blood stream producing serious toxicities. The field of antibody-conjugates was quiet while technology for humanisation of mouse antibodies and the means of producing fully human antibodies evolved, and linker chemistry was developed, which allowed stable transport of antibody-conjugates to the target cells and release of the cytotoxic agent inside the target cells (Fig. 4.1) [1–3]. The first antibody-drug conjugate to reach Food and Drug Administration (FDA) approval in 2000 was gemtuzumab ozogamicin (Mylotarg), which targeted CD33 on the surface of acute myeloid leukaemia cells and delivered the potent cytotoxic agent, calicheamicin, inside the leukaemia cells. In 2010, gemtuzumab ozogamicin was withdrawn from the market after failing to produce sufficient efficacy in follow-up clinical trials [4]. Two antibody-drug conjugates (ADCs), trastuzumab emtansine (T-DM1; Kadcyla) and brentuximab vedotin (SGN-35; Adcetris) reached FDA approval in 2014 and 2011 for treatment of metastatic breast cancer and refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively [5, 6]. Approximately 50 ADCs have reached clinical trial to date, with more than 40 in trials currently and nearly 20 in, or having completed Phase 2 clinical trials (Table 4.1). The ADCs under investigation target haematological and solid tumours [7, 8]. The current chapter focuses on those that may be useful in the treatment of GI cancers.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Esteva FJ, Miller KD, Teicher BA. What can we learn about antibody-drug conjugates from the T-DM1 experience? Am Soc Clin Oncol Educ Book. 2015;2015:e117–25.

    Article  Google Scholar 

  2. Teicher BA. Antibody-drug conjugate targets. Curr Cancer Drug Targets. 2009;9:982–1004.

    Article  CAS  PubMed  Google Scholar 

  3. Teicher BA, Chari RV. Antibody conjugate therapeutics: challenges and potential. Clin Cancer Res. 2011;17:6389–97.

    Article  CAS  PubMed  Google Scholar 

  4. Shor B, Gerber H-P, Sapra P. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. Mol Immunol. 2015;67:107–16.

    Article  CAS  PubMed  Google Scholar 

  5. Martinez MT, Perez-Fidalgo JA, Martin-Martorell P, Cejalvo JM, Pons V, Bermejo B, Martin M, Albanell J, Lluch A. Treatment of HER2 positive advanced breast cancer with T-DM1: a review of the literature. Crit Rev Oncol Hematol. 2016;97:96–106.

    Article  PubMed  Google Scholar 

  6. Zinzani PL, Sasse S, Radford J, Shonukan O, Bonthapally V. Experience of brentuximab vedotin in relapsesd/refractory hodgkin lymphoma in the Named Patient Program: review of the literature. Crit Rev Oncol Hematol. 2015;95:359–69.

    Article  CAS  PubMed  Google Scholar 

  7. Drachman JG. The next generation of ADCs. Proceed AACR 2015; SY35-01.

    Google Scholar 

  8. Shord SS, Schrieber SJ, Zhao H, Booth B, RahmanNA. Regulatory considerations for clinical pharmacology during development of antibody-drug conjugates. J Clin Oncol. 2015;33:abstr 2569.

    Google Scholar 

  9. Noguchi T, Ritter G, Nishikawa H. Antibody-based therapy in colorectal cancer. Immunotherapy. 2013;5:533–45.

    Article  CAS  PubMed  Google Scholar 

  10. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  PubMed Central  Google Scholar 

  11. Sukhdeo K, Paramban RI, Vidal JG, Elia J, Martin J, Rivera M, Carrasco DR, Jarrar A, et al. Multiplex flow cytometry barcoding and antibody arrays identify surface antigen profiles of primary and metastatic colon cancer cell lines. PLoS One. 2013;8, e53015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tamas K, Walenkamp AME, de Vries EGE, van Vugt MATM, Beets-Tan RG, van Etten B, de Groot DJA, Hospers GAP. Rectal and colon cancer: not just a different anatomic site. Cancer Treat Rev. 2015;41:671–9.

    Article  CAS  PubMed  Google Scholar 

  13. Norguet E, Dahan L, Seitz J-F. Targeting esophageal and gastric cancers with monoclonal antibodies. Curr Top Med Chem. 2012;12:1678–82.

    Article  CAS  PubMed  Google Scholar 

  14. Dittmar Y, Settmacher U. Individualized treatment of gastric cancer: impact of molecular biology and pathohistological features. World J Gastrointest Oncol. 2015;7:292–302.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Satolli MA, Buffoni L, Spadi R, Roata I. Gastric cancer: the times they are a-changin’. World J Gastrointest Oncol. 2015;7:303–16.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: a comprehensive review. World J Gastrointest Oncol. 2015;7:2648–63.

    Google Scholar 

  17. Feng M, Gao W, Wang R, Chen W, Man YG, Figg WD, Wang XW, Dimitrov DS, Ho M. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2013;110:E1083–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Beyoğlu D, Imbeaud S, Maurhofer O, Bioulac-Sage P, Zucman-Rossi J, Dufour JF, Idle JR. Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification. Hepatology. 2013;58:229–38.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Perera RM, Bardeesy N. Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov. 2015;5:1247–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dodson LF, Hawkins WG, Goedegebuure P. Potential targets for pancreatic cancer immunotherapies. Immunotherapy. 2011;3:517–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chames P, Kerfelec B, Baty D. Therapeutic antibodies for the treatment of pancreatic cancer. Sci World J. 2010;10:1107–20.

    Article  CAS  Google Scholar 

  22. Moldenhauer G, Sainikov AV, Luttgau S, Herr I, Anderl J, Faulstich H. Therapeutic potential of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against pancreatic cancer. J Natl Cancer Inst. 2012;104:622–34.

    Article  CAS  PubMed  Google Scholar 

  23. Shvartsur A, Bonavida B. Trop2 and its overexperssion in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015;6:84–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Guerra E, Treotola M, Aloisi AL, Tripaldi R, Vacca G, La Sorda R, Lattanzio R, Piantelli M, et al. The Trop-2 signaling network in cancer growth. Oncogene. 2013;32:1594–600.

    Article  CAS  PubMed  Google Scholar 

  25. Treotola M, Cantelli P, Guerra E, Tripaldi R, Aloisi AL, Bonasera V, Lattanzio R, de Lange R, et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene. 2013;32:222–33.

    Article  Google Scholar 

  26. Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem. 2011;59:701–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ohmachi T, Tanaka F, Mimori K, Inoue H, Yanaga K, Mori M. Clinical significance of Trop2 expression in colorectal cancer. Clin Cancer Res. 2006;12:3057–63.

    Article  CAS  PubMed  Google Scholar 

  28. Zhao W, Zhu H, Zhang S, Yong H, Wang W, Zhou Y, Wang B, Wen J, et al. Trop2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget. 2016;7(5):6136–45.

    PubMed  Google Scholar 

  29. Wang J, Day R, Dong Y, Weintraub SJ, Michel L. Identification of Trop-2 as an oncogene and an attractive therapeutic target in colon cancers. Mol Cancer Ther. 2008;7:280–5.

    Article  CAS  PubMed  Google Scholar 

  30. Chen M-B, Wu H-F, Zhan Y, Fu X-L, Wang A-K, Wang L-S, Lei H-M. Prognostic value of TROP2 expression in patients with gallbladder cancer. Tumour Biol. 2014;35:11565–9.

    Article  CAS  PubMed  Google Scholar 

  31. Fong D, Moser P, Krammel C, Gostner JM, Margreiter R, Mitterer M, Gastl G, Spizzo G. High expression of Trop2 correlates with poor prognosis in pancreatic cancer. Br J Cancer. 2001;99:1290–5.

    Article  Google Scholar 

  32. Stein R, Basu A, Chen S, Shih LB, Goldenberg DM. Specificity and properties of MAb RS7-3G11 and the antigen defined by this pancarcinoma monoclonal antibody. Int J Cancer. 1993;55:938–46.

    Article  CAS  PubMed  Google Scholar 

  33. Basu A, Goldenberg DM, Stein R. The epithelial/carcinoma antigen EGP-1, recognized by monoclonal antibody RS7-3G11, is phosphorylated on serine 303. Int J Cancer. 1995;62:472–9.

    Article  CAS  PubMed  Google Scholar 

  34. Shih LB, Xuan H, Aninipot R, Stein R, Goldenberg DM. In vitro and in vivo reactivity of an internalizing antibody, RS7, with human breast cancer. Cancer Res. 1995;55(suppl):5857s–63s.

    CAS  PubMed  Google Scholar 

  35. Govindan SV, Stein R, Qu Z, Chen S, Andrews P, Ma H, Hansen HJ, Griffiths GL, Horak ID, Goldenberg DM. Preclinical therapy of breast cancer with a radioiodinated humanized anti-EGP-1 monoclonal antibody: advantage of a residualizing iodine radiolabel. Breast Cancer Res Treat. 2004;84:173–82.

    Article  CAS  PubMed  Google Scholar 

  36. Varughese J, Cocco E, Bellone S, Bellone M, Todeschini P, Carrara L, Schwartz PE, Rutherford TJ, Pecorelli S, Santin AD. High-grade, chemotherapy-resistant primary ovarian carcinoma cell lines overexpress human trophoblast cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti- Trop2 antibody. Gynecol Oncol. 2011;122:171–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cardillo TM, Govindan SV, Sharkey RM, Trisai P, Goldenberg DM. Humanized anti-Trop2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin Cancer Res. 2011;17:3157–69.

    Article  CAS  PubMed  Google Scholar 

  38. Govindan SV, Goldenberg DM. New antibody conjugates in cancer therapy. Sci World J. 2010;10:2070–89.

    Article  CAS  Google Scholar 

  39. Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Arrojo R, Liu D, Rossi EA, Chang CH, Goldenberg DM. Sacituzumab govitecan (IMMU-132), an anti-Trop/SN-38 antibody-drug conjugate: characterization and efficacy in pancreatic, gastric and other cancers. Bioconjug Chem. 2015;26:919–31.

    Article  CAS  PubMed  Google Scholar 

  40. Sharkey RM, McBride WJ, Cardillo TM, Govindan SV, Wang Y, Rossi EA, Chang CH, Goldenberg DM. Enhanced delivery of SN-38 to human tumor xenografts with an anti-Trop-2-SN-38 antibody conjugate (Sacituzumab govitecan). Clin Cancer Res. 2015;21:5131–8.

    Article  CAS  PubMed  Google Scholar 

  41. Goldenberg DM, Rossi EA, Govindan SV, Cardillo TM, McBride WJ, Zalath M, Terracina G, Trisal P, et al. Characterization of anti-Trop-2-SN-38 antibody-drug conjugate (IMMU-132) with potent activity against solid cancers. J Clin Oncol. 2014;32(suppl):Abstr 3107.

    Google Scholar 

  42. Starodub AN, Ocean AJ, Shah MA, Guarino MJ, Picozzi VJ, Vahdat LT, Thomas SS, Govindan SV, Maliakal PP, Wegener WA, Hamburger SA, Sharkey RM, Goldenberg DM. First-in-human trial of a novel anti-Trop-2 antibody-SN-38 conjugate sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res. 2015;21:3870–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Starodub AN, Ocean AJ, Bardia A, Guarino MJ, Messersmith W, Berlin J, Picozzi VJ, et al. Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results. Proc AACR. 2015:Abstr CT236.

    Google Scholar 

  44. Guarino MJ, Starodub AN, Masters GA, Heist RS, Messersmith WA, Bardia A, Ocean AJ, et al. Therapy of advanced metastatic lung cancer with an anti-trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132):phase I/II clinical experience. J Clin Oncol. 2015;33(suppl):Abstr 2504.

    Google Scholar 

  45. Starodub AN, Ocean AJ, Messersmith WA, Picozzi VJ, Guarino MJ, Bardia A, Thomas S, et al. Therapy of gastrointestinal malignancies with an anti-trop-2-SN-38 antibody-drug conjugate (ADC) (sacituzumab govitecan): phase I/II clinical experience. J Clin Oncol. 2015;33(suppl):Abstr 3546.

    Google Scholar 

  46. Starodub AN, Ocean AJ, Messersmith WA, Picozzi VJ, Guarino MJ, Thomas SS, Bardia A, Shah MA, et al. Phase I/II trial of IMMU-132 (sacituzumab govitecan), an anti-Trop-2-SN-38 antibody drug conjugate (ADC): results in patients with metastatic gastrointestinal (GI) cancers. J Clin Oncol. 2015;33(suppl):Abstr 703.

    Google Scholar 

  47. Bardia A, Vahdat LT, Diamond JR, Starodub A, Moroose RL, Isakoff SJ, Ocean AJ, Berlin J, et al. Therapy of refractory/relapsed metastatic triple-negative breast cancer (TNBC) with an anti-trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): phase I/II clinical experience. J Clin Oncol. 2015;33(suppl):Abstr 1016.

    Google Scholar 

  48. Bardia A, Mayer I, Diamond J, Starodub A, Moroose R, Isakoff S, Ocean A, Guarino M, Kalinsky K, O’Shaugnessy J, Wilhelm F, Maliakal P, Sharkey R, Goldenberg D, Vahdat L. Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): an ongoing Phase II trial. World ADC San Diego Conference. 2015:Abstr LB-C16.

    Google Scholar 

  49. Cardillo TM, Govindan SV, Zalath M, Arrojo R, Sharkey RM, Goldenberg DM. Combining an anti-Trop-2 antibody-SN-38 conjugate (sacituzumab govitecan) with microtubule inhibitors (paclitaxel and eribulin mesylate) or PARP inhibitor (olaparib) significantly improves therapeutic outcome in experimental triple-negative breast cancer (TNBC). World ADC San Diego Conference. 2015. Abstr C166.

    Google Scholar 

  50. Chan CHF, Stanners CP. Recent advances in the tumor biology of the GPI-anchored carcinoembryonic antigen family members CEACAM5 and CEACAM6. Curr Oncol. 2007;14:70–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Blumenthal RD, Hansen HJ, Goldenberg DM. Inhibition of adhesion and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (carcinoembryonic antigen). Cancer Res. 2005;65:8809–17.

    Article  CAS  PubMed  Google Scholar 

  52. Blumenthal RD, Leon E, Hansen HJ, Goldenberg DM. Expression patterns of CEACAM5 and CEACAM6 in primary and metastatic cancers. BMC Cancer. 2007;7:2.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Han S-U, Kwak T-H, Her KH, Cho Y-H, Choi C, Lee H-J, Hong S, Park YS, Kim Y-S, Kim T-A, Kim S-J. CEACAM5 and CEACAM6 are major target genes for Smad3-mediated TGF-β signaling. Oncogene. 2008;27:675–83.

    Article  CAS  PubMed  Google Scholar 

  54. Beauchemin N, Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev. 2013;32:643–71.

    Article  CAS  PubMed  Google Scholar 

  55. Zheng C, Feng J, Lu D, Wang P, Xing S, Coll J-L, Yang D, Yan X. A novel anti-CEACAM5 monoclonal antibody, CC4, suppresses colorectal tumor growth and enhances NK cells-mediated tumor immunity. PLoS One. 2011;6, e21146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Govindan SV, Cardillo TM, Moon S-J, Hansen HJ, Goldenberg DM. CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates. Clin Cancer Res. 2009;15:6052–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Govindan SV, Cardillo TM, Rossi EA, Trisal P, McBride WJ, Sharkey RM, Goldenberg DM. Improving the therapeutic index in cancer therapy by using antibody-drug conjugates designed with a moderately cytotoxic drug. Mol Pharm. 2015;12:1836–47.

    Article  CAS  PubMed  Google Scholar 

  58. Segal NH, Dotan E, Berlin JD, Storadub AN, Guarino MJ, Saltz LB, Maliakal PP, Govindan SV, et al. IMMU-130, an SN-38 antibody-drug conjugate (ADC) targeting CEACAM5, is therapeutically active in metastatic colorectal cancer (mCRC): initial results of two Phase 1 studies. Proc AACR. 2014:Abstr CT211.

    Google Scholar 

  59. Dotan E, Starodub A, Berlin J, Lieu CH, Guarino MJ, Marshall J, Hecht JR, Cohen SJ, et al. A new anti-CEA-SN-38 antibody-drug conjugate (ADC), IMMU-130, is active in controlling metastatic colorectal cancer (mCRC) in patients (pts) refractory or relapsing after irinotecan-containing chemotherapies. Initial results of a phase I/II study. J Clin Oncol. 2015;33(suppl):Abstr 2505.

    Google Scholar 

  60. Decary S, Berne PF, Nicolazzi C, Lefebvre AM, Dabdoubi T, Cameron B, Devaud C, et al. A novel anti-CEACAM5 maytansinoid-antibody-drug conjugate for the treatment of colorectal, lung and gastric tumors. Proc AACR. 2015:Abstr 1688.

    Google Scholar 

  61. Johns TG, Stockert E, Ritter G, Jungbluth AA, Huang HJ, Cavenee WK, Smyth FE, Hall CM, et al. Novel monoclonal antibody specific for the de2-7 epidermal growth factor receptor (EGFR) that also recognizes the EGFR expressed in cells containing amplification of the EGFR gene. Int J Cancer. 2002;98(3):398–408.

    Article  CAS  PubMed  Google Scholar 

  62. Jungbluth AA, Stockert E, Huang HJ, Collins VP, Coplan K, Iversen K, Kolb D, Johns TJ, et al. A monoclonal antibody recognizing human cancers with amplification/overexpression of the human epidermal growth factor receptor. Proc Natl Acad Sci U S A. 2003;100:639–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Vega J, Ke S, Fan Z, Wallace S, Charsangavej C, Li C. Targeting doxorubicin to epidermal growth factor receptors by site-specific conjugation of C225 to poly(L-glutamic acid) through a polyethylene glycol spacer. Pharm Res. 2003;20:826–32.

    Article  CAS  PubMed  Google Scholar 

  64. Safavy A, Bonner JA, Waksal HW, Buchsbaum DJ, Gillespie GY, Khazaeli MB, Arani R, Chen DT, Carpenter M, Raisch KP. Synthesis and biological evaluation of paclitaxel-C225 conjugate as a model for targeted drug delivery. Bioconjug Chem. 2003;14:302–10.

    Article  CAS  PubMed  Google Scholar 

  65. Doronina SO, Bovee TD, Meyer DW, Miyamoto JB, Anderson ME, Morris-Tilden CA, Senter PD. Novel peptide linkers for highly potent antibody-auristatin conjugate. Bioconjug Chem. 2008;19:1960–3.

    Article  CAS  PubMed  Google Scholar 

  66. Kang H, Thakar M, Sen R, Chung CH. Antitumor effect of IMGN289, an anti-EGFR antibody-drug conjugate (ADC), in preclinical models of head and neck squamous cell carcinomas (HNSCC). J Clin Oncol. 2014;32(suppl):Abstr e17046.

    Google Scholar 

  67. Setiady YY, Park PU, Ponte JF, Dong L, Skaletskaya A, Coccia JA, Hong E, et al. Abstract 5463: development of a novel antibody-maytansinoid conjugate, IMGN289, for the treatment of EGFR-expressing solid tumors. Proc AACR. 2013;abstr 5463.

    Google Scholar 

  68. Ponte JF, Setiady YY, Dong L, Skaletskaya A, Carrigan CN, Anderson-Villaluz A, Lutz RJ, Pinkas J. Abstract 5483: preclinical evaluation of IMGN289, an anti-EGFR antibody-maytansoid conjugate for the treatment of squamous cell carcinoma of the head and neck. Proc AACR. 2013;abstr 5483.

    Google Scholar 

  69. Gan HK, Fichtel L, Lassman AB, Merrell R, Van Den Bent MJ, Kumthekar P, Scott AM, Pedersen M, Gomez E, et al. A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectable glioblastoma (GBM). J Clin Oncol. 2014;32(suppl):Abstr 2021.

    Google Scholar 

  70. Gan HK, Papadopoulos KP, Fichtel L, Lassman AB, Merrell R, Van Den Bent MJ, Kumthekar P, et al. Phase I study of ABT-414 mono- or combination therapy with temozolomide (TMZ) in recurrent glioblastoma (GBM). J Clin Oncol. 2015;33(suppl):Abstr 2016.

    Google Scholar 

  71. Phillips AC, Boghaert ER, Vaidya KS, Ansell PJ, Shalinsky DR, Zhang Y, Voorbach MJ, et al. Abstract A250: ABT-414: an anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors. Mol Cancer Ther. 2013;12(suppl):Abstr nr A250.

    Google Scholar 

  72. Goss GD, Vokes EE, Gordon MS, Gandhi L, Papadopoulos KP, Rasco DW, Pedersen M, Fischer JS, Chu K, Ames W, Xiong H, et al. ABT-414 in pateitns with advanced solid tumors likely to overexpress the epidermal growth factor receptor (EGFR). J Clin Oncol. 2015;33(suppl):abstr 2510.

    Google Scholar 

  73. LoRusso PM, Weiss D, Guardino E, Girish S, Sliwkowski MX. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2–positive cancer. Clin Cancer Res. 2011;17:6437–47.

    Article  CAS  PubMed  Google Scholar 

  74. Phillips GDL, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blattler WA, Lambert JM, Chari RVJ, Lutz RJ, Wong WLT, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–90.

    Article  Google Scholar 

  75. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lewis Phillips GD, Fields CT, Li G, et al. Dual targeting of HER2-positive cancer with trastuzumab-emtansine (T-DM1) and pertuzumab: Critical role for neuregulin blockade in anti-tumor response to combination therapy. Clin Cancer Res. 2014;20:456–68.

    Article  Google Scholar 

  77. Wildiers H, Kim S-B, Gonzalez-Martin A, et al. T-DM1 for HER2-positive metastatic breast cancer (MBC): primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician’s choice. Presented at the European Cancer Congress 2013, Amsterdam; 2013. (abstr LBA-15).

    Google Scholar 

  78. Krop IE, LoRusso P, Miller KD, et al. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2012;30:3234–41.

    Article  CAS  PubMed  Google Scholar 

  79. Burris 3rd HA, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, et al. 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. 2011;29:398–405.

    Article  CAS  PubMed  Google Scholar 

  80. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010;28:1138–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Miller KD, Diéras V, Harbeck N, Andre F, Mahtani RL, Gianni L, Albain KS, Crivellari D, Fang L, Michelson G, de Haas SL, Burris HA. Phase IIa trial of trastuzumab emtansine with pertuzumab for patients with human epidermal growth factor receptor 2-positive, locally advanced, or metastatic breast cancer. J Clin Oncol. 2014;32(14):1437–44.

    Article  CAS  PubMed  Google Scholar 

  82. Korkola JE, Liu M, Liby T, Heiser L, Feiler H, Gray JW. Detrimental effects of sequential compared to concurrent treatment of pertuzumab plus T-DM1 in HER2+ breast cancer cell lines. San Antonio Br Ca Sym. 2014;Abstr S6-07.

    Google Scholar 

  83. Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27:5538–46.

    Article  CAS  PubMed  Google Scholar 

  84. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27:5529–37.

    Article  CAS  PubMed  Google Scholar 

  85. Gluz O, Nitz U, Sherko K, Stefan K, Braun M, Schumacher C, Aktas B, Forstbauer H, Reimer T, Fasching P, Potenberg J, Hofmann D, Kates RE, Wuerstlein R, Christgen M, Kreipe HH, Harbeck N. Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial. San Antonio Br Ca Sym. 2014;Abstr P4-15-01.

    Google Scholar 

  86. Verheijden G, Beusker P, Ubink R, van der Lee M, Groothuis P, Goedings PJ, Egging D, Mattaar E, Timmers M, Dokter W. Toward clinical development of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC). J Clin Oncol. 2014;32:5s. abstr 626.

    Google Scholar 

  87. Yamashita-Kashima Y, Shu S, Harada N, Fujimoto-Ouchi K. Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model. J Clin Oncol. 2012;30(suppl):abstr e13502.

    Google Scholar 

  88. Ellis PA, Barrios CH, Eiermann W, Toi M, Im YH, Conte PF, Martin M, Pienkowski T, Pivot XB, Burris HA, Strasak A, Patre M, Perez EA. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study. J Clin Oncol. 2015;33(suppl):abstr 507.

    Google Scholar 

  89. Kang YK, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, van der Horst T, Harle-Yge ML, Piao Y, Althaus B, Thuss-Patience PC. A randomized, open-label, multicenter, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1) versus a taxane (TAX) in patients (pts) with previously treated HER2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (LA/MGC/GEJC). J Clin Oncol. 2016;34(suppl):4S. abstr 5.

    Google Scholar 

  90. Li BT, Zauderer M, Chaft J, Drilon A, Eng J, Sima C, Makker V, Iyer G, Janjigian Y, Hyman D, et al. Ado-trastuzumab emtansine for HER2 amplified or HER2 overexpressed cancers: a phase II “basket” trial. Proc AACR. 2015:Abstr CT225.

    Google Scholar 

  91. Muller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, Savic S, Harbeck N, Nitz U, Gluz O, et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Trans Med. 2015;7:315ra188.

    Google Scholar 

  92. Humphreys RC, Kirtely J, Hewit A, Biroc S, Knudsen N, Skidmore L, Wahl A. Site specific conjugation of ARX-788, an antibody drug conjugate (ADC) targeting HER2, generates a potent and stable targeted therapeutic for multiple cancers. Proc AACR. 2015:Abstr 639.

    Google Scholar 

  93. Zhang H, Li Z, Zhu T, Cao S, Chen G, Miao D. Superior anti-tumor activity compared to T-DM1 in preclinical studies of targeted therapies for her2-postitive cancers by a novel her2-ADC ZV0201. Proc AACR. 2015:Abstr 651.

    Google Scholar 

  94. Zhu Z, Boopathy R, Li J, Probakaran P, Colantonio S, Feng Y, Wang Y, Dyba MA, et al. Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar. Proc AACR. 2015. Abstr 2486.

    Google Scholar 

  95. Demeule M, Das S, Che C, Yang G, Currie JC, Lord-Dufour S, Tripathy S, Regina A, et al. Targeting HER2-positive brain metastases by incorporating the brain-penetrant angiopep-2 peptide to an anti-HER2 antibody and anti-HER2 antibody drug conjugate. Proc AACR. 2015:Abstr 2465.

    Google Scholar 

  96. Black JD, Lopez S, Cocco E, Bellone S, Bonazzoli E, Schwab C, English DP, et al. SYD985, a novel HER2-targeting antibody-drug conjugate, shows strong antitumor activity in primary USC cell lines with low (1+) and moderate (2+) HER2/Neu expression. Proc AACR. 2016:Abstr 2461.

    Google Scholar 

  97. Black J, Lopez S, Cocco E, Bellone S, Bonazzoli E, Schwab C, English DP, et al. SYD985, a novel HER2-targeting antibody-drug conjugate in preclinical models for USC, both in vitro and in vivo. J Clin Oncol. 2015;33:Abstr e16527.

    Google Scholar 

  98. Jia J, Zhou X, Huang Y, Xie H, Guo H, Gai S, Qu L, Li W, Chen L, Li X, Sun S, et al. Functional evaluation of novel tubulysin analogs as payloads for antibody-drug conjugates. Proc AACR. 2015:Abstr 4532.

    Google Scholar 

  99. Tomblyn MB, Katin MJ, Wallner PE. The golden era for radioimmunotherapy: not just for lymphomas anymore. Cancer Control. 2013;20:60–71.

    PubMed  Google Scholar 

  100. Kawashima H. Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies. Sci World J. 2014;2014, e492061.

    Article  Google Scholar 

  101. Song H, Sgouros G. Radioimmunotherapy of solid tumors: searching for the right target. Curr Drug Deliv. 2011;8:26–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. American Cancer Society. Cancer facts and figures 2015. Atlanta: American Cancer Society; 2015.

    Google Scholar 

  103. Willett CG, Daly WJ, Warshaw AL. CA 19-9 is an index of response to neoadjunctive chemoradiation therapy in pancreatic cancer. Am J Surg. 1996;172(4):350–2.

    Article  CAS  PubMed  Google Scholar 

  104. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol. 1996;7(4):347–53.

    Article  CAS  PubMed  Google Scholar 

  105. Burris 3rd HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–13.

    CAS  PubMed  Google Scholar 

  106. Storniolo AM, Enas NH, Brown CA, et al. An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer. 1999;85(6):1261–8.

    Article  CAS  PubMed  Google Scholar 

  107. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.

    Article  Google Scholar 

  108. Shi C, Merchant N, Newsome G, Goldenberg DM, Gold DV. Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry. Arch Pathol Lab Med. 2014;138:220–8.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Gulec SA, Cohen SJ, Pennington KL, Zuckier LS, Hauke RJ, Horne H, Wegener WA, Teoh N, Gold DV, Sharkey RM, Goldenberg DM. Treatment of advanced pancreatic carcinoma with 90Y- clivatuzumab tetraxetan: phase I single-dose escalation trial. Clin Cancer Res. 2011;17:4091–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ocean AJ, Pennington KL, Guarino MJ, Sheikh A, Bekail-Saab T, Serafini AN, Lee D, Sung MW, Gulec SA, Goldsmith SJ, Manzone T, Holt M, O’Neil BH, Hall N, Montero AJ, Kauh J, Gold DV, Horne H, Wegener WA, Goldenberg DM. Fractionated radioimmunotherapy with 90Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer. A phase I trial. Cancer. 2012;118:5497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Picozzi VJ, Ramanathan RK, Lowery MA, Ocean AJ, Mitchel EP, O’Neil BH, Guarino MJ, Conkling PR, Cohen SJ, et al. 90Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: a phase 1B study in patients with metastatic pancreatic cancer after two or more prior therapies. Eur J Cancer. 2015;51:1857–64.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Pharmacology Branch, National Cancer Institute, RM 4-W602, MSC 9735, 9609 Medical Center Drive, Bethesda, MD, 20892, USA

    Beverly A. Teicher

Authors
  1. Beverly A. Teicher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Beverly A. Teicher .

Editor information

Editors and Affiliations

  1. Nuffield Division of Clinical and Laboratory Sciences, University of Oxford, Oxford, United Kingdom

    David Kerr

  2. John Radcliffe Hospital, Oxford University Hospitals NHS Trust John Radcliffe Hospital, Oxfordshire, United Kingdom

    Rebecca Johnson

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Teicher, B.A. (2017). Antibody Drug and Radionuclide Conjugates for GI Cancers. In: Kerr, D., Johnson, R. (eds) Immunotherapy for Gastrointestinal Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-43063-8_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-43063-8_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-43061-4

  • Online ISBN: 978-3-319-43063-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation