Top

Published in:

01-12-2017 | Review Article

Antibody–Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments

Authors: Aiko Nagayama, Leif W. Ellisen, Bruce Chabner, Aditya Bardia

Published in: Targeted Oncology | Issue 6/2017

Abstract

Antibody–drug conjugates (ADCs) are complex immunoconjugates designed to selectively deliver toxic small molecules preferentially to cancer cells. These immunoconjugates consist of a monoclonal antibody - directed to a tumor antigen - and a cytotoxic agent that is conjugated to the antibody via a molecular linker. Following the binding to a specific antigen on the surface of cancer cells, the conjugate is internalized and releases its cytotoxic payload to kill the malignant cell. ADCs that have gained regulatory approval from the US Food and Drug Administration (FDA) include brentuximab vedotin for CD30-positive Hodgkin’s lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several other agents are in advanced stages of clinical development, including sacituzumab govitecan for breast cancer, mirvetuximab soravtansine for ovarian cancer, rovalpituzumab tesirine for lung cancer, depatuxizumab mafodotin for glioblastoma, and oportuzumab monatox for bladder cancer. This review provides an overview of the recent clinical experience with the approved, most advanced, and other promising candidates of ADCs for solid tumors, including a description of biology and chemistry of ADCs, drug resistance and biomarkers, and the future perspective on combination strategies with these new immunoconjugates.

Goodman LS, Wintrobe MM, et al. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc. 1946;132:126–32.

Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948;238(23):787–93. https://doi.org/10.1056/NEJM194806032382301. PubMedCrossRef

Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–7.PubMedCrossRef

Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15(6):361–70. https://doi.org/10.1038/nrc3930.PubMedPubMedCentralCrossRef

Schwartz RS. Paul Ehrlich's magic bullets. N Engl J Med. 2004;350(11):1079–80. https://doi.org/10.1056/NEJMp048021. PubMedCrossRef

Panowski S, Bhakta S, Raab H, Polakis P, Junutula JR. Site-specific antibody drug conjugates for cancer therapy. MAbs. 2014;6(1):34–45. https://doi.org/10.4161/mabs.27022.PubMedCrossRef

Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19(13):3244–54. https://doi.org/10.1200/JCO.2001.19.13.3244. PubMedCrossRef

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.PubMed

Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–6. https://doi.org/10.1200/JCO.2011.38.0402.PubMedCrossRef

10.

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. https://doi.org/10.1200/JCO.2011.38.0410. PubMedPubMedCentralCrossRef

11.

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. https://doi.org/10.1056/NEJMoa1209124. PubMedPubMedCentralCrossRef

12.

Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer. 2006;6(9):714–27. https://doi.org/10.1038/nrc1913.PubMedCrossRef

13.

Patil R, Portilla-Arias J, Ding H, Konda B, Rekechenetskiy A, Inoue S, et al. Cellular delivery of doxorubicin via pH-controlled hydrazone linkage using multifunctional nano vehicle based on poly(beta-l-malic acid). Int J Mol Sci. 2012;13(9):11681–93. https://doi.org/10.3390/ijms130911681.PubMedPubMedCentralCrossRef

14.

Jain N, Smith SW, Ghone S, Tomczuk B. Current ADC linker chemistry. Pharm Res. 2015;32(11):3526–40. https://doi.org/10.1007/s11095-015-1657-7.PubMedPubMedCentralCrossRef

15.

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. https://doi.org/10.1158/0008-5472.CAN-08-2250.PubMedCrossRef

16.

Smith AL, Nicolaou KC. The enediyne antibiotics. J Med Chem. 1996;39(11):2103–17. https://doi.org/10.1021/jm9600398.PubMedCrossRef

17.

David M, Goldenberg TMC, Serengulam V, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6(26):22496–512.

18.

Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006;6(10):789–802. https://doi.org/10.1038/nrc1977.PubMedCrossRef

19.

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. https://doi.org/10.1182/blood-2003-01-0039.PubMedCrossRef

20.

Li F, Emmerton KK, Jonas M, Zhang X, Miyamoto JB, Setter JR, et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 2016;76(9):2710–9. https://doi.org/10.1158/0008-5472.CAN-15-1795.PubMedCrossRef

21.

Hinrichs MJ, Dixit R. Antibody drug conjugates: nonclinical safety considerations. AAPS J. 2015;17(5):1055–64. https://doi.org/10.1208/s12248-015-9790-0.PubMedPubMedCentralCrossRef

22.

Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8(4):659–71. https://doi.org/10.1080/19420862.2016.1156829.PubMedPubMedCentralCrossRef

23.

Peters C, Brown S. Antibody-drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015;35(4):e00225–e. https://doi.org/10.1042/bsr20150089.PubMedPubMedCentralCrossRef

24.

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. 1999;17(2):478–84. https://doi.org/10.1200/JCO.1999.17.2.478. PubMedCrossRef

25.

Gorovits B, Krinos-Fiorotti C. Proposed mechanism of off-target toxicity for antibody-drug conjugates driven by mannose receptor uptake. Cancer Immunol Immunother. 2013;62(2):217–23. https://doi.org/10.1007/s00262-012-1369-3. PubMedCrossRef

26.

Bareford LM, Swaan PW. Endocytic mechanisms for targeted drug delivery. Adv Drug Deliv Rev. 2007;59(8):748–58. https://doi.org/10.1016/j.addr.2007.06.008.PubMedPubMedCentralCrossRef

27.

Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235–44. https://doi.org/10.1016/j.cbpa.2009.03.023.PubMedCrossRef

28.

Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25. https://doi.org/10.1038/nri2155.PubMedCrossRef

29.

Vu T, Claret FX. Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol. 2012;2:62. https://doi.org/10.3389/fonc.2012.00062.PubMedPubMedCentralCrossRef

30.

Weiner GJ. Rituximab: mechanism of action. Semin Hematol. 2010;47(2):115–23. https://doi.org/10.1053/j.seminhematol.2010.01.011.PubMedPubMedCentralCrossRef

31.

Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9(7):463–75. https://doi.org/10.1038/nrc2656.PubMedCrossRef

32.

Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. https://doi.org/10.1038/35052073. PubMedCrossRef

33.

Weinberg RA. Twisted epithelial-mesenchymal transition blocks senescence. Nat Cell Biol. 2008;10(9):1021–3. https://doi.org/10.1038/ncb0908-1021.PubMedCrossRef

34.

Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001;61(12):4744–9.PubMed

35.

Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009;27(34):5838–47. https://doi.org/10.1200/JCO.2009.22.1507.PubMedCrossRef

36.

Bardia A, Baselga J. Targeted Therapies in Breast Cancer. In: Sledge G, Baselga J, editors. Targeted therapies in breast cancer (therapeutic strategies). 1st ed. Oxford: Clinical Publishing; 2013. p. 43–50.

37.

Weiner LM, Surana R, Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010;10(5):317–27. https://doi.org/10.1038/nri2744.PubMedPubMedCentralCrossRef

38.

Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20(1):34–50. https://doi.org/10.1038/cr.2009.139.PubMedCrossRef

39.

Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729–40. https://doi.org/10.1038/nri2620. PubMedCrossRef

40.

Stoermer KA, Morrison TE. Complement and viral pathogenesis. Virology. 2011;411(2):362–73. https://doi.org/10.1016/j.virol.2010.12.045.PubMedCrossRef

41.

Falini B, Pileri S, Pizzolo G, Durkop H, Flenghi L, Stirpe F, et al. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995;85(1):1–14.PubMed

42.

Al-Shamkhani A. The role of CD30 in the pathogenesis of haematopoietic malignancies. Curr Opin Pharmacol. 2004;4(4):355–9. https://doi.org/10.1016/j.coph.2004.02.007.PubMedCrossRef

43.

Matsumoto K, Terakawa M, Miura K, Fukuda S, Nakajima T, Saito H. Extremely rapid and intense induction of apoptosis in human eosinophils by anti-CD30 antibody treatment in vitro. J Immunol. 2004;172(4):2186–93.PubMedCrossRef

44.

Wahl AF, Klussman K, Thompson JD, Chen JH, Francisco LV, Risdon G, et al. The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin's disease. Cancer Res. 2002;62(13):3736–42.PubMed

45.

Forero-Torres A, Leonard JP, Younes A, Rosenblatt JD, Brice P, Bartlett NL, et al. A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009;146(2):171–9. https://doi.org/10.1111/j.1365-2141.2009.07740.x.PubMedCrossRef

46.

Sutherland MS, Sanderson RJ, Gordon KA, Andreyka J, Cerveny CG, Yu C, et al. Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem. 2006;281(15):10540–7. https://doi.org/10.1074/jbc.M510026200. PubMedCrossRef

47.

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. https://doi.org/10.1158/1078-0432.CCR-09-2069. PubMedCrossRef

48.

Chen R, Hou J, Newman E, Kim Y, Donohue C, Liu X, et al. CD30 Downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin. Mol Cancer Ther. 2015;14(6):1376–84. https://doi.org/10.1158/1535-7163.MCT-15-0036.

49.

Oflazoglu E, Stone IJ, Gordon KA, Grewal IS, van Rooijen N, Law CL, et al. Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. Blood. 2007;110(13):4370–2. https://doi.org/10.1182/blood-2007-06-097014.PubMedCrossRef

50.

Bartlett NL, Niedzwiecki D, Johnson JL, Friedberg JW, Johnson KB, van Besien K, et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol. 2007;18(6):1071–9. https://doi.org/10.1093/annonc/mdm090. PubMedCrossRef

51.

Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853–62. https://doi.org/10.1016/S0140-6736(15)60165-9.PubMedCrossRef

52.

O'Connor OA. Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182–9. https://doi.org/10.1200/JCO.2010.29.9024. PubMedPubMedCentralCrossRef

53.

Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;390(10094):555–66. https://doi.org/10.1016/S0140-6736(17)31266-7.

54.

Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990;5(7):953–62.PubMed

55.

Krop I, Winer EP. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer. Clin Cancer Res. 2014;20(1):15–20. https://doi.org/10.1158/1078-0432.CCR-13-0541. PubMedCrossRef

56.

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. https://doi.org/10.1158/1535-7163.MCT-10-0645.PubMedPubMedCentralCrossRef

57.

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. https://doi.org/10.1158/0008-5472.CAN-08-1776.PubMedCrossRef

58.

Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. 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. 2011;128(2):347–56. https://doi.org/10.1007/s10549-010-1090-x.PubMedCrossRef

59.

Krop IE, Kim SB, Gonzalez-Martin A, LoRusso PM, Ferrero JM, Smitt M, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(7):689–99. https://doi.org/10.1016/S1470-2045(14)70178-0.PubMedCrossRef

60.

Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Kuemmel S, et al. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): final analysis of the west German study group adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of Neoadjuvant Trastuzumab Emtansine with or without endocrine therapy (ET) versus Trastuzumab plus ET. J Clin Oncol. 2017;35(26):3046–54. https://doi.org/10.1200/JCO.2016.71.9815.

61.

Phillips GD, Fields CT, Li G, Dowbenko D, Schaefer G, Miller K, et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res. 2014;20(2):456–68. https://doi.org/10.1158/1078-0432.CCR-13-0358. PubMedCrossRef

62.

Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, et al. Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol. 2017;35(2):141–8.PubMedCrossRef

63.

Boku N. HER2-positive gastric cancer. Gastric Cancer. 2014;17(1):1–12. https://doi.org/10.1007/s10120-013-0252-z. PubMedCrossRef

64.

Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18(3):476–84. https://doi.org/10.1007/s10120-014-0402-y. PubMedCrossRef

65.

Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640–53. https://doi.org/10.1016/S1470-2045(17)30111-0.

66.

Ruschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F, et al. HER2 testing in gastric cancer: a practical approach. Mod Pathol. 2012;25(5):637–50. https://doi.org/10.1038/modpathol.2011.198. PubMedCrossRef

67.

Peng Z, Zou J, Zhang X, Yang Y, Gao J, Li Y, et al. HER2 discordance between paired primary gastric cancer and metastasis: a meta-analysis. Chin J Cancer Res. 2015;27(2):163–71. https://doi.org/10.3978/j.issn.1000-9604.2014.12.09. PubMedPubMedCentralCrossRef

68.

Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res. 2014;16(2):209. https://doi.org/10.1186/bcr3621. PubMedPubMedCentralCrossRef

69.

Loganzo F, Tan X, Sung M, Jin G, Myers JS, Melamud E, et al. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther. 2015;14(4):952–63. https://doi.org/10.1158/1535-7163.MCT-14-0862.PubMedCrossRef

70.

Sendur MA, Aksoy S, Altundag K. Cardiotoxicity of novel HER2-targeted therapies. Curr Med Res Opin. 2013;29(8):1015–24. https://doi.org/10.1185/03007995.2013.807232.PubMedCrossRef

71.

Bardia A, Mayer IA, Diamond JR, Moroose RL, Isakoff SJ, Starodub AN, et al. Efficacy and safety of anti-Trop-2 antibody drug conjugate Sacituzumab Govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol. 2017;35(19):2141–8. https://doi.org/10.1200/JCO.2016.70.8297.

72.

Heist RS, Guarino MJ, Masters G, Purcell WT, Starodub AN, Horn L, et al. Therapy of advanced non-small-cell lung cancer with an SN-38-anti-Trop-2 drug conjugate, Sacituzumab Govitecan. J Clin Oncol. 2017;35(24):2790–7. https://doi.org/10.1200/JCO.2016.72.1894.

73.

Faltas B, Goldenberg DM, Ocean AJ, Govindan SV, Wilhelm F, Sharkey RM, et al. Sacituzumab Govitecan, a novel antibody--drug conjugate, in patients with metastatic platinum-resistant Urothelial carcinoma. Clin Genitourin Cancer. 2016;14(1):e75–9. https://doi.org/10.1016/j.clgc.2015.10.002.

74.

Yardley DA, Weaver R, Melisko ME, Saleh MN, Arena FP, Forero A, et al. EMERGE: a randomized phase II study of the antibody-drug conjugate Glembatumumab Vedotin in advanced glycoprotein NMB-expressing breast cancer. J Clin Oncol. 2015;33(14):1609–19. https://doi.org/10.1200/JCO.2014.56.2959.

75.

Ott PA, Hamid O, Pavlick AC, Kluger H, Kim KB, Boasberg PD, et al. Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma. J Clin Oncol. 2014;32(32):3659–66. https://doi.org/10.1200/JCO.2013.54.8115. PubMedPubMedCentralCrossRef

76.

Lipinski M, Parks DR, Rouse RV, Herzenberg LA. Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proc Natl Acad Sci U S A. 1981;78(8):5147–50.PubMedPubMedCentralCrossRef

77.

Ripani E, Sacchetti A, Corda D, Alberti S. Human Trop-2 is a tumor-associated calcium signal transducer. Int J Cancer. 1998;76(5):671–6.PubMedCrossRef

78.

Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM. Humanized anti-Trop-2 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(10):3157–69. https://doi.org/10.1158/1078-0432.CCR-10-2939. PubMedCrossRef

79.

Trerotola M, Cantanelli P, Guerra E, Tripaldi R, Aloisi AL, Bonasera V, et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene. 2013;32(2):222–33. https://doi.org/10.1038/onc.2012.36.PubMedCrossRef

80.

Lin H, Huang JF, Qiu JR, Zhang HL, Tang XJ, Li H, et al. Significantly upregulated TACSTD2 and Cyclin D1 correlate with poor prognosis of invasive ductal breast cancer. Exp Mol Pathol. 2013;94(1):73–8. https://doi.org/10.1016/j.yexmp.2012.08.004.PubMedCrossRef

81.

Liu LF, Desai SD, Li TK, Mao Y, Sun M, Sim SP. Mechanism of action of camptothecin. Ann N Y Acad Sci. 2000;922:1–10.PubMedCrossRef

82.

Xu Y. Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol. 2002;13(12):1841–51. https://doi.org/10.1093/annonc/mdf337. PubMedCrossRef

83.

Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Arrojo R, Liu D, et al. Sacituzumab Govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate: characterization and efficacy in pancreatic, gastric, and other cancers. Bioconjug Chem. 2015;26(5):919–31. https://doi.org/10.1021/acs.bioconjchem.5b00223.PubMedCrossRef

84.

Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. 2001;7(8):2182–94.PubMed

85.

Weterman MA, Ajubi N, van Dinter IM, Degen WG, van Muijen GN, Ruitter DJ, et al. Nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J Cancer. 1995;60(1):73–81.PubMedCrossRef

86.

Ripoll VM, Irvine KM, Ravasi T, Sweet MJ, Hume DA. Gpnmb is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. J Immunol. 2007;178(10):6557–66.PubMedCrossRef

87.

Abdelmagid SM, Barbe MF, Rico MC, Salihoglu S, Arango-Hisijara I, Selim AH, et al. Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. Exp Cell Res. 2008;314(13):2334–51. https://doi.org/10.1016/j.yexcr.2008.02.006.PubMedCrossRef

88.

Selim AA, Abdelmagid SM, Kanaan RA, Smock SL, Owen TA, Popoff SN, et al. Anti-osteoactivin antibody inhibits osteoblast differentiation and function in vitro. Crit Rev Eukaryot Gene Expr. 2003;13(2–4):265–75.PubMed

89.

Rose AA, Grosset AA, Dong Z, Russo C, Macdonald PA, Bertos NR, et al. Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res. 2010;16(7):2147–56. https://doi.org/10.1158/1078-0432.CCR-09-1611. PubMedCrossRef

90.

Kuan CT, Wakiya K, Dowell JM, Herndon JE 2nd, Reardon DA, Graner MW, et al. Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin Cancer Res. 2006;12(7 Pt 1):1970–82. https://doi.org/10.1158/1078-0432.CCR-05-2797. PubMedCrossRef

91.

Rich JN, Shi Q, Hjelmeland M, Cummings TJ, Kuan CT, Bigner DD, et al. Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem. 2003;278(18):15951–7. https://doi.org/10.1074/jbc.M211498200. PubMedCrossRef

92.

Rose AA, Annis MG, Dong Z, Pepin F, Hallett M, Park M, et al. ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties. PLoS One. 2010;5(8):e12093. https://doi.org/10.1371/journal.pone.0012093.

93.

Tse KF, Jeffers M, Pollack VA, McCabe DA, Shadish ML, Khramtsov NV, et al. CR011, a fully human monoclonal antibody-auristatin E conjugate, for the treatment of melanoma. Clin Cancer Res. 2006;12(4):1373–82. https://doi.org/10.1158/1078-0432.CCR-05-2018. PubMedCrossRef

94.

Pollack VA, Alvarez E, Tse KF, Torgov MY, Xie S, Shenoy SG, et al. Treatment parameters modulating regression of human melanoma xenografts by an antibody-drug conjugate (CR011-vcMMAE) targeting GPNMB. Cancer Chemother Pharmacol. 2007;60(3):423–35. https://doi.org/10.1007/s00280-007-0490-z.PubMedCrossRef

95.

Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum Mol Genet. 2011;20(5):905–16. https://doi.org/10.1093/hmg/ddq529.PubMedCrossRef

96.

Morimoto M, Nishinakamura R, Saga Y, Kopan R. Different assemblies of notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development. 2012;139(23):4365–73. https://doi.org/10.1242/dev.083840.PubMedPubMedCentralCrossRef

97.

Kunnimalaiyaan M, Chen H. Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Oncologist. 2007;12(5):535–42. https://doi.org/10.1634/theoncologist.12-5-535.PubMedCrossRef

98.

Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. https://doi.org/10.1126/scitranslmed.aac9459.PubMedPubMedCentralCrossRef

99.

Rudin CM, Pietanza MC, Bauer TM, Ready N, Morgensztern D, Glisson BS, et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 2017;18(1):42–51. https://doi.org/10.1016/S1470-2045(16)30565-4.PubMedCrossRef

100.

Elnakat H, Ratnam M. Distribution, functionality and gene regulation of folate receptor isoforms: implications in targeted therapy. Adv Drug Deliv Rev. 2004;56(8):1067–84. https://doi.org/10.1016/j.addr.2004.01.001.PubMedCrossRef

101.

Salazar MD, Ratnam M. The folate receptor: what does it promise in tissue-targeted therapeutics? Cancer Metastasis Rev. 2007;26(1):141–52. https://doi.org/10.1007/s10555-007-9048-0.PubMedCrossRef

102.

Ledermann JA, Canevari S, Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments. Ann Oncol. 2015;26(10):2034–43. https://doi.org/10.1093/annonc/mdv250. PubMedCrossRef

103.

Toffoli G, Russo A, Gallo A, Cernigoi C, Miotti S, Sorio R, et al. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int J Cancer. 1998;79(2):121–6.PubMedCrossRef

104.

Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, et al. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):619–26. https://doi.org/10.1016/j.ygyno.2007.11.020.PubMedPubMedCentralCrossRef

105.

Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, Kovtun Y, et al. Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem. 2006;49(14):4392–408. https://doi.org/10.1021/jm060319f.PubMedCrossRef

106.

Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, et al. IMGN853, a Folate receptor-alpha (FRalpha)-targeting antibody-drug conjugate, exhibits potent targeted antitumor activity against FRalpha-expressing Tumors. Mol Cancer Ther. 2015;14(7):1605–13. https://doi.org/10.1158/1535-7163.MCT-14-1095.

107.

Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, Perez RP, et al. Safety and activity of Mirvetuximab Soravtansine (IMGN853), a Folate receptor alpha-targeting antibody-drug conjugate, in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a phase I expansion study. J Clin Oncol. 2017;35(10):1112–8. https://doi.org/10.1200/JCO.2016.69.9538.

108.

Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006;33(4):369–85. https://doi.org/10.1053/j.seminoncol.2006.04.003.PubMedCrossRef

109.

Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19(11):1389–400. https://doi.org/10.1038/nm.3388.PubMedPubMedCentralCrossRef

110.

Gan HK, Burgess AW, Clayton AH, Scott AM. Targeting of a conformationally exposed, tumor-specific epitope of EGFR as a strategy for cancer therapy. Cancer Res. 2012;72(12):2924–30. https://doi.org/10.1158/0008-5472.CAN-11-3898.PubMedCrossRef

111.

Gan HK, Burge ME, Solomon BJ, Holen KD, Zhang Y, Ciprotti M, et al. A phase I and biodistribution study of ABT-806i, an 111indium-labeled conjugate of the tumor-specific anti-EGFR antibody ABT-806. J Clin Oncol. 2013;31(15_suppl):2520. https://doi.org/10.1200/jco.2013.31.15_suppl.2520.CrossRef

112.

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):661–9. https://doi.org/10.1158/1535-7163.MCT-15-0901.

113.

Gan HK, Fichtel L, Lassman A, Merrell R, Bent M, Kumthekar P. A phase I study evaluating ABT414 with concurrent radiotherapy (RT) and temozolomide (TMZ) in glioblastoma (GBM) [abstract no. ET-19]. Neuro Oncol. 2014;16(Suppl 5):v83.

114.

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. 2017 Jul 1;19(7):965–75. https://doi.org/10.1093/neuonc/now257.

115.

Di Paolo C, Willuda J, Kubetzko S, Lauffer I, Tschudi D, Waibel R, et al. A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity. Clin Cancer Res. 2003;9(7):2837–48.PubMed

116.

Balzar M, Winter MJ, de Boer CJ, Litvinov SV. The biology of the 17-1A antigen (Ep-CAM). J Mol Med (Berl). 1999;77(10):699–712.CrossRef

117.

Oppenheimer NJ, Bodley JW. Diphtheria toxin. Site and configuration of ADP-ribosylation of diphthamide in elongation factor 2. J Biol Chem. 1981;256(16):8579–81.PubMed

118.

Perentesis JP, Miller SP, Bodley JW. Protein toxin inhibitors of protein synthesis. Biofactors. 1992;3(3):173–84.PubMed

119.

Kowalski M, Guindon J, Brazas L, Moore C, Entwistle J, Cizeau J, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guerin. J Urol. 2012;188(5):1712–8. https://doi.org/10.1016/j.juro.2012.07.020.PubMedCrossRef

120.

Manning DL, Daly RJ, Lord PG, Kelly KF, Green CD. Effects of oestrogen on the expression of a 4.4 kb mRNA in the ZR-75-1 human breast cancer cell line. Mol Cell Endocrinol. 1988;59(3):205–12.PubMedCrossRef

121.

Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J. 2003;375(Pt 1):51–9. https://doi.org/10.1042/BJ20030478. PubMedPubMedCentralCrossRef

122.

Taylor KM, Hiscox S, Nicholson RI. Zinc transporter LIV-1: a link between cellular development and cancer progression. Trends Endocrinol Metab. 2004;15(10):461–3. https://doi.org/10.1016/j.tem.2004.10.003. PubMedCrossRef

123.

Sussman D, Smith LM, Anderson ME, Duniho S, Hunter JH, Kostner H, et al. SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther. 2014;13(12):2991–3000. https://doi.org/10.1158/1535-7163.MCT-13-0896.PubMedCrossRef

124.

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. https://doi.org/10.1158/1078-0432.CCR-15-2822. PubMedCrossRef

125.

Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107(7):1039–46. https://doi.org/10.1111/cas.12966.PubMedPubMedCentralCrossRef

126.

Shiose Y, Ochi Y, Kuga H, Yamashita F, Hashida M. Relationship between drug release of DE-310, macromolecular prodrug of DX-8951f, and cathepsins activity in several tumors. Biol Pharm Bull. 2007;30(12):2365–70.PubMedCrossRef

127.

Nakada T, Masuda T, Naito H, Yoshida M, Ashida S, Morita K, et al. Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett. 2016;26(6):1542–5. https://doi.org/10.1016/j.bmcl.2016.02.020.PubMedCrossRef

128.

Bergstrom D, Bodyak N, Park P, Yurkovetskiy A, DeVit M, Yin M, et al. XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer [abstract no. P4-14-28]. Cancer Res. 2016;76(4 Suppl):P4-14-28-P4-14-28. https://doi.org/10.1158/1538-7445.sabcs15-p4-14-28.

129.

Hamilton GS. Antibody-drug conjugates for cancer therapy: the technological and regulatory challenges of developing drug-biologic hybrids. Biologicals. 2015;43(5):318–32. https://doi.org/10.1016/j.biologicals.2015.05.006. PubMedCrossRef

130.

Baselga J, Lewis Phillips GD, Verma S, Ro J, Huober J, Guardino AE, et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of Trastuzumab Emtansine in HER2-positive metastatic breast cancer. Clin Cancer Res. 2016;22(15):3755–63. https://doi.org/10.1158/1078-0432.CCR-15-2499.

131.

Baselga J, Cortes J, Im SA, Clark E, Ross G, Kiermaier A, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol. 2014;32(33):3753–61. https://doi.org/10.1200/JCO.2013.54.5384.PubMedCrossRef

132.

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. https://doi.org/10.4161/mabs.22854.PubMedPubMedCentralCrossRef

133.

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. Sci Transl Med. 2015;7(315):315ra188. https://doi.org/10.1126/scitranslmed.aac4925.PubMedCrossRef

134.

Cardillo TM, Sharkey RM, Rossi DL, Arrojo R, Mostafa AA, Goldenberg DM. Synthetic lethality exploitation by an anti-Trop-2-SN-38 antibody-drug conjugate, IMMU-132, plus PARP inhibitors in BRCA1/2-wild-type triple-negative breast cancer. Clin Cancer Res. 2017 Jul 1;23(13):3405–15. https://doi.org/10.1158/1078-0432.CCR-16-2401.

Title: Antibody–Drug Conjugates for the Treatment of Solid Tumors: Clinical Experience and Latest Developments
Authors: Aiko Nagayama
Leif W. Ellisen
Bruce Chabner
Aditya Bardia
Publication date: 01-12-2017
Publisher: Springer International Publishing
Published in: Targeted Oncology / Issue 6/2017
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-017-0535-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2017

Author’s Reply to Arnaud Uguen: “Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocations: Clinical Characteristics and Management in a Real-Life Setting: a French Retrospective Analysis (GFPC 02–14 Study)”

The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors

Impact of Imatinib on the Fertility of Male Patients with Chronic Myelogenous Leukaemia in the Chronic Phase

CEA Response and Depth of Response (DpR) to Predict Clinical Outcomes of First-Line Cetuximab Treatment for Metastatic Colorectal Cancer

Validation of a Simple Scoring System to Predict Sorafenib Effectiveness in Patients with Hepatocellular Carcinoma

Targeting FGFR in Squamous Cell Carcinoma of the Lung

Keynote webinar | Spotlight on antibody–drug conjugates in cancer