Antibody–Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review

Advances in Therapy

Volumn 34, Issue 5, 2017, Pages 1015-1035

  Lambert, John M ^a   Morris, Charles Q ^a  

^a IMMUNOGEN INC   (United States)

Author keywords

ADC; Antibody drug conjugate; Auristatin; Calicheamicin; Cancer therapy; Maytansine; Monoclonal antibodies; Oncology; Payload; Targeted drug delivery

Indexed keywords

AMINOBENZOIC ACID DERIVATIVE; AMINOGLYCOSIDE; ANTIBODY CONJUGATE; ANTINEOPLASTIC AGENT; AURISTATIN; CD33 ANTIGEN; GEMTUZUMAB; MAYTANSINE; MONOCLONAL ANTIBODY; OLIGOPEPTIDE; TRASTUZUMAB EMTANSINE;

ANALOGS AND DERIVATIVES; HUMAN; IMMUNOLOGY; NEOPLASMS;

AMINOBENZOATES; AMINOGLYCOSIDES; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; HUMANS; IMMUNOCONJUGATES; MAYTANSINE; NEOPLASMS; OLIGOPEPTIDES; SIALIC ACID BINDING IG-LIKE LECTIN 3;

EID: 85028013998     PISSN: 0741238X     EISSN: 18658652     Source Type: Journal    
DOI: 10.1007/s12325-017-0519-6     Document Type: Review

References (96)

1. Miller DR. A tribute to Sidney Farber—the father of modern chemotherapy. Br J Haematol. 2006;134:20–6.
2. Frei E III. Combination cancer therapy: presidential address. Cancer Res. 1972;32:2593–607.
3. Haag R, Kratz F. Polymer therapeutics: concepts and applications. Angew Chem Int Ed. 2006;45:1198–215.
4. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495–7.
5. Chari RVJ, Miller ML, Widdison WC. Antibody-drug conjugates: an emerging concept in cancer therapy. Angew Chem Int Ed. 2014;53:3796–827.
6. Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nature Biotech. 2012;30:631–7.
7. Lambert JM, Chari RVJ. Ado-trastuzumab emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. 2014;57:6949–64.
8. Smith AL, Nicolaou KC. The enediyne antibiotics. J Med Chem. 1996;39:2103–17.
9. Pettit GR, Kamano Y, Herald CL, Tuinman AA, Boettner FE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB, Bontems RJ. The isolation and structure of a remarkable marine animal antineoplastic constituent: dolastatin 10. J Am Chem Soc. 1987;109:6883–5.
10. Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, Kovtun Y, Goldmacher VS, Xie H, Steeves RM, Lutz RJ, Zhao R, Wang L, Blättler WA, Chari RVJ. Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem. 2006;49:4392–408.
11. Kupchan SM, Sneden AT, Branfman AR, Howie GA, Rebhun LI, McIvor WE, Wang RW, Schnaitman TC. Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids. J Med Chem. 1978;21:31–7.
12. Blum RH, Wittenberg BK, Canellos GP, Mayer RJ, Skarin AT, Henderson IC, Parker LM, Frei E 3rd. A therapeutic trial of maytansine. Cancer Clin Trials. 1978;1(2):113–7.
13. Issel BF, Crooke ST. Maytansine. Cancer Treat Rev. 1978;5:199–207.
14. Perez EA, Hillman DW, Fishkin PA, Krook JE, Tan WW, Kuriakose PA, Alberts SR, Dakhil SR. Phase II trial of dolastatin-10 in patients with advanced breast cancer. Invest New Drugs. 2005;23:257–61.
15. Saad ED, Kraut EH, Hoff PM, Moore DF Jr, Jones D, Pazdur R, Abbruzzese JL. Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer. Am J Clin Oncol. 2002;25:451–3.
16. Singh R, Lambert JM, Chari RVJ. Antibody–drug conjugates (ADCs): new frontier in cancer therapeutics. In: Dubel S, Reichert JM, editors. Handbook of therapeutic antibodies, vol. 1. 2nd edn. Hoboken, NJ: Wiley-VCH; 2014. p. 341–62.
17. Lambert JM. Typical antibody-drug conjugates. In: Olivier Jr KJ, Hurvitz SA, editors. Antibody-drug conjugates: fundamentals, drug development, and clinical outcomes to target cancer. Hoboken: Wiley; 2017. p. 3–32.
18. Singh R, Setiady YY, Ponte J, Kovtun YV, Lai KC, Hong EE, Fishkin N, Dong L, Jones GE, Coccia JA, Lanieri L, Veale K, Costoplus JA, Skaletskaya A, Gabriel R, Salomon P, Wu R, Qiu Q, Erickson HK, Lambert JM, Chari RV, Widdison WC. A new triglycyl peptide linker for antibody-drug conjugates (ADCs) with improved targeted killing of cancer cells. Mol Cancer Ther. 2016;15:1311–20.
19. Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, Lutz RJ, Goldmacher VS, Blättler WA. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006;66:4426–33.
20. Erickson HK, Widdison WC, Mayo MF, Whiteman K, Audette C, Wilhelm SD, Singh R. Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates. Bioconj Chem. 2010;21:84–92.
21. Erickson HK, Lambert JM. ADME of antibody-maytansinoid conjugates. AAPS J. 2012;14:799–805.
22. Sharkey RM, Goldenberg DM. Use of antibodies and immunoconjugates for the therapy of more accessible cancers. Adv Drug Deliv Rev. 2008;60:1407–20.
23. Sievers EL, Larson RA, Stadtmauer EA, Estey E, Löwenberg B, Dombret H, Karanes C, Theobald M, Bennett JM, Sherman ML, Berger MS, Eten CB, Loken MR, van Dongen JJM, Bernstein ID, Appelbaum FR. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19:3244–54.
24. Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7:1490–6.
25. Giles FJ, Kantarjian HM, Kornblau SM, Thomas DA, Garcia-Manero G, Waddelow TA, David CL, Phan AT, Colburn DE, Rashid A, Estey EH. Mylotarg™ (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer. 2001;92:406–13.
26. Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and post-consolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121:4854–60.
27. Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, Estey EH, Dombret H, Chevret S, Ifrah N, Cahn J-Y, Récher C, Chilton L, Moorman AV, Burnett AK. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomized controlled trials. Lancet Oncol. 2014;15:986–96.
28. Rowe JM, Löwenberg B. Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug. Blood. 2013;121:4838–41.
29. Forero-Torres A, Leonard JP, Younes A, Rosenblatt JD, Brice P, Bartlett NL, Bosly A, Pinter-Brown L, Kennedy D, Sievers EL, Gopal AK. A phase II study of SGN-30 (anti-CD30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009;146:171–9.
30. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodkgin’s lymphoma. J Clin Oncol. 2012;30:2183–9.
31. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A. 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;30:2190–6.
32. DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, Kunz A, Hamann PR, Gorovits B, Udata C, Moran JK, Popplewell AG, Stephens S, Frost P, Damle NK. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004;103:1807–14.
33. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravavdi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O’Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13(4):403–11.
34. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, Gökbuget N, O’Brien S, Wang K, Wang T, Paccagnella L, Sleight B, Vandendries E, Advani AS. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740–53.
35. Lewis Phillips GD, Li G, Dugger D, Crocker LM, Parsons KL, Mai E, Blättler WA, Lambert JM, Chari RJ, Lutz RJ, Wong WLT, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spenser SD, Sliwkowski MX. Targeting HER2-positive breast cancer with trastuzumab-DM1, and antibody–cytotoxic drug conjugate. Cancer Res. 2008;68:9280–90.
36. Erickson HK, Lewis Phillips GD, Leipold DD, Provenzano CA, Mai E, Johnson HA, Gunter B, Audette CA, Gupta M, Pinkas J, Tibbitts J. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther. 2012;11:1133–42.
37. Wakankar A, Chen Y, Gokarn Y, Jacobson FS. Analytical methods for physicochemical characterization of antibody drug conjugates. MABS. 2011;3:161–72.
38. Wakankar AA, Feeney MB, Rivera J, Chen Y, Kim M, Sharma VK, Wang YJ. Physicochemical stability of the antibody-drug conjugate Trastuzumab-DM1: changes due to modification and conjugation processes. Bioconj Chem. 2010;21:1588–95.
39. Goldmacher VS, Amphlett G, Wang L, Lazar AC. Statistics of the distribution of the abundance of molecules with various drug loads in maytansinoid antibody-drug conjugates. Mol Pharm. 2015;12:1738–44.
40. Kim MT, Chen Y, Marhoul J, Jacobson F. Statistical modeling of the drug load distribution on trastuzumab emtansine (Kadcyla), a lysine-linked antibody drug conjugate. Bioconj Chem. 2014;25:1223–32.
41. Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA. 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. 2010;28:2698–704.
42. Beeram M, Krop IE, Burris HA, Girish SR, Yu W, Lu MW, Holden SN, Modi SA. Phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer. 2012;118:5733–40.
43. Burris HA III, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O’Shaughnessy JA. 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.
44. Krop IE, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, Guardino E, Lu M, Zheng M, Girish S, Amler L, Winer EP, Rugo HS. 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.
45. Bender BC, Schaedeli-Stark F, Koch R, Joshi A, Chu YW, Rugo H, Krop IE, Girish S, Friberg LE, Gupta M. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemother Pharmacol. 2012;70:591–601.
46. Poon KA, Flagella K, Beyer J, Tibbitts J, Kaur S, Saad O, Yi JH, Girish S, Dybdal N, Reynolds T. Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability. Toxicol Appl Pharmacol. 2013;273:298–313.
47. Girish S, Gupta M, Wang B, Lu D, Krop IE, Vogel CL, Burris HA III, LoRusso PM, Yi JH, Saad O, Tong B, Chu YW, Holden S, Joshi A. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol. 2012;69:1229–40.
48. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K. Trastuzumab emtansine for HER2-positive advanced breast cancer. New Engl J Med. 2012;367:1783–91.
49. Krop IE, Kim S-B, González-Martin A, LoRusso PM, Ferrero J-M, Smitt M, Yu R, Leung ACF, Wildiers H. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-lable, phase 3 trial. Lancet Oncol. 2014;15:689–99.
50. Carlson RM. TH3RESA trial: in advanced HER2+ breast cancer overall survival with T-DM1 beats “physician’s choice”. Oncol Times. 2016;38(3):32–3.
51. Perez EA, Barrios C, Eiermann W, Toi M, Im Y-H, Conte P, Martin M, Pienkowski T, Pivot X, Burris H 3rd, Petersen JA, Stanzel S, Strasak A, Patre M, Ellis P. 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. 2016;35:141–8.
52. Lewis Phillips GD, Fields CT, Li G, Dowbenko D, Schaefer G, Miller K, Andre F, Burris HA 3rd, Albain KS, Harbeck N, Diéras V, Crivellari D, Fanf L, Guardino E, Olsen SR, Crocker LM, Sliwkowski MX. 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;20:456–68.
53. Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013;31:1157–63.
54. 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;32:1437–44.
55. Baselga J, Cortés J, Kim S-B, Im S-A, Hegg R, Im Y-H, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19.
56. Perez EA, Hurvits SA, Amler LC, Mundt KE, Ng V, Guardino E, Gianni L. Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450 g: a randomized phase II study of patients with previously untreated HER2-positive breast cancer. Breast Cancer Res. 2014;16:R50.
57. McKarty K, Cornelisseb B, Scollard DA, Done SJ, Chun K, Reilly RM. Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts. Eur J Nucl Med Mol Imaging. 2009;36:81–93.
58. de Goeij BE, Lambert JM. New developments for antibody-drug conjugate-based therapeutic approaches. Curr Opin Immunol. 2016;40:14–23.
59. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MABS. 2016;8:659–71.
60. Jones TD, Carter PJ, Plűckthun A, Vásquez M, Holgate RGE, Hötzel I, Popplewell AG, Parren PWHI, Enzelberger M, Rademaker HJ, Clark MR, Lowe DC, Dahiyat BI, Smith V, Lambert JM, Wu H, Reilly M, Haurum JS, Dűbel S, Huston JS, Schirrmann T, Lanssen RAJ, Steegmaier M, Gross JA, Bradbury ARM, Burton DR, Dimitrov DS, Chester KA, Glennie MJ, Davies J, Walker A, Martin S, McCafferty J, Baker MP. The INNs and outs of antibody nonproprietary names. MABS. 2016;8(1):1–9.
61. Ott PA, Hamid O, Pavlick AC, Kluger H, Kim KB, Boasberg PD, Simantov R, Crowley E, Green JA, Hawthorne T, Davis TA, Sznol M, Hwu P. Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma. J Clin Oncol. 2014;32:3659–66.
62. Yardley DA, Weaver R, Melisko ME, Saleh MN, Arena FP, Forero A, Cigler T, Stopeck A, Citrin D, Oliff I, Bechhold R, Loutfi R, Garcia AA, Cruickshank S, Crowley E, Green J, Hawthorne T, Yellin MJ, Davis TA, Vahdat LT. EMERGE: a randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. J Clin Oncol. 2015;33:1609–19.
63. Lambert JM. Drug-conjugated antibodies for the treatment of cancer. Br J Clin Pharmacol. 2013;76:248–62.
64. Pitot HC, McElroy EA Jr, Reid JM, Windebank AJ, Sloan JA, Erlichman C, Bagniewski PG, Walker DL, Rubin J, Goldberg RM, Adjei AA, Ames MM. Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced tumors. Clin Cancer Res. 1999;5:525–31.
65. Hamid O, Sznol M, Pavlick AC, Kluger HM, Kim KB, Boasberg PD, Simantov R, Davis TA, Crowley E, Hawthorne T, Green J, Hwu P. Frequent dosing and GPNMB expression with CDX-011 (CR011-vcMMAE), an antibody-drug conjugate (ADC), in patients with advanced melanoma. J Clin Oncol. 2010;28(suppl):abstr 8525.
66. Yardley DA, Melisko ME, Forero A, Daniel BR, Montero AJ, Guthrie TH, Canfield VA, Oakman C, Chew HK, Ferrario C, Volas-Redd GH, Young RR, Henry NL, Aneiro L, He Y, Turner CD, Davis TA, Vahdat LT. METRIC: a randomized international study of the antibody-drug conjugate glembatumumab vedotin (GV or CDX-011) in patients (pts) with metastatic gpNMB-overexpressing triple-negative breast cancer (TNBC). American Society of Clinical Oncology Annual Meeting 2015; Abstr TPS1110.
67. Golfier S, Kopitz C, Kahnert A, Heisler I, Schatz CA, Stelte-Ludwig B, Mayer-Bartschmid A, Unterschemmann K, Bruder S, Linden L, Harrenga A, Hauff P, Scholle FD, Müller-Tiemann B, Kreft B, Ziegelbauer K. Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther. 2014;13:1537–48.
68. Blumenschein GR, Hassan R, Moore KN, Santin A, Kindler HL, Nemunaitis JJ, Seward SM, Rajagopalan P, Walter A, Sarapa N, Bendell JC. Phase I study of anti-mesothelin antibody-drug conjugate anetumab ravtansine (AR). J Clin Oncol. 2016;34(suppl):abstr 2509.
69. Younes A, Kim S, Romaguera J, Copeland A, de Castro Farial S, Kwak LW, Fayad L, Hagemeister F, Fanale M, Neelapu S, Lambert JM, Morariu-Zamfir R, Payard S, Gordon LI. Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2012;22:2776–82.
70. Hassan R, Bendell JC, Blumenschein Jr G, Kindler HL, Moore KN, Santin AD, Seward SM, Nemunaitis J, Rajagopalan P, Walter A, Sarapa N. Phase I study of anti-mesothelin antibody-drug conjugate anetumab ravtansine (BAY 94-9394). 16th World Conference on Lung Cancer, Denver CO. 2015; presentation No. 1574.
71. Hassan R, Jennens R, van Meerbeeck JP, Nemunaitis JJ, Blumenschein Jr GR, Fenner DA, Kinder HL, Novello S, Elbi C, Walter A, Serpico D, Siegel J, Childs BH. A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or pleural metastatic mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140). Americal Society of Clinical Oncology Annual Meeting 2016; Abstr TPS8576.
72. Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A, Payne G, Lutz RJ, Pinkas J, Goldmacher VS, Chittenden T, Lambert JM. IMGN853, a folate receptor-α (FRα)-targeting antibody-drug conjugate, exhibits potent targeted antitumor activity against FRα-expressing tumors. Mol Cancer Ther. 2015;14:1605–13.
73. Borghaei H, O’Malley DM, Seward SM, Bauer TM, Perez RP, Oza AM, Jeong W, Michenzie MF, Kirby MW, Chandorkar G, Ruiz-Soto R, Birrer MJ, Moore KN. Phase I study of IMGN853, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) in patients (pts) with epithelial ovarian cancer (EOC) and other FRα-positive solid tumors. J Clin Oncol. 2015;33(suppl):abstr 5558.
74. Ribrag V, Dupuis J, Tilly H, Morschhauser F, Laine F, Houot R, Haioun C, Copie C, Varga A, Lambert J, Hatteville L, Ziti-Ljajic S, Caron A, Payrard S, Coiffier B. A dose-escalation study of SAR3419, an anti-CD19 antibody maytansinoid conjugate, administered by intravenous infusion once weekly in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2014;20:213–20.
75. Van Den Bent MJ, Gan HK, Lassman AB, Kumthekar P, Merrell R, Butowski NA, Lwin Z, Mikkelsen T, Nabors LB, Papadopoulos KP, Penas-Prado M, Simes J, Wheeler H, Gomez EJ, Lee H-J, Roberts-Rapp L, Xiong H, Bain EE, Holen KD, Reardon DA. Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM). J Clin Oncol. 2016;34(suppl):abstr 2542.
76. Moskowitz CH, Fanale MA, Shah BD, Advani RH, Chen R, Kim S, Kostic A, Liu T, Peng J, Forero-Torres A. A phase I study of denintuzumab mafodotin (SGN-CD19A) in relapsed/refractory B-lineage non-Hodgkin lymphoma. Blood. 2015;126:182 (abstract).
77. Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, Esmaeli B, Ring SE, Bedikian A, Hortobagyi GN, Ellerhorst JA. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002;8:1038–44.
78. Moore KN, Martin LP, O’Malley DM, Matulonis UA, Konner JA, Perez RP, Bauer TM, Ruiz-Soto R, Birrer MJ. Safety and activity of mirevetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, in platinum-resistant ovarian cancer, fallopian tube, or primary peritoneal cancer: a phase I expansion study [published online December 27, 2016]. J Clin Oncol. 2016;. doi:10.1200/JCO.2016.69.9538.
79. Gunderson CC, Moore KN. Mirevetuximab soravtansine. Drugs Future. 2016;41:1–7.
80. Martin LP, Moore K, O’Malley DM, Seward S, Bauer TM, Perez R, Jeong W, Zhou Y, Ponte J, Kirby M, Al-Adhami M, Ruiz-Soto R, Birrer M. Association of folate receptor alpha (FR) expression level and clinical activity of IMGN853 (mirvetuximab soravtansine), a FR-targeting antibody-drug conjugate (ADC), in FR-expressing platinum-resistant epithelial ovarian cancer (EOC) patients (pts). Mol Cancer Ther. 2015;14(12 suppl 2):abstr C47.
81. Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, DeVries PJ, Cheng D, Meulbroek JA, Buchanan FG, McKay LM, Goodwin NC, Reilly EB. ABT-414, an antibody-drug conjugate targeting a tumor-selective EGFR epitope. Mol Cancer Ther. 2016;15:661–9.
82. Cleary JM, Reardon DA, Azad N, Gandhi L, Shapiro GI, Chaves J, Pedersen M, Ansell P, Ames W, Xiong H, Munasinghe W, Dudley M, Reilly EB, Holen K, Humerickhouse R. A phase 1 study of ABT-806 in subjects with advanced solid tumors. Invest New Drugs. 2015;33:671–8.
83. Gan HK, Papadopoulos KP, Fichtel L, Lassman AB, Merrell R, Van Den Bent MJ, Kumthekar P, Scott AM, Pedersen M, Gomez EJ, Fischer JS, Ames W, Xiong H, Lee H-J, Munasinghe W, Roberts-Rapp L, Ansell P, Holen KD, Lai R, Reardon DA. 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.
84. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, Desai R, Escarpe PA, Hampl J, Laysang A, Liu D, Lopez-Molina J, Milton M, Park A, Pysz MA, Shao H, Slingerland B, Torgov M, Williams SA, Foord O, Howard P, Jassem J, Badzio A, Czapiewski P, Harpole DH, Dowlati A, Massion PP, Travis WD, Pietanza MC, Poirier JT, Rudin CM, Stull RA, Dylla SJ. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136.
85. Rudin CR, Pietanza MC, Bauer TM, Spigel DR, Ready N, Morgensztern D, Glisson BS, Byers LA, Johnson ML, Burris HA, Robert F, Strickland DK, Zayed H, Govindan R, Dylla S, Peng SL. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). J Clin Oncol. 2016;34(suppl):abstr LBA8505.
86. Banerjee SN, Oza AM, Birrer MJ, Hamilton EP, Hasan J, Leary A, Moore KN, Mackowiak-Matejczyk B, Pikiel J, Ray-Coquard I, Trask P, Lin K, Vase A, Choi Y, Marsters J, Maslyar DJ, Lemahieu V, Wang Y, Humke EW, Liu JF. A randomized, open-label, phase II study of anti-NaPi2b antibody-drug conjugate (ADC) lifastuzumab (Lifa) vedotin (DNIB0600A) compared to pegylated liposomal doxorubicin (PLD) in patients (pts) with platinum-resistant ovarian cancer (PROC). J Clin Oncol. 2016;34(suppl):abstr 5569.
87. Gomez-Roca CA, Boni V, Moreno V, Morris JC, DeLord J-P, Calvo E, Papadopoulos KP, Rixe O, Cohen P, Tellier A, Ziti-Ljajic S, Tolcher AW. A phase I study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870). J Clin Oncol. 2016;34(suppl):abstr 2511.
88. Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Maelandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A. Patient derived xenograft models: an emerging platform for translational research. Cancer Discov. 2014;4:998–1013.
89. O’Malley DM, Martin LP, Moore KN, Nepert D, Ruiz-Soto R, Vergote I. FORWARD II: a phase 1b study to evaluate the safety, tolerability and pharmacokinetics of mirevetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin, or pembrolizumab in adults with folate receptor alphas (FR)-positive advanced epithelial ovarian cancer, primary peritoneal, fallopian tube, or endometrial cancer (NCT02606305). American Society of Clinical Oncology Annual Meeting 2016; Abstr TPS5611.
90. Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma—are we there yet? Neuro-oncology. 2013;15:4–27.
91. Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, Spitznagel EL, Piccirillo J. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24:4539–44.
92. Műller P, Martin K, Theurich S, Schreiner J, Savic S, Terszowski G, Lardinois D, Heinzelmann-Schwarz VA, Schlaak M, Kvasnicka H-M, Spagnoli G, Dirnhofer S, Speiser DE, von Bergwelt-Baildon M, Zippelius A. Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol Res. 2014;2:741–55.
93. Martin K, Műller P, Schreiner J, Savi Prince S, Lardinois D, Heinzelmann-Schwarz VA, Thommen DS, Zippelius A. The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity. Cancer Immunol Immunother. 2014;63:925–38.
94. Műller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, Savic S, Harbeck N, Nitz U, Gluz O, von Bergwelt-Baildon M, Kreipe H, Reddy S, Christgen M, Zippelius A. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med. 2015;7(315):315ra188.
95. Martin K, Schreiner J, Zippelius A. Modulation of APC function and anti-tumor immunity by anti-cancer drugs. Front Immunol. 2015;. doi:10.3389/fimmu.2015.00501.
96. Chari RVJ. Targeted delivery of chemotherapeutics: tumor-activated prodrug therapy. Adv Drug Deliv Rev. 1998;31:89–104.