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Improving the Safety Profile of ADCs

  • Magali Guffroy
  • Hadi Falahatpisheh
  • Martin Finkelstein
Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver cytotoxic agents directly into tumor cells. The plethora of ADCs investigated in clinical trials in recent years has enabled characterization of the major challenges faced by this therapeutic modality. With regard to safety, non-target-mediated toxicities, which are independent of the targeted antigens and similar for ADCs with the same linker-payloads, often drive dose-limiting events in patients and at the same time question the targeting efficiency of current ADCs. Development-limiting target-mediated toxicities have only been reported for a few ADCs. This manuscript will provide an overview of the major clinically relevant toxicities of ADCs with a presentation of key ADC attributes influencing these toxicities and discussion of potential mechanisms. Current research efforts to mitigate ADC-associated toxicities, including among others site-specific conjugation chemistry and prevention of normal tissue binding, will be presented and could be critical to future ADC endeavors.

Keywords

Toxicology Safety Toxicity Thrombocytopenia Neutropenia Off-target On-target Target Dependent Independent Liver Kidney Peripheral neuropathy Ocular Dose-limiting DLT Auristatin Microtubule inhibitor Calicheamicin Maximum tolerated dose MTD Therapeutic index 

Notes

Acknowledgements

All procedures performed on animals were conducted in accordance with regulations and established guidelines and were reviewed and approved by an Institutional Animal Care and Use Committee or through an ethical review process.

References

  1. 1.
    Schrama D, Reisfeld RA, Becker JC (2006) Antibody targeted drugs as cancer therapeutics. Nat Rev Drug Discov 5:147–159CrossRefPubMedGoogle Scholar
  2. 2.
    Damelin M, Zhong W, Myers J, Sapra P (2015) Evolving strategies for target selection for antibody-drug conjugates. Pharm Res 32:3494–3507CrossRefPubMedGoogle Scholar
  3. 3.
    Saber H, Leighton JK (2015) An FDA oncology analysis of antibody-drug conjugates. Regul Toxicol Pharmacol 71:444–452CrossRefPubMedGoogle Scholar
  4. 4.
    Drake PM, Rabuka D (2015) An emerging playbook for antibody-drug conjugates: lessons from the laboratory and clinic suggest a strategy for improving efficacy and safety. Curr Opin Chem Biol 28:174–180CrossRefPubMedGoogle Scholar
  5. 5.
    Gutierrez C, Schiff R (2011) HER2: biology, detection, and clinical implications. Arch Pathol Lab Med 135:55–62PubMedPubMedCentralGoogle Scholar
  6. 6.
    Kim SB, Wildiers H, Krop IE, Smitt M, Yu R, Lysbet de Haas S et al (2016) Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician’s choice in previously treated HER2-positive advanced breast cancer. Int J Cancer 139:2336–2342CrossRefPubMedGoogle Scholar
  7. 7.
    Stinchcombe T, Stahel R, Bubendorf L, Bonomi F, Villegas AE, Kowalski D et al (2017) Efficacy, safety and biomarker results of trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC). J Clin Oncol 35(suppl):abstr 8509CrossRefGoogle Scholar
  8. 8.
    Sochaj AM, Świderska KW, Otlewski J (2015) Current methods for the synthesis of homogeneous antibody-drug conjugates. Biotechnol Adv 33:775–784CrossRefPubMedGoogle Scholar
  9. 9.
    Jackson DY (2016) Processes for constructing homogeneous antibody drug conjugates. Org Process Res Dev 20:852–866CrossRefGoogle Scholar
  10. 10.
    Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S et al (2008) Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 26:925–932CrossRefPubMedGoogle Scholar
  11. 11.
    Beck A, Goetsch L, Dumontet C, Corvaïa N (2017) Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov (5):315–337CrossRefPubMedGoogle Scholar
  12. 12.
    Polu KR, Lowman HB (2014) Probody therapeutics for targeting antibodies to diseased tissue. Expert Opin Biol Ther 14:1049–1053CrossRefPubMedGoogle Scholar
  13. 13.
    Chang C, Frey G, Boyle WJ, Sharp LL, Short JM (2016) Novel conditionally active biologic anti-Axl antibody-drug conjugate demonstrates anti-tumor efficacy and improved safety profile. In: Proceedings of the 107th annual meeting of the American Association for Cancer Research, 16–20 Apr 2016, New Orleans. Cancer Res 76 (14 Suppl): Abstract nr 3836CrossRefGoogle Scholar
  14. 14.
    Mazor Y, Hansen A, Yang C, Chowdhury PS, Wang J, Stephens G et al (2015) Insights into the molecular basis of a bispecific antibody’s target selectivity. MAbs 7:461–469CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bander NH (2013) Antibody–drug conjugate target selection: critical factors. In: Ducry L (ed) Antibody-drug conjugates. Methods in molecular biology (Methods and protocols), vol 1045. Humana Press, Totowa, pp 29–40CrossRefGoogle Scholar
  16. 16.
    Carter P, Smith L, Ryan M (2004) Identification and validation of cell surface antigens for antibody targeting in oncology. Endocr Relat Cancer 11:659–687CrossRefPubMedGoogle Scholar
  17. 17.
    Weinstein JN, Collisson EA, Mills GB, Shaw KM, Ozenberger BA, Ellrott K et al (2013) The cancer genome atlas pan-cancer analysis project. Nat Genet 45:1113–1120CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    The GTEx Consortium (2013) The genotype-tissue expression (GTEx) project. Nat Genet 45:580–585CrossRefPubMedCentralGoogle Scholar
  19. 19.
    www.illumina.com; ArrayExpress ID: E-MTAB-513
  20. 20.
    Kim MS, Pinto SM, Getnet D, Nirujogi RS, Manda SS, Chaerkady R et al (2014) A draft map of the human proteome. Nature 509:575–581PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Balakrishnan A, Goodpaster T, Randolph-Habecker J, Hoffstrom BG, Jalikis FG, Koch LK et al (2017) Analysis of ROR1 protein expression in human cancer and normal tissues. Clin Cancer Res 23:3061–3071CrossRefPubMedGoogle Scholar
  22. 22.
    Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL (2011) Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem 59:701–710CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Nolan-Stevaux O, Fajardo F, Liu L, Coberly S, McElroy P, Nazarian A, et al (2016) Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy. In: Proceedings of the 107th annual meeting of the American Association for Cancer Research, 16–20 Apr 2016, New Orleans. Cancer Res 76 (14 Suppl): Abstract nr 585CrossRefGoogle Scholar
  24. 24.
    Kim EG, Kim KM (2015) Strategies and advancement in antibody-drug conjugate optimization for targeted cancer therapeutics. Biomol Ther (Seoul) 23:493–509CrossRefGoogle Scholar
  25. 25.
    Salfeld JG (2007) Isotype selection in antibody engineering. Nat Biotechnol 25:1369–1372CrossRefPubMedGoogle Scholar
  26. 26.
    Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX (2011) Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 128:347–356CrossRefPubMedGoogle Scholar
  27. 27.
    McDonagh CF, Kim KM, Turcott E, Brown LL, Westendorf L, Feist T et al (2008) Engineered anti-CD70 antibody-drug conjugate with increased therapeutic index. Mol Cancer Ther 7:2913–2923CrossRefPubMedGoogle Scholar
  28. 28.
    Kim KM, McDonagh CF, Westendorf L, Brown LL, Sussman D, Feist T et al (2008) Anti-CD30 diabody-drug conjugates with potent antitumor activity. Mol Cancer Ther 7:2486–2497CrossRefPubMedGoogle Scholar
  29. 29.
    Chen H, Lin Z, Arnst KE, Miller DD, Li W (2017) Tubulin inhibitor-based antibody-drug conjugates for cancer therapy. Molecules 22(8):1281.  https://doi.org/10.3390/molecules22081281 CrossRefGoogle Scholar
  30. 30.
    Dumontet C, Jordan MA (2010) Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov 9:790–803CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yang H, Ganguly A, Cabral F (2010) Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs. J Biol Chem 285:32242–32250CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cashman CR, Höke A (2015) Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett 596:33–50CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Schutten MM (2014) Antibody-drug conjugates: key challenges in safety assessment. Oral presentation at 2014 annual meeting of the American College of Veterinary Pathologists (ACVP). In: Industrial and toxicologic pathology focused scientific session II. Available via http://acvp2014.cmiav.com/schutten/
  34. 34.
    Tan C (2015) Payloads of antibody-drug conjugates. In: Wang J, Shen WC, Zaro J (eds) Antibody-drug conjugates, AAPS advances in the pharmaceutical sciences Series, vol 17. Springer, ChamGoogle Scholar
  35. 35.
    Junttila MR, Mao W, Wang X, Wang B-E, Pham T, Flygare J, Yu S-F, Yee S, Goldenberg D, Fields C et al (2015) Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. Sci Transl Med 7:314ra186.  https://doi.org/10.1126/scitranslmed.aac7433 CrossRefPubMedGoogle Scholar
  36. 36.
    Guffroy M, Falahatpisheh H, Biddle K, Kreeger J, Obert L, Walters K et al (2017) Liver microvascular injury and thrombocytopenia of antibody-calicheamicin conjugates in cynomolgus monkeys – mechanism and monitoring. Clin Cancer Res 23:1760–1770CrossRefPubMedGoogle Scholar
  37. 37.
    Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG et al (2004) Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10:7063–7070CrossRefPubMedGoogle Scholar
  38. 38.
    McCombs JR, Owen SC (2015) Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J 17:339–351CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li F, Emmerton KK, Jonas M, Zhang X, Miyamoto JB, Setter JR et al (2016) Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res 76(9):2710–2719CrossRefPubMedGoogle Scholar
  40. 40.
    Nakada T, Masuda T, Naito H, Yoshida M, Ashida S, Morita K et al (2016) Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett 26:1542–1545CrossRefPubMedGoogle Scholar
  41. 41.
    Burke PJ, Hamilton JZ, Jeffrey SC, Hunter JH, Doronina SO, Okeley NM et al (2017) Optimization of a PEGylated glucuronide-monomethylauristatin E linker for antibody-drug conjugates. Mol Cancer Ther 16:116–123CrossRefPubMedGoogle Scholar
  42. 42.
    Castañeda L, Maruani A, Schumacher FF, Miranda E, Chudasama V, Chester KA et al (2013) Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation. Chem Commun (Camb) 49:8187–8189CrossRefGoogle Scholar
  43. 43.
    Kim MT, Chen Y, Marhoul J, Jacobson F (2014) Statistical modeling of the drug load distribution on trastuzumab emtansine (Kadcyla), a lysine-linked antibody drug conjugate. Bioconjug Chem 25:1223–1232CrossRefPubMedGoogle Scholar
  44. 44.
    Strop P, Liu SH, Dorywalska M, Delaria K, Dushin RG, Tran TT et al (2013) Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol 20:161–167CrossRefPubMedGoogle Scholar
  45. 45.
    Shen BQ, Xu K, Liu L, Raab H, Bhakta S, Kenrick M et al (2012) Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol 30:184–189CrossRefPubMedGoogle Scholar
  46. 46.
    Tijink BM, Buter J, de Bree R, Giaccone G, Lang MS, Staab A et al (2008) A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res 12(20 Pt 1):6064–6072Google Scholar
  47. 47.
    Riechelmann H, Sauter A, Golze W, Hanft G, Schroen C, Hoermann K et al (2008) Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma. Oral Oncol 44(9):823CrossRefGoogle Scholar
  48. 48.
    Fox SB, Fawcett J, Jackson DG, Collins I, Gatter KC, Harris AL et al (1994) Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms. Cancer Res 54:4539–4546PubMedGoogle Scholar
  49. 49.
    Tolcher AW, Ochoa L, Hammond LA, Patnaik A, Edwards T, Takimoto C et al (2003) Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study. J Clin Oncol 21:211–222CrossRefPubMedGoogle Scholar
  50. 50.
    Ott PA, Hamid O, Pavlick AC, Kluger H, Kim KB, Boasberg PD et al (2014) Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma. J Clin Oncol 32:3659–3666CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Rose AAN, Biondini M, Curiel R, Siegel PM (2017) Targeting GPNMB with glembatumumab vedotin: current developments and future opportunities for the treatment of cancer. Pharmacol Ther 179:127–141CrossRefPubMedGoogle Scholar
  52. 52.
    Tomihari M, Hwang SH, Chung JS, Cruz PD Jr, Ariizumi K (2009) Gpnmb is a melanosome-associated glycoprotein that contributes to melanocyte/keratinocyte adhesion in a RGD-dependent fashion. Exp Dermatol 18:586–595CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Naumovski L, Junutula JR (2010) Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer. Curr Opin Mol Ther 12:248–257PubMedGoogle Scholar
  54. 54.
    Press MF, Cordon-Cardo C, Slamon DJ (1990) Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 5:953–962PubMedGoogle Scholar
  55. 55.
    Peddi PF, Hurvitz SA (2014) Ado-trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer: latest evidence and clinical potential. Ther Adv Med Oncol 6:202–209CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Stathis A, Freedman AS, Flinn IW, Maddocks KJ, Weitman S, Berdeja JG et al (2014) A phase I study of IMGN529, an antibody-drug conjugate (ADC) targeting CD37, in adult patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Blood 124:1760. [abstract]Google Scholar
  57. 57.
    Weekes CD, Lamberts LE, Borad MJ, Voortman J, McWilliams RR, Diamond JR et al (2016) Phase I study of DMOT4039A, an antibody-drug conjugate targeting mesothelin, in patients with unresectable pancreatic or platinum-resistant ovarian cancer. Mol Cancer Ther 15:439–447CrossRefGoogle Scholar
  58. 58.
    Xu H, Bai L, Collins JF, Ghishan FK (1999) Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodium-phosphate (Na+-Pi) transporter (SLC34A2). Genomics 62:281–284CrossRefPubMedGoogle Scholar
  59. 59.
    Traebert M, Hattenhauer O, Murer H, Kaissling B, Biber J (1999) Expression of type II Na-P(i) cotransporter in alveolar type II cells. Am J Phys 277:L868–L873Google Scholar
  60. 60.
    Burris HA, Gordon MS, Gerber DE, Spigel DR, Mendelson SD, Schiller JH et al (2014) A phase I study of DNIB0600A, an antibody-drug conjugate targeting NaPi2b, in patients with non-small cell lung cancer (NSCLC) or platinum-resistant ovarian cancer (OC). J Clin Oncol 32:5s. (suppl; abstr 2504)Google Scholar
  61. 61.
    Bodyak N, Yurkovetskiy A, Yin M, Gumerov D, Bollu R, Conlon P, et al (2016) Discovery and preclinical development of a highly potent NaPi2b-targeted antibody-drug conjugate (ADC) with significant activity in patient-derived non-small cell lung cancer (NSCLC) xenograft models. In: Proceedings of the 107th annual meeting of the American Association for Cancer Research, 16–20 Apr 2016, New Orleans. Cancer Res 76 (14 Suppl): Abstract nr 1194CrossRefGoogle Scholar
  62. 62.
    Almhanna K, Kalebic T, Cruz C, Faris JE, Ryan DP, Jung J et al (2016) Phase I study of the investigational anti-guanylyl cyclase antibody-drug conjugate TAK-264 (MLN0264) in adult patients with advanced gastrointestinal malignancies. Clin Cancer Res 22:5049–5057CrossRefPubMedGoogle Scholar
  63. 63.
    Yardley DA, Weaver R, Melisko ME, Saleh MN, Arena FP, Forero A et al (2015) EMERGE: a randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. J Clin Oncol 33:1609–1619CrossRefPubMedGoogle Scholar
  64. 64.
    Modi S, Eder JP, Lorusso P, Weekes C, Chandarlapaty S, Tolaney SM et al (2016) A phase I study evaluating DLYE5953A, an antibody-drug conjugate targeting the tumor-associated antigen lymphocyte antigen 6 complex locus E (Ly6E), in patients with solid tumors. Ann Oncol 27(Suppl 6):abstract nr 3570Google Scholar
  65. 65.
    Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ et al (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30:2183–2189CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Advani RH, Lebovic D, Chen A, Brunvand M, Goy A, Chang JE et al (2017) Phase I study of the anti-CD22 antibody-drug conjugate pinatuzumab vedotin with/without rituximab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 23:1167–1176CrossRefPubMedGoogle Scholar
  67. 67.
    Palanca-Wessels MC, Czuczman M, Salles G, Assouline S, Sehn LH, Flinn I et al (2015) Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 16:704–715CrossRefPubMedGoogle Scholar
  68. 68.
    Tannir NM, Forero-Torres A, Ramchandren R, Pal SK, Ansell SM, Infante JR et al (2014) Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Investig New Drugs 32:1246–1257CrossRefGoogle Scholar
  69. 69.
    Gan HK, Reardon DA, Lassman AB, Merrell R, van den Bent M, Butowski N et al (2017) Safety, pharmacokinetics and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma. Neuro Oncol.  https://doi.org/10.1093/neuonc/nox202. [Epub ahead of print]
  70. 70.
    Thompson JA, Motzer R, Molina AM, Choueiri TK, Heath EI, Kollmannsberger CK et al (2015) Phase I studies of anti-ENPP3 antibody drug conjugates (ADCs) in advanced refractory renal cell carcinomas (RRCC). J Clin Oncol 33:2503CrossRefGoogle Scholar
  71. 71.
    Reardon DA, Lassman AB, van den Bent M, Kumthekar P, Merrell R, Scott AM et al (2017) Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma. Neuro-Oncology 19:965–975PubMedGoogle Scholar
  72. 72.
    Fathi AT, Borate U, DeAngelo DJ, O’Brien MM, Trippett T, Shah BD et al (2015) A phase 1 study of denintuzumab mafodotin (SGN-CD19A) in adults with relapsed or refractory B-lineage acute leukemia (B-ALL) and highly aggressive lymphoma. Blood 126:1328Google Scholar
  73. 73.
    Force J, Saxena R, Schneider BP, Storniolo AM, Sledge GW Jr, Chalasani N et al (2016) Nodular regenerative hyperplasia after treatment with trastuzumab emtansine. J Clin Oncol 34:e9-12CrossRefPubMedGoogle Scholar
  74. 74.
    Prochaska LH, Damjanov I, Ash RM, Olson JC, Khan QJ, Sharma P (2016) Trastuzumab emtansine associated nodular regenerative hyperplasia: a case report and review of literature. Cancer Treatment Commun 5:26–30CrossRefGoogle Scholar
  75. 75.
    Gan HK, van den Bent M, Lassman AB, Reardon DA, Scott AM (2017) Antibody-drug conjugates in glioblastoma therapy: the right drugs to the right cells. Nat Rev Clin Oncol 14:695–707CrossRefPubMedGoogle Scholar
  76. 76.
    Younes A, Kim S, Romaquera J, Copeland A, Farial S de C, Kwak LW et al (2012) 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 30:2776–2782CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Moore KN, Borghaei H, O’Malley DM, Jeong W, Seward SM, Bauer TM et al (2017) Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors. Cancer 123:3080–3087CrossRefPubMedGoogle Scholar
  78. 78.
    Mita MM, Ricart AD, Mita AC, Patnaik A, Sarantopoulos J, Sankhala K et al (2007) A phase I study of a CanAg-targeted immunoconjugate, huC242-DM4, in patients with Can Ag-expressing solid tumors. J Clin Oncol 25:3062Google Scholar
  79. 79.
    Advani A, Coiffier B, Czuczman MS, Dreyling M, Foran J, Gine E et al (2010) Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol 28:2085–2093CrossRefPubMedGoogle Scholar
  80. 80.
    Kantarjian HM, DeAngelo DJ, Advani AS, Stelljes M, Kebriaei P, Cassaday RD et al (2017) Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol 4:e387–e398CrossRefPubMedGoogle Scholar
  81. 81.
    Rudin CM, Pietanza C, Bauer TM, Ready N, Morgensztern D, Glisson BS et al (2017) 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 18:42–51CrossRefPubMedGoogle Scholar
  82. 82.
    Bender BC, Schaedeli-Stark F, Koch R, Joshi A, Chu YW, Rugo H et al (2012) 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 70:591–601CrossRefPubMedGoogle Scholar
  83. 83.
    Bardia A, Mayer IA, Diamond JR, Moroose RL, Isakoff SJ, Starodub AN et al (2017) 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 35:2141–2148CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W et al (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 28:2698–2704CrossRefPubMedGoogle Scholar
  85. 85.
    Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Uppal H, Doudement E, Mahapatra K, Darbonne WC, Bumbaca D, Shen B-Q et al (2015) Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1). Clin Cancer Res 21:123–133CrossRefPubMedGoogle Scholar
  87. 87.
    Zhao H, Gulesserian S, Ganesan SK, Ou J, Morrison K, Zeng Z et al (2017) Inhibition of megakaryocyte differentiation by antibody-drug conjugates (ADCs) is mediated by macropinocytosis: implications for ADC-induced thrombocytopenia. Mol Cancer Ther 16:1877–1886CrossRefPubMedGoogle Scholar
  88. 88.
    Hartleb M, Gutkowski K, Milkiewicz P (2011) Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension. World J Gastroenterol 17:1400–1409CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A et al (2013) BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. B J Haematol 163:444–457CrossRefGoogle Scholar
  90. 90.
    Wanless IR, Huang W-Y (2012) Vascular disorders. In: Burt A, Portmann B, Ferrell L (eds) MacSween’s pathology of the liver, 6th edn. Churchill Livingstone/Elsevier, Edinburgh, pp 601–643CrossRefGoogle Scholar
  91. 91.
    Rubbia-Brandt L, Lauwers GY, Wang H, Majno PE, Tanabe K, Zhu AX et al (2010) Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology 56:430–439CrossRefPubMedGoogle Scholar
  92. 92.
    Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL et al (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812–1821CrossRefPubMedGoogle Scholar
  93. 93.
    Grisold W, Cavaletti G, Windebank AJ (2012) Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro-Oncology 14(Suppl 4):iv45–iv54CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Stagg NJ, Shen BQ, Brunstein F, Li C, Kamath AV, Zhong F et al (2016) Peripheral neuropathy with microtubule inhibitor containing antibody drug conjugates: challenges and perspectives in translatability from nonclinical toxicology studies to the clinic. Regul Toxicol Pharmacol 82:1–13CrossRefPubMedGoogle Scholar
  95. 95.
    Eaton JS, Miller PE, Mannis MJ, Murphy CJ (2015) Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther 31:589–604CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Stentoft J (1990) The toxicity of cytarabine. Drug Saf 1:7–27CrossRefGoogle Scholar
  97. 97.
    Hopen G, Mondino BJ, Johnson BL, Chervenick PA (1981) Corneal toxicity with systemic cytarabine. Am J Ophthalmol 91(4):500CrossRefPubMedGoogle Scholar
  98. 98.
    Stein EM, Stein A, Walter RB, Fathi AT, Lancet JE, Kovacsovics TJ et al (2014) Interim analysis of a phase 1 trial of SGN-CD33A in patients with CD33-positive acute myeloid leukemia (AML). Blood 124:623. (abstract)CrossRefGoogle Scholar
  99. 99.
    Hochhauser D, Meyer T, Spanswick VJ, Wu J, Clingen PH, Loadman P et al (2009) Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. Clin Cancer Res 15:2140–2147CrossRefPubMedGoogle Scholar
  100. 100.
    Owonikoko TK, Hussain A, Stadler WM, Smith DC, Kluger H, Molina AM et al (2016) First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70. Cancer Chemother Pharmacol 77:155–162CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Magali Guffroy
    • 1
  • Hadi Falahatpisheh
    • 2
  • Martin Finkelstein
    • 1
  1. 1.Pfizer Inc, Drug Safety Research and DevelopmentPearl RiverUSA
  2. 2.Preclinical Safety Oncology, AbbVie Stemcentrx LLCSouth San FranciscoUSA

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