Next Generation Payloads for ADCs

  • L. Nathan TumeyEmail author
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The clinical success of gemtuzumab ozogamicin, brentuximab vedotin and ado-trastuzumab emtansine has spurred significant investment into new ADC payloads that may expand the utility of ADC technology. Innovations in the past 5–10 years have resulted in the identification of new payloads that are overcoming resistance mechanisms, showing efficacy against slow growing tumors, and enabling the use of biomarkers to better understand ADC PK/PD relationships. Moreover, ADC technology is now enabling the delivery of steroids, anti-inflammatory agents, and anti-infectives to specific cell types.


Antibody drug conjugate Targeted drug delivery ADC payload Oncology Tubulin Calicheamicin Spliceosome RNA-polymerase Glucocorticoid 


  1. 1.
    Perez HL, Cardarelli PM, Deshpande S et al (2014) Antibody-drug conjugates: current status and future directions. Drug Discov Today 19:869–881. CrossRefPubMedGoogle Scholar
  2. 2.
    Ricart AD (2011) Antibody-drug conjugates of calicheamicin derivative: Gemtuzumab ozogamicin and inotuzumab ozogamicin. Clin Cancer Res 17:6417–6427. CrossRefPubMedGoogle Scholar
  3. 3.
    Terriou L, Bonnet S, Debarri H et al (2013) Brentuximab vedotin: new treatment for CD30+ lymphomas. Bull Cancer 100:775–779. CrossRefPubMedGoogle Scholar
  4. 4.
    Corrigan PA, Cicci TA, Auten JJ, Lowe DK (2014) Ado-trastuzumab emtansine: a HER2-positive targeted antibody-drug conjugate. Ann Pharmacother 48:1484–1493CrossRefPubMedGoogle Scholar
  5. 5.
    Mendelsohn BA, Barnscher SD, Snyder JT et al (2017) Investigation of hydrophilic Auristatin derivatives for use in antibody drug conjugates. Bioconjug Chem 28:371–381. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lyon RP, Bovee TD, Doronina SO et al (2015) Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol 33:733–736. CrossRefPubMedGoogle Scholar
  7. 7.
    Maderna A, Doroski M, Subramanyam C et al (2014) Discovery of cytotoxic Dolastatin 10 analogues with N-terminal modifications. J Med Chem 57:10527–10543. CrossRefPubMedGoogle Scholar
  8. 8.
    Damelin M, Bankovich A, Bernstein J et al (2017) A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci Transl Med 9:1–12. CrossRefGoogle Scholar
  9. 9.
    Tumey LN, Li F, Rago B et al (2017) Site selection: a case study in the identification of optimal cysteine engineered antibody drug conjugates. AAPS J 19:1123–1135. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Strop P, Tran T-T, Dorywalska M et al (2016) RN927C, a site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther 15:2698–2708. CrossRefPubMedGoogle Scholar
  11. 11.
    Geierstanger J, Grunewald B, Yunho OW, et al (2015) Cytotoxic Peptides and Conjugates Thereof. WO2015/95301Google Scholar
  12. 12.
    Murray BC, Peterson MT, R a F (2015) Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers. Nat Prod Rep 32:654. CrossRefPubMedGoogle Scholar
  13. 13.
    Reddy JA, Dorton R, Dawson A et al (2009) In vivo structural activity and optimization studies of folate-tubulysin conjugates. Mol Pharm 6:1518–1525. CrossRefPubMedGoogle Scholar
  14. 14.
    Kularatne SA, Venkatesh C, Santhapuram HK et al (2010) Synthesis and biological analysis of prostate-specific membrane antigen-targeted anticancer prodrugs. J Med Chem 53:7767–7777. CrossRefGoogle Scholar
  15. 15.
    Leverett CA, Sukuru SCK, Vetelino BC et al (2016) Design, synthesis, and cytotoxic evaluation of novel Tubulysin analogs as ADC payloads. ACS Med Chem Lett. acsmedchemlett.6b00274.
  16. 16.
    Nathan Tumey L, Leverett CA, Vetelino B et al (2016) Optimization of Tubulysin antibody-drug conjugates: a case study in addressing ADC metabolism. ACS Med Chem Lett 7:977–982. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cong Q, Cheng H, Gangwar S (2014) Preparation of antimitotic compounds structurally related to tubulysins and their conjugates for targeted delivery and their use for treating cancers. US2014/0227295Google Scholar
  18. 18.
    Li JY, Perry SR, Muniz-Medina V et al (2016) A Biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29:117–129. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kovtun YV, Audette CA, Mayo MF et al (2010) Antibody-maytansinoid conjugates designed to bypass multidrug resistance. Cancer Res 70:2528–2537. CrossRefPubMedGoogle Scholar
  20. 20.
    Pillow TH, Tien J, Parsons-Reponte KL et al (2014) Site-specific trastuzumab maytansinoid antibody-drug conjugates with improved therapeutic activity through linker and antibody engineering. J Med Chem 57:7890–7899. CrossRefPubMedGoogle Scholar
  21. 21.
    Widdison WC, Ponte JF, Coccia JA et al (2015) Development of Anilino-Maytansinoid ADCs that efficiently release cytotoxic metabolites in cancer cells and induce high levels of bystander killing. Bioconjug Chem 26:2261–2278. CrossRefPubMedGoogle Scholar
  22. 22.
    Steinkuhler MC, Gallinari MP, Osswald B et al (2016) Cryptophycin-based antibody-drug conjugates with novel self-immolative linkers. WO2016146638A1Google Scholar
  23. 23.
    Bernardes Goncalo JL, Casi G, Trussel S et al (2012) A traceless vascular-targeting antibody-drug conjugate for cancer therapy. Angew Chem Int Ed Engl 51:941–944CrossRefPubMedGoogle Scholar
  24. 24.
    Liang ZX (2010) Complexity and simplicity in the biosynthesis of enediyne natural products. Nat Prod Rep 27:499–528. CrossRefPubMedGoogle Scholar
  25. 25.
    Damelin M, Bankovich A, Park A et al (2015) Anti-EFNA4 calicheamicin conjugates effectively target triple-negative breast and ovarian tumor-initiating cells to result in sustained tumor regressions. Clin Cancer Res 21:4165–4173. CrossRefPubMedGoogle Scholar
  26. 26.
    Jain N, O’Brien S, Thomas D, Kantarjian H (2014) Inotuzumab ozogamicin in the treatment of acute lymphoblastic leukemia. Front Biosci (Elite Ed) 6:40–45Google Scholar
  27. 27.
    Pilorge S, Rigaudeau S, Rabian F et al (2014) Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse. Am J Hematol 89:399–403. CrossRefPubMedGoogle Scholar
  28. 28.
    Gavrilyuk J, Sisodiya, Vikram N (2016) Calicheamicin Constructs and Methods of Use. WO/2016/172273Google Scholar
  29. 29.
    Donaghy H (2016) Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs 8:659–671. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Chowdari NS, Gangwar S, Sufi B (2013) Enediyne compounds, conjugates thereof, and uses and methods thereof. WO/2013/122823Google Scholar
  31. 31.
    Mantaj J, Jackson PJM, Rahman KM, Thurston DE (2017) From Anthramycin to Pyrrolobenzodiazepine (PBD)-containing antibody–drug conjugates (ADCs). Angew Chem Int Ed 56:462–488. CrossRefGoogle Scholar
  32. 32.
    Jeffrey SC, Burke PJ, Lyon RP et al (2013) A potent anti-CD70 antibody-drug conjugate combining a Dimeric Pyrrolobenzodiazepine drug with site-specific conjugation technology. Bioconjug Chem 24:1256–1263. CrossRefPubMedGoogle Scholar
  33. 33.
    Sutherland MSK, Walter RB, Jeffrey SC et al (2013) SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 122:1455–1463. CrossRefGoogle Scholar
  34. 34.
    Sutherland MSK, Yu C, Walter RB et al (2015) SGN-CD123A, a Pyrrolobenzodiazepine dimer linked anti-CD123 antibody drug conjugate, demonstrates effective anti-leukemic activity in multiple preclinical models of AML. Blood 126:330Google Scholar
  35. 35.
    Lewis T, Olson DJ, Gordon KA et al (2016) Abstract 1195: SGN-CD352A: a novel humanized anti-CD352 antibody-drug conjugate for the treatment of multiple myeloma. Cancer Res 76:1195–1195. CrossRefGoogle Scholar
  36. 36.
    Takeshita A (2013) Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia. Int J Hematol 97:703–716. CrossRefPubMedGoogle Scholar
  37. 37.
    Cianfriglia M (2013) The biology of MDR1-P-glycoprotein (MDR1-Pgp) in designing functional antibody drug conjugates (ADCs): the experience of gemtuzumab ozogamicin. Ann Ist Super Sanita 49:150–168. CrossRefPubMedGoogle Scholar
  38. 38.
    Tiberghien AC, Levy JN, Masterson LA et al (2016) Design and synthesis of Tesirine, a clinical antibody-drug conjugate Pyrrolobenzodiazepine dimer payload. ACS Med Chem Lett 7:983–987. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Saunders LR, Bankovich AJ, Anderson WC et al (2015) A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo HHS public access. Sci Transl Med 7:302–136. CrossRefGoogle Scholar
  40. 40.
    Flynn MJ, Zammarchi F, Tyrer PC et al (2016) ADCT-301, a Pyrrolobenzodiazepine (PBD) dimer-containing antibody-drug conjugate (ADC) targeting CD25-expressing hematological malignancies. Mol Cancer Ther 15:2709–2721. CrossRefPubMedGoogle Scholar
  41. 41.
    Miller ML, Fishkin NE, Li W et al (2016) A new class of antibody-drug conjugates with potent DNA alkylating activity. Mol Cancer Ther 15:1870–1878. CrossRefPubMedGoogle Scholar
  42. 42.
    Zhao RY, Wilhelm SD, Audette C et al (2011) Synthesis and evaluation of hydrophilic linkers for antibody-Maytansinoid conjugates. J Med Chem 54:3606–3623. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ma Y, Khojasteh SC, Hop CECA et al (2016) Antibody drug conjugates differentiate uptake and DNA alkylation of pyrrolobenzodiazepines in tumors from organs of xenograft mice. Drug Metab Dispos 44:1958–1962. CrossRefPubMedGoogle Scholar
  44. 44.
    Thevanayagam L, Bell A, Chakraborty I et al (2013) Novel detection of DNA-alkylated adducts of antibody-drug conjugates with potentially unique preclinical and biomarker applications. Bioanalysis 5:1073–1081. CrossRefPubMedGoogle Scholar
  45. 45.
    Carter CA, Waud WR, Li LH et al (1996) Preclinical antitumor activity of bizelesin in mice. Clin Cancer Res 2:1143–1149PubMedGoogle Scholar
  46. 46.
    Chari RVJ, Jackel KA, Bourret LA et al (1995) Enhancement of the selectivity and antitumor efficacy of a CC-1065 analog through immunoconjugate formation. Cancer Res 55:4079–4084PubMedGoogle Scholar
  47. 47.
    Zhao RY, Erickson HK, Leece BA et al (2012) Synthesis and biological evaluation of antibody conjugates of phosphate prodrugs of cytotoxic DNA alkylators for the targeted treatment of cancer. J Med Chem 55:766–782. CrossRefPubMedGoogle Scholar
  48. 48.
    Tumey LN, Rago B, Han X (2015) In vivo biotransformations of antibody-drug conjugates. Bioanalysis 7:1649–1664. CrossRefPubMedGoogle Scholar
  49. 49.
    Owonikoko TK, Hussain A, Stadler WM et al (2016) First-in-human multicenter phase i study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70. Cancer Chemother Pharmacol 77:155–162. CrossRefPubMedGoogle Scholar
  50. 50.
    Dokter W, Ubink R, van der Lee M et al (2014) Preclinical profile of the HER2-targeting ADC SYD983/SYD985: introduction of a new duocarmycin-based linker-drug platform. Mol Cancer Ther 13:2618–2629. CrossRefPubMedGoogle Scholar
  51. 51.
    van der Lee MMC, Groothuis PG, Ubink R et al (2015) The preclinical profile of the Duocarmycin-based HER2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers. Mol Cancer Ther 14:692–703. CrossRefPubMedGoogle Scholar
  52. 52.
    O’Donnell CJ Discovery of Novel Linker payloads and antibody drug conjugates for the treatment of cancer. Accessed 28 Mar 2017
  53. 53.
    Maderna A, Subramanyam C, Tumey LN, et al (2016) Preparation of bifunctional cytotoxic agents containing the CTI pharmacophore including dimers and antibody conjugates for treating cancer. WO/2016/151432Google Scholar
  54. 54.
    Trail PA, Willner D, Lasch SJ et al (1993) Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 261:212–215. CrossRefPubMedGoogle Scholar
  55. 55.
    Burke PJ, Senter PD, Meyer DW et al (2009) Design, synthesis , and biological evaluation of antibody - drug conjugates comprised of potent Camptothecin analogues. Bioconjug Chem 20:1242–1250CrossRefPubMedGoogle Scholar
  56. 56.
    Nakada T, Masuda T, Naito H et al (2016) Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett 26:1542–1545. CrossRefPubMedGoogle Scholar
  57. 57.
    Ogitani Y, Hagihara K, Oitate M et al (2016) 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 107:1039–1046. CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Tamura K, Shitara K, Naito Y et al (2016) Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in breast cancer patients previously treated with T-DM1: phase 1 dose escalation. Ann Oncol 27:552–587. CrossRefGoogle Scholar
  59. 59.
    Cardillo TM, Govindan SV, Sharkey RM et al (2015) Sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate: characterization and efficacy in pancreatic, gastric, and other cancers. Bioconjug Chem 26:919–931. CrossRefPubMedGoogle Scholar
  60. 60.
    Govindan SV, Cardillo TM, Sharkey RM et al (2013) Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers. Mol Cancer Ther 12:968–978. CrossRefPubMedGoogle Scholar
  61. 61.
    Sharkey RM, Govindan SV, Cardillo TM, Goldenberg DM (2012) Epratuzumab-SN-38: a new antibody-drug conjugate for the therapy of hematologic malignancies. Mol Cancer Ther 11:224–234. CrossRefPubMedGoogle Scholar
  62. 62.
    Cardillo TM, Govindan SV, Sharkey RM et al (2011) 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 17:3157–3169. CrossRefPubMedGoogle Scholar
  63. 63.
    Starodub AN, Ocean AJ, Shah MA et al (2015) First-in-human trial of a novel anti-trop-2 antibody-SN-38 conjugate, sacituzumab govitecan, for the treatment of diverse metastatic solid tumors. Clin Cancer Res 21:3870–3878. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Yu SF, Zheng B, Go M et al (2015) A novel anti-CD22 anthracycline-based antibody-drug conjugate (ADC) that overcomes resistance to auristatin-based ADCs. Clin Cancer Res 21:3298–3306. CrossRefPubMedGoogle Scholar
  65. 65.
    Stefan N, Gébleux R, Waldmeier L et al (2017) Highly potent, Anthracycline-based antibody-drug conjugates generated by enzymatic, site-specific conjugation. Mol Cancer Ther 16:879–892. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Hennessy EJ (2016) Selective inhibitors of Bcl-2 and Bcl-xL: balancing antitumor activity with on-target toxicity. Bioorg Med Chem Lett 26:2105–2114. CrossRefPubMedGoogle Scholar
  67. 67.
    Tao Z-F, Doherty G, Wang X, et al (2016) Preparation of Bcl-xL inhibitory compounds having low cell permeability and antibody drug conjugates containing them. WO2016094509 A1Google Scholar
  68. 68.
    Ackler SL, Bennett NB, Boghaert ER, et al (2016) Bcl-xl inhibitory compounds and antibody drug conjugates including the same. US20160158377A1Google Scholar
  69. 69.
    He H, Ratnayake AS, Janso JE et al (2014) Cytotoxic spliceostatins from Burkholderia sp. and their semisynthetic analogs. J Nat Prod 77:1864–1870. CrossRefPubMedGoogle Scholar
  70. 70.
    Moldenhauer G, Salnikov AV, Lüttgau S et al (2012) Therapeutic potential of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against pancreatic carcinoma. J Natl Cancer Inst 104:622–634. CrossRefPubMedGoogle Scholar
  71. 71.
    Grunewald J, Jin Y, Ou W, Uno T (2016) Preparation of amatoxin derivatives and their immunoconjugates as inhibitors of RNA polymerase for treating cell proliferative disorders. WO2016071856 A1Google Scholar
  72. 72.
    Mendelsohn BA, Moon SJ (2013) Amatoxin derivatives and cell-permeable conjugates thereof as inhibitors of rna polymerase. WO2014043403 A1Google Scholar
  73. 73.
    Muller C, Anderl J, Simon W, et al (2014) Amatoxin derivatives. WO/2014/135282Google Scholar
  74. 74.
    Lerchen H-G, Wittrock S, Cancho Grande Y, et al (2016) Preparation of antibody-drug conjugates (ADCS) of KSP inhibitors with aglycosylated anti-TWEAKR antibodies. WO2016096610 A1Google Scholar
  75. 75.
    Marshall DJ, Harried SS, Murphy JL et al (2016) Extracellular antibody drug conjugates exploiting the proximity of two proteins. Mol Ther 24:1760–1770. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Graversen JH, Svendsen P, Dagnæs-Hansen F et al (2012) Targeting the hemoglobin scavenger receptor CD163 in macrophages highly increases the anti-inflammatory potency of dexamethasone. Mol Ther 20:1550–1558. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Granfeldt A, Hvas CL, Graversen JH et al (2013) Targeting dexamethasone to macrophages in a porcine endotoxemic model. Crit Care Med 41:e309–e318. CrossRefPubMedGoogle Scholar
  78. 78.
    Thomsen KL, Møller HJ, Graversen JH et al (2016) Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats. World J Hepatol 8:726–730. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Moller LN, Knudsen AR, Andersen KJ et al (2015) Anti-CD163-dexamethasone protects against apoptosis after ischemia/reperfusion injuries in the rat liver. Ann Med Surg 4:331–337. CrossRefGoogle Scholar
  80. 80.
    Kern JC, Cancilla M, Dooney D et al (2016) Discovery of pyrophosphate Diesters as tunable, soluble, and bioorthogonal linkers for site-specific antibody-drug conjugates. J Am Chem Soc 138:1430–1445. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Kern JC, Dooney D, Zhang R et al (2016) Novel phosphate modified Cathepsin B linkers: improving aqueous solubility and enhancing payload scope of ADCs. Bioconjug Chem 27:2081–2088. CrossRefPubMedGoogle Scholar
  82. 82.
    Wang RE, Liu T, Wang Y et al (2015) An immunosuppressive antibody-drug conjugate. J Am Chem Soc 137:3229–3232. CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Lim RKV, Yu S, Cheng B et al (2015) Targeted delivery of LXR agonist using a site-specific antibody-drug conjugate. Bioconjug Chem 26:2216–2222. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Lehar SM, Pillow T, Xu M et al (2015) Novel antibody–antibiotic conjugate eliminates intracellular S. aureus. Nature 527:323–328. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Sugo T, Terada M, Oikawa T et al (2016) Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release 237:1–13. CrossRefPubMedGoogle Scholar
  86. 86.
    Cuellar TL, Barnes D, Nelson C et al (2015) Systematic evaluation of antibody-mediated siRNA delivery using an industrial platform of THIOMAB-siRNA conjugates. Nucleic Acids Res 43:1189–1203. CrossRefPubMedGoogle Scholar
  87. 87.
    Chari RVJ (2016) Expanding the reach of antibody-drug conjugates. ACS Med Chem Lett 7:974–976. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Binghamton UniversityBinghamtonUSA

Personalised recommendations