Next Horizons: ADCs Beyond Oncology

  • Shan Yu
  • Andrew Lim
  • Matthew S. TremblayEmail author
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Most ADCs developed thus far have been explored for oncology indications. Emerging ADC technologies present many opportunities to apply the modality beyond oncology. The key variables for oncology ADCs in terms of the targeted cell type, targeting strategy, and payload are often clearer while the corresponding elements for non-oncology indications are more complex. Challenges in designing such non-oncology ADCs include selecting the targeting cell type(s) from among potentially several contributing to the disease, a distinct surface marker expressed on the targeting cells, which often overlaps healthy cells, and a potent, non-cytotoxic payload drug. So far, only a few ADCs were designed for non-oncology indications, with none yet successfully progressing through clinical trials. Here, we summarize those that have been reported. In addition, we discuss some considerations to be taken into account for designing ADCs for non-oncology indications, including payload and antibody selection. With the evolution of ADC platform and technology, more ADCs for non-oncology indications are yet to be developed.


Non-oncology ADC Inflammation Anti-inflammatory Steroid Anti-infective Antibiotic Antibiotic-antibody conjugate Payload selection Antigen selection Antibody-drug conjugate 


  1. 1.
    Akassoglou K, Douni E, Bauer J, Lassmann H, Kollias G, Probert L (2003) Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice. Proc Natl Acad Sci 100:709–714CrossRefPubMedGoogle Scholar
  2. 2.
    Ashley JW, Shi Z, Zhao H, Li X, Kesterson RA, Feng X (2011) Genetic ablation of CD68 results in mice with increased bone and dysfunctional osteoclasts. PLoS One 6:e25838CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Balagué C, Kunkel SL, Godessart N (2009) Understanding autoimmune disease: new targets for drug discovery. Drug Discov Today 14:926–934CrossRefPubMedGoogle Scholar
  4. 4.
    Baumer S, Baumer N, Appel N, Terheyden L, Fremerey J, Schelhaas S, Wardelmann E, Buchholz F, Berdel WE, Muller-Tidow C (2015) Antibody-mediated delivery of anti-KRAS-siRNA in vivo overcomes therapy resistance in Colon Cancer. Clin Cancer Res 21:1383–1394CrossRefPubMedGoogle Scholar
  5. 5.
    Bergamaschi G, Perfetti V, Tonon L, Novella A, Lucotti C, Danova M, Glennie MJ, Merlini G, Cazzola M (1996) Saporin, a ribosome-inactivating protein used to prepare immunotoxins, induces cell death via apoptosis. Br J Haematol 93:789–794CrossRefPubMedGoogle Scholar
  6. 6.
    Bornstein GG (2015) Antibody drug conjugates: preclinical considerations. AAPS J 17:525–534CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bover LC, Cardó-Vila M, Kuniyasu A, Sun J, Rangel R, Takeya M, Aggarwal BB, Arap W, Pasqualini R (2007) A Previously Unrecognized Protein-Protein Interaction between TWEAK and CD163: Potential Biological Implications. J Immunol 178(12):8183–8194. CrossRefPubMedGoogle Scholar
  8. 8.
    Chittasupho C, Siahaan TJ, Vines CM, Berkland C (2011) Autoimmune therapies targeting costimulation and emerging trends in multivalent therapeutics. Ther Deliv 2:873–889CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D’Haens G, Panaccione R, Loftus EV, Sankoh S, Fox I, et al (2016) The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut gutjnl-2015-311079Google Scholar
  10. 10.
    Conchon M, Freitas CMB d M, Rego MA d C, Braga Junior JWR (2010) Dasatinib. Rev Bras Hematol E Hemoter 33:131–139CrossRefGoogle Scholar
  11. 11.
    Deora A, Hegde S, Lee J, Choi C-H, Chang Q, Lee C, Eaton L, Tang H, Wang D, Lee D et al (2017) Transmembrane TNF-dependent uptake of anti-TNF antibodies. MAbs 9:680–695CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Evans BJ, Haskard DO, Sempowksi G, Landis RC (2013) Evolution of the macrophage CD163 phenotype and cytokine profiles in a human model of resolving inflammation. Int J Inflamm 2013:1–9CrossRefGoogle Scholar
  13. 13.
    Fabriek BO, Van Bruggen R, Deng DM, Ligtenberg AJ, Nazmi K, Schornagel K, Vloet RP, Dijkstra CD, van den Berg TK. The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria. Blood 2009 113(4):887-892. doi: Scholar
  14. 14.
    Gautam N, Puligujja P, Balkundi S, Thakare R, Liu X-M, Fox HS, McMillan J, Gendelman HE, Alnouti Y (2014) Pharmacokinetics, biodistribution, and toxicity of folic acid-coated antiretroviral Nanoformulations. Antimicrob Agents Chemother 58:7510–7519CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Gent YY, Weijers K, Molthoff CF, Windhorst AD, Huisman MC, Smith DE, Kularatne SA, Jansen G, Low PS, Lammertsma AA et al (2013) Evaluation of the novel folate receptor ligand [18F]fluoro-PEG-folate for macrophage targeting in a rat model of arthritis. Arthritis Res Ther 15:R37CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke PA, Garovoy M (2002) Psoriasis as a model for T-cell–mediated disease: Immunobiologic and clinical effects of treatment with multiple doses of Efalizumab, an anti–CD11a antibody. Arch Dermatol 138:591CrossRefPubMedGoogle Scholar
  17. 17.
    Graversen JH, Moestrup SK (2015) Drug Trafficking into Macrophages via the Endocytotic Receptor CD163. Membranes (Basel) 5(2):228–252. CrossRefGoogle Scholar
  18. 18.
    Graversen JH, Svendsen P, Dagnæs-Hansen F, Dal J, Anton G, Etzerodt A, Petersen MD, Christensen PA, Møller HJ, Moestrup SK (2012) Targeting the hemoglobin scavenger receptor CD163 in macrophages highly increases the anti-inflammatory potency of dexamethasone. Mol Ther 20:1550–1558CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Han W, Zaynagetdinov R, Yull FE, Polosukhin VV, Gleaves LA, Tanjore H, Young LR, Peterson TE, Manning HC, Prince LS et al (2015) Molecular imaging of folate receptor β–positive macrophages during acute lung inflammation. Am J Respir Cell Mol Biol 53:50–59CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hauser PV, Pippin JW, Kaiser C, Krofft RD, Brinkkoetter PT, Hudkins KL, Kerjaschki D, Reiser J, Alpers CE, Shankland SJ (2010) Novel siRNA delivery system to target Podocytes in vivo. PLoS One 5:e9463CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hoepner R, Faissner S, Salmen A, Gold R, Chan A (2014) Efficacy and side effects of Natalizumab therapy in patients with multiple sclerosis. J Cent Nerv Syst Dis 6:41CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Jager, N.A., Westra, J., Golestani, R., van Dam, G.M., Low, P.S., Tio, R.A., Slart, R.H.J.A., Boersma, H.H., Bijl, M., and Zeebregts, C.J. (2014). Folate receptor- imaging using 99mTc-folate to explore distribution of polarized macrophage populations in human atherosclerotic plaque. J Nucl Med 55, 1945–1951CrossRefPubMedGoogle Scholar
  23. 23.
    Kamen BA, Capdevila A (1986) Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci 83:5983–5987CrossRefPubMedGoogle Scholar
  24. 24.
    Kelderhouse LE, Mahalingam S, Low PS (2016) Predicting response to therapy for autoimmune and inflammatory diseases using a folate receptor-targeted near-infrared fluorescent imaging agent. Mol Imaging Biol 18:201–208CrossRefPubMedGoogle Scholar
  25. 25.
    Kern JC, Dooney D, Zhang R, Liang L, Brandish PE, Cheng M, Feng G, Beck A, Bresson D, Firdos J et al (2016) Novel phosphate modified Cathepsin B linkers: improving aqueous solubility and enhancing payload scope of ADCs. Bioconjug Chem 27:2081–2088CrossRefPubMedGoogle Scholar
  26. 26.
    Kim CH, Axup JY, Schultz PG (2013) Protein conjugation with genetically encoded unnatural amino acids. Curr Opin Chem Biol 17:412–419CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kuhn C, Weiner HL (2016) Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy 8:889–906CrossRefPubMedGoogle Scholar
  28. 28.
    Larrede S, Quinn CM, Jessup W, Frisdal E, Olivier M, Hsieh V, Kim M-J, Van Eck M, Couvert P, Carrie A et al (2009) Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arterioscler. Thromb Vasc Biol 29:1930–1936CrossRefGoogle Scholar
  29. 29.
    Leamon CP, Low PS (1991) Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis. Proc Natl Acad Sci 88:5572–5576CrossRefPubMedGoogle Scholar
  30. 30.
    Lee KC, Ouwehand I, Giannini AL, Thomas NS, Dibb NJ, Bijlmakers MJ (2010) Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia 24:896–900CrossRefPubMedGoogle Scholar
  31. 31.
    Lehar SM, Pillow T, Xu M, Staben L, Kajihara KK, Vandlen R, DePalatis L, Raab H, Hazenbos WL, Hiroshi Morisaki J et al (2015) Novel antibody–antibiotic conjugate eliminates intracellular S. Aureus. Nature 527:323–328CrossRefPubMedGoogle Scholar
  32. 32.
    Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su J-L, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA et al (1997) Activation of the nuclear receptor LXR by Oxysterols defines a new hormone response pathway. J Biol Chem 272:3137–3140CrossRefPubMedGoogle Scholar
  33. 33.
    Li W, Xu LH, Yuan XM (2004) Macrophage hemoglobin scavenger receptor and ferritin accumulation in human atherosclerotic lesions. Ann N Y Acad Sci 1030:196–201. CrossRefPubMedGoogle Scholar
  34. 34.
    Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, Brown MS (2002) Diminished hepatic response to fasting/Refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 277:9520–9528CrossRefPubMedGoogle Scholar
  35. 35.
    Lim RKV, Yu S, Cheng B, Li S, Kim N-J, Cao Y, Chi V, Kim JY, Chatterjee AK, Schultz PG et al (2015) Targeted delivery of LXR agonist using a site-specific antibody–drug conjugate. Bioconjug Chem 26:2216–2222CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Liu B (2007) Exploring cell type-specific internalizing antibodies for targeted delivery of siRNA. Brief Funct Genomic Proteomic 6:112–119CrossRefPubMedGoogle Scholar
  37. 37.
    Low PS, Kularatne SA (2009) Folate-targeted therapeutic and imaging agents for cancer. Curr Opin Chem Biol 13:256–262CrossRefPubMedGoogle Scholar
  38. 38.
    Lu Y, Wollak KN, Cross VA, Westrick E, Wheeler LW, Stinnette TW, Vaughn JF, Hahn SJ, Xu LC, Vlahov IR, Leamon CP (2014) Folate receptor-targeted aminopterin therapy is highly effective and specific in experimental models of autoimmune uveitis and autoimmune encephalomyelitis. Immunol 150(1):64–77. CrossRefGoogle Scholar
  39. 39.
    Luettig B, Decker T, Lohmann-Matthes ML (1989) Evidence for the existence of two forms of membrane tumor necrosis factor: an integral protein and a molecule attached to its receptor. J Immunol Baltim Md. 1950 143:4034–4038Google Scholar
  40. 40.
    Mariathasan S, Tan M-W (2017) Antibody–antibiotic conjugates: a novel therapeutic platform against bacterial infections. Trends Mol Med 23:135–149CrossRefPubMedGoogle Scholar
  41. 41.
    Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    McCann FE, Palfreeman AC, Andrews M, Perocheau DP, Inglis JJ, Schafer P, Feldmann M, Williams RO, Brennan FM (2010) Apremilast, a novel PDE4 inhibitor, inhibits spontaneous production of tumour necrosis factor-alpha from human rheumatoid synovial cells and ameliorates experimental arthritis. Arthritis Res Ther 12:R107CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    McColl A, Michlewska S, Dransfield I, Rossi AG (2007) Effects of glucocorticoids on apoptosis and clearance of apoptotic cells. Sci World J 7:1165–1181CrossRefGoogle Scholar
  44. 44.
    Mohammadi M, Li Y, Abebe DG, Xie Y, Kandil R, Kraus T, Gomez-Lopez N, Fujiwara T, Merkel OM (2016) Folate receptor targeted three-layered micelles and hydrogels for gene delivery to activated macrophages. J Control Release 244:269–279CrossRefPubMedGoogle Scholar
  45. 45.
    Moreno JA, Muñoz-García B, Martín-Ventura JL, Madrigal-Matute J, Orbe J, Páramo JA, Ortega L, Egido J, Blanco-Colio LM (2009) The CD163-expressing macrophages recognize and internalize TWEAK: potential consequences in atherosclerosis. Atherosclerosis 207(1):103–110. CrossRefPubMedGoogle Scholar
  46. 46.
    Nimmerjahn F, Ravetch JV (2008) Fcγ receptors as regulators of immune responses. Nat Rev Immunol 8:34–47CrossRefPubMedGoogle Scholar
  47. 47.
    Otten MA, van der Bij GJ, Verbeek SJ, Nimmerjahn F, Ravetch JV, Beelen RHJ, van de Winkel JGJ, van Egmond M (2008) Experimental antibody therapy of liver metastases reveals functional redundancy between fc RI and fc RIV. J Immunol 181:6829–6836CrossRefPubMedGoogle Scholar
  48. 48.
    Palchaudhuri R, Saez B, Hoggatt J, Schajnovitz A, Sykes DB, Tate TA, Czechowicz A, Kfoury Y, Ruchika F, Rossi DJ et al (2016) Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738–745CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RGB, Hu C, Stevens RM, Day RM, Gordon KB et al (2015) Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (efficacy and safety trial evaluating the effects of Apremilast in psoriasis [ESTEEM] 1). J Am Acad Dermatol 73:37–49CrossRefGoogle Scholar
  50. 50.
    Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2006) Immunotoxin therapy of cancer. Nat Rev Cancer 6:559–565CrossRefPubMedGoogle Scholar
  51. 51.
    Patarroyo M (1994) Adhesion molecules mediating recruitment of monocytes to inflamed tissue. Immunobiology 191:474–477CrossRefPubMedGoogle Scholar
  52. 52.
    Peer D, Zhu P, Carman CV, Lieberman J, Shimaoka M (2007) Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1. Proc Natl Acad Sci 104:4095–4100CrossRefPubMedGoogle Scholar
  53. 53.
    Pietersz G (2005) Book Reviews. Immunol Cell Biol 83:450–450CrossRefGoogle Scholar
  54. 54.
    van der Poel CE, Spaapen RM, van de Winkel JGJ, Leusen JHW (2011) Functional characteristics of the high affinity IgG receptor, Fc RI. J Immunol 186:2699–2704CrossRefPubMedGoogle Scholar
  55. 55.
    Puligujja P, Araínga M, Dash P, Palandri D, Mosley RL, Gorantla S, Poluektova L, McMillan J, Gendelman HE (2015) Pharmacodynamics of folic acid receptor targeted antiretroviral nanotherapy in HIV-1-infected humanized mice. Antivir Res 120:85–88CrossRefPubMedGoogle Scholar
  56. 56.
    Qi R, Majoros I, Misra AC, Koch AE, Campbell P, Marotte H, Bergin IL, Cao Z, Goonewardena S, Morry J et al (2015) Folate receptor-targeted Dendrimer-methotrexate conjugate for inflammatory arthritis. J Biomed Nanotechnol 11:1431–1441CrossRefPubMedGoogle Scholar
  57. 57.
    Repa JJ (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14:2819–2830CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Repa JJ, Mangelsdorf DJ (2002) The liver X receptor gene team: potential new players in atherosclerosis. Nat Med 8:1243–1248CrossRefPubMedGoogle Scholar
  59. 59.
    Rogers DE (1952) The survival of staphylococci within human leukocytes. J Exp Med 95:209–230CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    de Rycke L, Verhelst X, Kruithof E, Van den Bosch F, Hoffman IE, Veys EM, De Keyser F. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis 2005 64(2):299-302. doi: CrossRefPubMedGoogle Scholar
  61. 61.
    Salari-Sharif P, Abdollahi M (2010) Phosphodiesterase 4 inhibitors in inflammatory bowel disease: a comprehensive review. Curr Pharm Des 16:3661–3667CrossRefPubMedGoogle Scholar
  62. 62.
    Schade AE, Schieven GL, Townsend R, Jankowska AM, Susulic V, Zhang R, Szpurka H, Maciejewski JP (2007) Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 111:1366–1377CrossRefPubMedGoogle Scholar
  63. 63.
    Sega EI, Low PS (2008) Tumor detection using folate receptor-targeted imaging agents. Cancer Metastasis Rev 27:655–664CrossRefPubMedGoogle Scholar
  64. 64.
    Song E, Zhu P, Lee S-K, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P et al (2005) Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol 23:709–717CrossRefGoogle Scholar
  65. 65.
    Song L, Lee C, Schindler C (2011) Deletion of the murine scavenger receptor CD68. J Lipid Res 52:1542–1550CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Sugo T, Terada M, Oikawa T, Miyata K, Nishimura S, Kenjo E, Ogasawara-Shimizu M, Makita Y, Imaichi S, Murata S et al (2016) Development of antibody-siRNA conjugate targeted to cardiac and skeletal muscles. J Control Release 237:1–13CrossRefPubMedGoogle Scholar
  67. 67.
    Thwaites GE, Gant V (2011) Are bloodstream leukocytes Trojan horses for the metastasis of Staphylococcus aureus? Nat Rev Microbiol 9:215–222CrossRefPubMedGoogle Scholar
  68. 68.
    Tralau-Stewart CJ, Williamson RA, Nials AT, Gascoigne M, Dawson J, Hart GJ, Angell ADR, Solanke YE, Lucas FS, Wiseman J et al (2011) GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization. J Pharmacol Exp Ther 337:145–154CrossRefPubMedGoogle Scholar
  69. 69.
    Varghese B, Vlashi E, Xia W, Ayala Lopez W, Paulos CM, Reddy J, Xu L-C, Low PS (2014) Folate receptor-β in activated macrophages: ligand binding and receptor recycling kinetics. Mol Pharm 11:3609–3616CrossRefPubMedGoogle Scholar
  70. 70.
    Wang RE, Liu T, Wang Y, Cao Y, Du J, Luo X, Deshmukh V, Kim CH, Lawson BR, Tremblay MS et al (2015) An immunosuppressive antibody-drug conjugate. J Am Chem Soc 137:3229–3232CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Winograd-Katz SE, Fässler R, Geiger B, Legate KR (2014) The integrin adhesome: from genes and proteins to human disease. Nat Rev Mol Cell Biol 15:273–288CrossRefPubMedGoogle Scholar
  72. 72.
    Yamamoto N, Ikeda H, Tandon NN, Herman J, Tomiyama Y, Mitani T, Sekiguchi S, Lipsky R, Kralisz U, Jamieson GA (1990) A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36). Blood 76:1698–1703PubMedGoogle Scholar
  73. 73.
    Yao Y-D, Sun T-M, Huang S-Y, Dou S, Lin L, Chen J-N, Ruan J-B, Mao C-Q, Yu F-Y, Zeng M-S et al (2012) Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast Cancer growth and metastasis. Sci Transl Med 4:130ra48–130ra48CrossRefPubMedGoogle Scholar
  74. 74.
    Yu S, Pearson AD, Lim RK, Rodgers DT, Li S, Parker HB, Weglarz M, Hampton EN, Bollong MJ, Shen J et al (2016) Targeted delivery of an anti-inflammatory PDE4 inhibitor to immune cells via an antibody–drug conjugate. Mol Ther 24:2078–2089CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Zhou C, Lehar S, Gutierrez J, Rosenberger CM, Ljumanovic N, Dinoso J, Koppada N, Hong K, Baruch A, Carrasco-Triguero M et al (2016) Pharmacokinetics and pharmacodynamics of DSTA4637A: a novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice. MAbs 8:1612–1619CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.California Institute for Biomedical Research (Calibr)La JollaUSA

Personalised recommendations