Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Strategies and challenges for the next generation of antibody–drug conjugates

Key Points

  • The development of antibody–drug conjugates (ADCs) has benefited from general improvements in the design of therapeutic monoclonal antibodies (mAbs) and from specific improvements in regard to methods for conjugate synthesis through which both homogeneity and stability is enhanced.

  • Diversification of linking strategies and payloads has opened new perspectives to improve drug delivery to tumours while reducing drug exposure to normal tissues. To enhance the therapeutic index of ADCs, either the potency of the cytotoxic agent has to be improved to lower the minimum effective dose or the tumour selectivity has to be improved to increase the maximum tolerated dose.

  • Protein structural characterization tools such as mass spectrometry and the development of quantitative bioanalytical assays will contribute to the identification of early-developability criteria for all of the ADC components (antibody, drug and linker).

  • Recent ADC development has created a renewed interest in natural cytotoxic products, which are typically highly potent cytotoxic agents but often have unacceptable toxicities. In the future, breakthroughs in the efficacy of ADCs are likely to involve conjugates with previously unknown mechanisms of action.

  • Alternative formats to mAbs, such as protein scaffolds (designed ankyrin-repeat proteins (DARPins), nanobodies, single-chain variable fragments (scFvs) and peptide–drug conjugates), dual-labelled ADCs and biparatopic drug conjugates, present new research avenues.

  • There are several possible indications for ADCs: as single agents in patients with refractory or relapsing disease; in palliative settings, for consolidation or maintenance; and in combination with other agents as first-line therapy or in relapsed patients.

Abstract

Antibody–drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody. Furthermore, lessons learned during the past decade are now being used in the development of third-generation ADCs. In this Review, we discuss strategies to select the best target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; the discovery of bioorthogonal conjugation chemistries; and toxicity issues. The selection and engineering of antibodies for site-specific drug conjugation, which will result in higher homogeneity and increased stability, as well as the quest for new conjugation chemistries and mechanisms of action, are priorities in ADC research.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structures of selected first-, second- and third-generation ADCs.
Figure 2: Example of first-, second- and third-generation ADC research and development.
Figure 3: Third-generation ADCs are designed to expand the therapeutic window.

Similar content being viewed by others

References

  1. Perez, H. L. et al. Antibody–drug conjugates: current status and future directions. Drug Discov. Today 19, 869–881 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Beck, A. et al. The next generation of antibody–drug conjugates comes of age. Discov. Med. 10, 329–339 (2010).

    PubMed  Google Scholar 

  3. Senter, P. D. & Sievers, E. L. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat. Biotechnol. 30, 631–637 (2012). This review discusses the discovery and development of brentuximab vedotin, which has been approved by the FDA and the EMA.

    Article  CAS  PubMed  Google Scholar 

  4. Younes, A., Yasothan, U. & Kirkpatrick, P. Brentuximab vedotin. Nat. Rev. Drug Discov. 11, 19–20 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Lambert, J. M. & Chari, R. V. Ado-trastuzumab emtansine (T-DM1): an antibody–drug conjugate (ADC) for HER2-positive breast cancer. J. Med. Chem. 57, 6949–6964 (2014). This review discusses the discovery and development of trastuzumab emtansine, which has been approved by the FDA and the EMA.

    Article  CAS  PubMed  Google Scholar 

  6. Mullard, A. Maturing antibody–drug conjugate pipeline hits 30. Nat. Rev. Drug Discov. 12, 329–332 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Beck, A. & Reichert, J. M. Antibody–drug conjugates: present and future. mAbs 6, 15–17 (2014).

    Article  PubMed  Google Scholar 

  8. Salomon, P. L. & Singh, R. Sensitive ELISA method for the measurement of catabolites of antibody–drug conjugates (ADCs) in target cancer cells. Mol. Pharm. 12, 1752–1761 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Verma, V. A. et al. The cryptophycins as potent payloads for antibody drug conjugates. Bioorg. Med. Chem. Lett. 25, 864–868 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Dumontet, C. & Jordan, M. A. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 9, 790–803 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Dere, R. et al. PK assays for antibody–drug conjugates: case study with ado-trastuzumab emtansine. Bioanalysis 5, 1025–1040 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. McDonagh, C. F. et al. Engineered antibody–drug conjugates with defined sites and stoichiometries of drug attachment. Protein Eng. Des. Sel. 19, 299–307 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Junutula, J. R. et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotechnol. 26, 925–932 (2008). This paper was the first to demonstrate the improvement of the therapeutic index for a site-specific ADC.

    Article  CAS  PubMed  Google Scholar 

  14. Shen, B. Q. et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody–drug conjugates. Nat. Biotechnol. 30, 184–189 (2012). This paper demonstrated the paramount importance of pharmacokinetic and metabolic studies to optimize ADC structures.

    Article  CAS  PubMed  Google Scholar 

  15. Agarwal, P. & Bertozzi, C. R. Site-specific antibody–drug conjugates: the nexus of bioorthogonal chemistry, protein engineering, and drug development. Bioconjug. Chem. 26, 176–192 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Damelin, M., Zhong, W., Myers, J. & Sapra, P. Evolving strategies for target selection for antibody–drug conjugates. Pharm. Res. 32, 3494–3507 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Shor, B. et al. Enhanced antitumor activity of an anti-5T4 antibody–drug conjugate in combination with PI3K/mTOR inhibitors or taxanes. Clin. Cancer Res. 22, 383–394 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Ter Weele, E. J. et al. Imaging the distribution of an antibody–drug conjugate constituent targeting mesothelin with 89Zr and IRDye 800CW in mice bearing human pancreatic tumor xenografts. Oncotarget 6, 42081–42090 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sondergeld, P., van de Donk, N. W., Richardson, P. G. & Plesner, T. Monoclonal antibodies in myeloma. Clin. Adv. Hematol. Oncol. 13, 599–609 (2015).

    PubMed  Google Scholar 

  20. Kim, S. Y. et al. A novel antibody–drug conjugate targeting SAIL for the treatment of hematologic malignancies. Blood Cancer J. 5, e316 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pereira, D. S. et al. AGS67E, an anti-CD37 monomethyl auristatin E antibody–drug conjugate as a potential therapeutic for B/T-cell malignancies and AML: a new role for CD37 in AML. Mol. Cancer Ther. 14, 1650–1660 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Visintin, A. et al. Novel anti-TM4SF1 antibody–drug conjugates with activity against tumor cells and tumor vasculature. Mol. Cancer Ther. 14, 1868–1876 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. List, T., Casi, G. & Neri, D. A chemically defined trifunctional antibody–cytokine–drug conjugate with potent antitumor activity. Mol. Cancer Ther. 13, 2641–2652 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Kovtun, Y. V. et al. Antibody–drug conjugates designed to eradicate tumors whh homogeneous and heterogeneous expression of the target antigen. Cancer Res. 66, 3214–3221 (2006). This paper shows that conjugates linked via a reducible disulfide bond were capable of exerting the bystander effect, whereas equally potent conjugates linked via a non-reducible thioether bond were not.

    Article  CAS  PubMed  Google Scholar 

  25. Ikeda, H. et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin. Cancer Res. 15, 4028–4037 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Palanca-Wessels, M. C. et al. 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, 704–715 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Hong, E. E. et al. Design of coltuximab ravtansine, a CD19-targeting antibody–drug conjugate (ADC) for the treatment of B-cell malignancies: structure–activity relationships and preclinical evaluation. Mol. Pharm. 12, 1703–1716 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Damelin, M. et al. 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 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Yardley, D. A. et al. EMERGE: a randomized phase II study of the antibody–drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. J. Clin. Oncol. 33, 1609–1619 (2015).

    Article  CAS  PubMed  Google Scholar 

  30. Fauteux, F. et al. Computational selection of antibody–drug conjugate targets for breast cancer. Oncotarget 7, 2555–2571 (2016).

    Article  PubMed  Google Scholar 

  31. Wagner-Rousset, E. et al. Antibody–drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion. mAbs 6, 173–184 (2014).

    Article  Google Scholar 

  32. Chari, R. V., Miller, M. L. & Widdison, W. C. Antibody–drug conjugates: an emerging concept in cancer therapy. Angew. Chem. Int. Ed. 53, 3796–3827 (2014).

    Article  CAS  Google Scholar 

  33. Maderna, A. et al. Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications. J. Med. Chem. 57, 10527–10543 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Rouleau, C. et al. Anti-endosialin antibody–drug conjugate: potential in sarcoma and other malignancies. Mol. Cancer Ther. 14, 2081–2089 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Issell, B. F. & Crooke, S. T. Maytansine. Cancer Treat. Rev. 5, 199–207 (1978).

    Article  CAS  PubMed  Google Scholar 

  36. Li, J. Y. et al. 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 (2016). This paper reports the discovery and the preclinical development of the first clinical-stage bispecific ADC.

    Article  CAS  PubMed  Google Scholar 

  37. Shor, B., Gerber, H. P. & Sapra, P. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. Mol. Immunol. 67, 107–116 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Owonikoko, T. K. et al. First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody–drug conjugate targeting CD70. Cancer Chemother. Pharmacol. 77, 155–162 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Elgersma, R. C. et al. Design, synthesis, and evaluation of linker-duocarmycin payloads: toward selection of HER2-targeting antibody–drug conjugate SYD985. Mol. Pharm. 12, 1813–1835 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. van der Lee, M. M. et al. 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 (2015). This paper shows that trastuzumab duocarmazine is 3-fold to 50-fold more potent than trastuzumab emtansine in cell lines with low HER2 expression.

    Article  CAS  PubMed  Google Scholar 

  41. Kolakowski, R. V., Young, T. D., Howard, P. W., Jeffrey, S. C. & Senter, P. D. Synthesis of a C2-aryl-pyrrolo[2,1-c][1,4]benzodiazepine monomer enabling the convergent construction of symmetrical and non-symmetrical dimeric analogs. Tetrahedron Lett. 56, 4512–4515 (2015).

    Article  CAS  Google Scholar 

  42. Mantaj, J., Jackson, P. J., Rahman, K. M. & Thurston, D. E. From anthramycin to pyrrolobenzodiazepine (PBD)-containing antibody–drug conjugates (ADCs). Angew. Chem. Int. Ed. 56, 462–488 (2017).

    Article  CAS  Google Scholar 

  43. Kung Sutherland, M. S. et al. SGN-CD33A: a novel CD33-targeting antibody–drug conjugate utilizing a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 122, 1455–1463 (2013). This paper reports preclinical data of the most advanced third-generation ADC that is currently in phase III trials.

    Article  CAS  PubMed  Google Scholar 

  44. Jeffrey, S. C. et al. A potent anti-CD70 antibody–drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology. Bioconjug. Chem. 24, 1256–1263 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Rudin, C. M. et al. Rovalpituzumab tesirine, a DLL3-targeted antibody–drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol., http://dx.doi.org/10.1016/S1470-2045(16)30565-4 (2017).

  46. Saunders, L. R. et al. A DLL3-targeted antibody–drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci. Transl Med. 7, 302ra136 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Flynn, M. J. et al. ADCT-301, a pyrrolobenzodiazepine (PBD) dimer-containing antibody–drug conjugate (ADC) targeting CD25-expressing hematological malignancies. Mol. Cancer Ther. 15, 2709–2721 (2009).

    Article  Google Scholar 

  48. Miller, M. L. et al. A new class of antibody–drug conjugates with potent DNA alkylating activity. Mol. Cancer Ther. 15, 1870–1878 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Sharkey, R. M. et al. Enhanced delivery of SN-38 to human tumor xenografts with an anti-trop-2-SN-38 antibody conjugate (sacituzumab govitecan). Clin. Cancer Res. 21, 5131–5138 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Starodub, A. N. et al. 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 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Goldenberg, D. M., Cardillo, T. M., Govindan, S. V., Rossi, E. A. & Sharkey, R. M. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody–drug conjugate (ADC). Oncotarget 6, 22496–22512 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Nakada, T. et al. Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg. Med. Chem. Lett. 26, 1542–1545 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Ogitani, Y. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising anti-tumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 22, 5097–5108 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Ross, H. J. et al. A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma. Lung Cancer 54, 69–77 (2006).

    Article  PubMed  Google Scholar 

  55. Govindan, S. V. et al. Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers. Mol. Cancer Ther. 12, 968–978 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Liu, Y. et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 520, 697–701 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Murray, B. C., Peterson, M. T. & Fecik, R. A. Chemistry and biology of tubulysins: antimitotic tetrapeptides with activity against drug resistant cancers. Nat. Prod. Rep. 32, 654–662 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Yu, S. F. et al. A novel anti-CD22 anthracycline-based antibody–drug conjugate (ADC) that overcomes resistance to auristatin-based ADCs. Clin. Cancer Res. 21, 3298–3306 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Prota, A. E. et al. A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proc. Natl Acad. Sci. USA 111, 13817–13821 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Eustaquio, A. S., Janso, J. E., Ratnayake, A. S., O'Donnell, C. J. & Koehn, F. E. Spliceostatin hemiketal biosynthesis in Burkholderia spp. is catalyzed by an iron/alpha-ketoglutarate-dependent dioxygenase. Proc. Natl Acad. Sci. USA 111, E3376–E3385 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Puthenveetil, S. et al. Development of solid-phase site-specific conjugation and its application towards generation of dual labeled antibody and Fab drug conjugates. Bioconjug. Chem. 27, 1030–1039 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Erickson, H. K. et al. Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody–maytansinoid conjugates. Bioconjug. Chem. 21, 84–92 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Senter, P. D. Potent antibody–drug conjugates for cancer therapy. Curr. Opin. Chem. Biol. 13, 235–244 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Alley, S. C., Okeley, N. M. & Senter, P. D. Antibody–drug conjugates: targeted drug delivery for cancer. Curr. Opin. Chem. Biol. 14, 529–537 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Kovtun, Y. V. & Goldmacher, V. S. Cell killing by antibody–drug conjugates. Cancer Lett. 255, 232–240 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Katz, J., Janik, J. E. & Younes, A. Brentuximab vedotin (SGN-35). Clin. Cancer Res. 17, 6428–6436 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Okeley, N. M. et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody–drug conjugate. Clin. Cancer Res. 16, 888–897 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. de Goeij, B. E. et al. High turnover of tissue factor enables efficient intracellular delivery of antibody–drug conjugates. Mol. Cancer Ther. 14, 1130–1140 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Golfier, S. et al. Anetumab ravtansine: a novel mesothelin-targeting antibody–drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol. Cancer Ther. 13, 1537–1548 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Ab, O. et al. IMGN853, a folate receptor-α (FRα)-targeting antibody–drug conjugate, exhibits potent targeted antitumor activity against FRα-expressing tumors. Mol. Cancer Ther. 14, 1605–1613 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Lyon, R. P. et al. Reducing hydrophobicity of homogeneous antibody–drug conjugates improves pharmacokinetics and therapeutic index. Nat. Biotechnol. 33, 733–735 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Hamblett, K. J. et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin. Cancer Res. 10, 7063–7070 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Beck, A., Wurch, T., Bailly, C. & Corvaia, N. Strategies and challenges for the next generation of therapeutic antibodies. Nat. Rev. Immunol. 10, 345–352 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Beck, A., Wagner-Rousset, E., Ayoub, D., Van Dorsselaer, A. & Sanglier-Cianferani, S. Characterization of therapeutic antibodies and related products. Anal. Chem. 85, 715–736 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Beck, A. et al. Cutting-edge mass spectrometry characterization of originator, biosimilar and biobetter antibodies. J. Mass Spectrom. 50, 285–297 (2015).

    Article  CAS  PubMed  Google Scholar 

  76. Beck, A. et al. Cutting-edge mass spectrometry methods for the multi-level structural characterization of antibody–drug conjugates. Expert. Rev. Proteomics 13, 157–183 (2016). This review describes the analytical and structural workflow to characterize ADCs.

    Article  CAS  PubMed  Google Scholar 

  77. Jones, T. D. et al. The INNs and outs of antibody nonproprietary names. mAbs 8, 1–9 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Pottier, J., Chastang, R., Dumet, C. & Watier, H. Rethinking the INN system for therapeutic antibodies. mAbs 9, 5–11 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Debaene, F. et al. Innovative native MS methodologies for antibody drug conjugate characterization: high resolution native MS and IM-MS for average DAR and DAR distribution assessment. Anal. Chem. 86, 10674–10683 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Marcoux, J. et al. Native mass spectrometry and ion mobility characterization of trastuzumab emtansine, a lysine-linked antibody drug conjugate. Protein Sci. 24, 1210–1223 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhang, A., Fang, J., Chou, R. Y., Bondarenko, P. V. & Zhang, Z. Conformational difference in human IgG2 disulfide isoforms revealed by hydrogen/deuterium exchange mass spectrometry. Biochemistry 54, 1956–1962 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Debaene, F. et al. Time resolved native ion-mobility mass spectrometry to monitor dynamics of IgG4 Fab arm exchange and “bispecific” monoclonal antibody formation. Anal. Chem. 85, 9785–9792 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. McDonagh, C. F. et al. Engineered anti-CD70 antibody–drug conjugate with increased therapeutic index. Mol. Cancer Ther. 7, 2913–2923 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Vafa, O. et al. An engineered Fc variant of an IgG eliminates all immune effector functions via structural perturbations. Methods 65, 114–126 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Junttila, T. T., Li, G., Parsons, K., Phillips, G. L. & Sliwkowski, M. X. 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, 347–356 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Wiggins, B., Liu-Shin, L., Yamaguchi, H. & Ratnaswamy, G. Characterization of cysteine-linked conjugation profiles of immunoglobulin G1 and immunoglobulin G2 antibody–drug conjugates. J. Pharm. Sci. 104, 1362–1372 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Tai, Y. T. et al. Novel anti-B-cell maturation antigen antibody–drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 123, 3128–3138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Beck, A. & Reichert, J. M. Marketing approval of mogamulizumab: a triumph for glyco-engineering. mAbs 4, 419–425 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Lyon, R. P. et al. Self-hydrolyzing maleimides improve the stability and pharmacological properties of antibody–drug conjugates. Nat. Biotechnol. 32, 1059–1062 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Dennler, P. Antibody conjugates: from heterogeneous populations to defined reagents. Antibodies 4, 197–224 (2015).

    Article  CAS  Google Scholar 

  91. Voynov, V. et al. Design and application of antibody cysteine variants. Bioconjug. Chem. 21, 385–392 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. Beck, A. et al. 8th Annual European Antibody Congress 2012: November 27–28, 2012, Geneva, Switzerland. mAbs 5, 339–357 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Patterson, J. T., Asano, S., Li, X., Rader, C. & Barbas, C. F. III. Improving the serum stability of site-specific antibody conjugates with sulfone linkers. Bioconjug. Chem. 25, 1402–1407 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kline, T. et al. Methods to make homogenous antibody drug conjugates. Pharm. Res. 32, 3480–3493 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Tian, F. et al. A general approach to site-specific antibody drug conjugates. Proc. Natl Acad. Sci. USA 111, 1766–1771 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zimmerman, E. S. et al. Production of site-specific antibody–drug conjugates using optimized non-natural amino acids in a cell-free expression system. Bioconjug. Chem. 25, 351–361 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. VanBrunt, M. P. et al. Genetically encoded azide containing amino acid in mammalian cells enables site-specific antibody–drug conjugates using click cycloaddition chemistry. Bioconjug. Chem. 26, 2249–2260 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Albers, A. E. et al. Exploring the effects of linker composition on site-specifically modified antibody–drug conjugates. Eur. J. Med. Chem. 88, 3–9 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Drake, P. M. et al. Aldehyde tag coupled with HIPS chemistry enables the production of ADCs conjugated site-specifically to different antibody regions with distinct in vivo efficacy and PK outcomes. Bioconjug. Chem. 25, 1331–1341 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Strop, P. et al. Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem. Biol. 20, 161–167 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Strop, P. et al. 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 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Lhospice, F. et al. Site-specific conjugation of monomethyl auristatin E to anti-CD30 antibodies improves their pharmacokinetics and therapeutic index in rodent models. Mol. Pharm. 12, 1863–1871 (2015).

    Article  CAS  PubMed  Google Scholar 

  103. Beerli, R. R., Hell, T., Merkel, A. S. & Grawunder, U. Sortase enzyme-mediated generation of site-specifically conjugated antibody drug conjugates with high in vitro and in vivo potency. PLoS ONE 10, e0131177 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Edelman, G. M. et al. The covalent structure of an entire gammaG immunoglobulin molecule. Proc. Natl Acad. Sci. USA 63, 78–85 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Beck, A., Wurch, T. & Corvaïa, N. Editorial: therapeutic antibodies and derivatives: from the bench to the clinic. Curr. Pharm. Biotechnol. 9, 421–422 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Ekholm, F. S. et al. Introducing glycolinkers for the functionalization of cytotoxic drugs and applications in antibody–drug conjugation chemistry. ChemMedChem 11, 2501–2505 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Okeley, N. M. et al. Metabolic engineering of monoclonal antibody carbohydrates for antibody–drug conjugation. Bioconjug. Chem. 24, 1650–1655 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Zuberbuhler, K., Casi, G., Bernardes, G. J. & Neri, D. Fucose-specific conjugation of hydrazide derivatives to a vascular-targeting monoclonal antibody in IgG format. Chem. Commun. (Camb.) 48, 7100–7102 (2012).

    Article  CAS  Google Scholar 

  109. Zhou, Q. et al. Site-specific antibody–drug conjugation through glycoengineering. Bioconjug. Chem. 25, 510–520 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Li, X., Fang, T. & Boons, G. J. Preparation of well-defined antibody–drug conjugates through glycan remodeling and strain-promoted azide-alkyne cycloadditions. Angew. Chem. Int. Ed. 53, 7179–7182 (2014).

    Article  CAS  Google Scholar 

  111. Qasba, P. K. Glycans of antibodies as a specific site for drug conjugation using glycosyltransferases. Bioconjug. Chem. 26, 2170–2175 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. van Geel, R. et al. Chemoenzymatic conjugation of toxic payloads to the globally conserved N-glycan of native mAbs provides homogeneous and highly efficacious antibody–drug conjugates. Bioconjug. Chem. 26, 2233–2242 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Thompson, P. et al. Hydrolytically stable site-specific conjugation at the N-terminus of an engineered antibody. Bioconjug. Chem. 26, 2085–2096 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Lac, D. et al. Covalent chemical ligation strategy for mono- and polyclonal immunoglobulins at their nucleotide binding sites. Bioconjug. Chem. 27, 159–169 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Bryant, P. et al. In vitro and in vivo evaluation of cysteine rebridged trastuzumab-MMAE antibody drug conjugates with defined drug-to-antibody ratios. Mol. Pharm. 12, 1872–1879 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Maruani, A. et al. A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy. Nat. Commun. 6, 6645 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Behrens, C. R. et al. Antibody–drug conjugates (ADCs) derived from interchain cysteine cross-linking demonstrate improved homogeneity and other pharmacological properties over conventional heterogeneous ADCs. Mol. Pharm. 12, 3986–3998 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Excoffier, M. et al. A new anti-human Fc method to capture and analyze ADCs for characterization of drug distribution and the drug-to-antibody ratio in serum from pre-clinical species. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1032, 149–154 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. Tumey, L. N. et al. Mild method for succinimide hydrolysis on ADCs: impact on ADC potency, stability, exposure, and efficacy. Bioconjug. Chem. 25, 1871–1880 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Shinmi, D. et al. One-step conjugation method for site-specific antibody–drug conjugates through reactive cysteine-engineered antibodies. Bioconjug. Chem. 27, 1324–1331 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Fontaine, S. D., Reid, R., Robinson, L., Ashley, G. W. & Santi, D. V. Long-term stabilization of maleimide-thiol conjugates. Bioconjug. Chem. 26, 145–152 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. James, C. R. et al. Stabilization of cysteine-linked antibody drug conjugates with N-aryl maleimides. J. Control. Release 220, 660–670 (2015).

    Article  CAS  Google Scholar 

  123. Kolodych, S. et al. CBTF: new amine-to-thiol coupling reagent for preparation of antibody conjugates with increased plasma stability. Bioconjug. Chem. 26, 197–200 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Dovgan, I., Kolodych, S., Koniev, O. & Wagner, A. 2-(Maleimidomethyl)-1,3-Dioxanes (MD): a serum-stable self-hydrolysable hydrophilic alternative to classical maleimide conjugation. Sci. Rep. 6, 30835 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Strop, P. et al. Site-specific conjugation improves therapeutic index of antibody drug conjugates with high drug loading. Nat. Biotechnol. 33, 694–696 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Yurkovetskiy, A. V. et al. A polymer-based antibody-vinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res. 75, 3365–3372 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Shefet-Carasso, L. & Benhar, I. Antibody-targeted drugs and drug resistance — challenges and solutions. Drug Resist. Updat. 18, 36–46 (2015).

    Article  PubMed  Google Scholar 

  128. Loganzo, F. et al. Tumor cells chronically treated with a trastuzumab-maytansinoid antibody–drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol. Cancer Ther. 14, 952–963 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Cianfriglia, M. 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 (2013).

    CAS  PubMed  Google Scholar 

  130. Chen, X., Soma, L. A. & Fromm, J. R. Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin. Onco Targets Ther. 19, 45–56 (2013).

    Google Scholar 

  131. Loganzo, F. et al. Tumor cells chronically treated with a trastuzumab–maytansinoid antibody–drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol. Cancer Ther. 14, 952–963 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Loganzo, F., Sung, M. & Gerber, H. P. Mechanisms of resistance to antibody–drug conjugates. Mol. Cancer Ther. 15, 2825–2834 (2016).

    Article  CAS  PubMed  Google Scholar 

  133. Epenetos, A. A., Snook, D., Durbin, H., Johnson, P. M. & Taylor-Papadimitriou, J. Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms. Cancer Res. 46, 3183–3191 (1986).

    CAS  PubMed  Google Scholar 

  134. Deonarain, M. P., Yahioglu, G., Stamati, I. & Marklew, J. Emerging formats for next-generation antibody drug conjugates. Expert. Opin. Drug Discov. 10, 463–481 (2015).

    Article  CAS  PubMed  Google Scholar 

  135. Merten, H., Brandl, F., Pluckthun, A. & Zangemeister-Wittke, U. Antibody–drug conjugates for tumor targeting-novel conjugation chemistries and the promise of non-IgG binding proteins. Bioconjug. Chem. 26, 2176–2185 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Gebleux, R., Wulhfard, S., Casi, G. & Neri, D. Antibody format and drug release rate determine the therapeutic activity of non-internalizing antibody–drug conjugates. Mol. Cancer Ther. 14, 2606–2612 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mullard, A. 2015 FDA drug approvals. Nat. Rev. Drug Discov. 15, 73–76 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Moskowitz, C. H. et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 385, 1853–1862 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Muller, P. et al. Microtubule-depolymerizing agents used in antibody–drug conjugates induce antitumor immunity by stimulation of dendritic cells. Cancer Immunol. Res. 2, 741–755 (2014).

    Article  CAS  PubMed  Google Scholar 

  141. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Gerber, H. P., Sapra, P., Loganzo, F. & May, C. Combining antibody–drug conjugates and immune-mediated cancer therapy: what to expect? Biochem. Pharmacol. 102, 1–6 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Muller, P. et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci. Transl Med. 7, 315 (2015). This paper shows that combined treatment with trastuzumab emtansine and immune checkpoint inhibitors is curative, because it triggered innate and adaptive immunity responses.

    Article  CAS  Google Scholar 

  144. Liu, R., Wang, R. E. & Wang, F. Antibody–drug conjugates for non-oncological indications. Expert. Opin. Biol. Ther. 16, 591–593 (2016).

    Article  PubMed  Google Scholar 

  145. Wang, R. E. et al. An immunosuppressive antibody–drug conjugate. J. Am. Chem. Soc. 137, 3229–3232 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lehar, S. M. et al. Novel antibody–antibiotic conjugate eliminates intracellular S. aureus. Nature 527, 323–328 (2015). This paper illustrates the potency of ADCs in infectious diseases.

    Article  CAS  PubMed  Google Scholar 

  147. Zhou, C. et al. Pharmacokinetics and pharmacodynamics of DSTA4637A: a novel THIOMAB antibody antibiotic conjugate against Staphylococcus aureus in mice. mAbs 8, 1612–1619 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hamilton, G. S. Antibody–drug conjugates for cancer therapy: the technological and regulatory challenges of developing drug-biologic hybrids. Biologicals 43, 318–332 (2015).

    Article  CAS  PubMed  Google Scholar 

  149. Rodriguez-Aller, M., Guillarme, D., Beck, A. & Fekete, S. Practical method development for the separation of monoclonal antibodies and antibody–drug-conjugate species in hydrophobic interaction chromatography, part 1: optimization of the mobile phase. J. Pharm. Biomed. Anal. 118, 393–403 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Terral, G., Beck, A. & Cianferani, S. Insights from native mass spectrometry and ion mobility-mass spectrometry for antibody and antibody-based product characterization. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1032, 79–90 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Sarrut, M. et al. Analysis of antibody–drug conjugates by comprehensive on-line two-dimensional hydrophobic interaction chromatography x reversed phase liquid chromatography hyphenated to high resolution mass spectrometry. I — optimization of separation conditions. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1032, 103–111 (2016).

    Article  CAS  PubMed  Google Scholar 

  152. Sarrut, M. et al. Analysis of antibody–drug conjugates by comprehensive on-line two-dimensional hydrophobic interaction chromatography x reversed phase liquid chromatography hyphenated to high resolution mass spectrometry. II — identification of sub-units for the characterization of even and odd load drug species. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1032, 91–102 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Stoll, D., Danforth, J., Zhang, K. & Beck, A. Characterization of therapeutic antibodies and related products by two-dimensional liquid chromatography coupled with UV absorbance and mass spectrometric detection. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1032, 51–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Birdsall, R. E. et al. A sensitive multidimensional method for the detection, characterization, and quantification of trace free drug species in antibody–drug conjugate samples using mass spectral detection. mAbs 8, 306–317 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Gahoual, R., Beck, A., Leize-Wagner, E. & Francois, Y. N. Cutting-edge capillary electrophoresis characterization of monoclonal antibodies and related products. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1032, 61–78 (2016).

    Article  CAS  PubMed  Google Scholar 

  156. Francois, Y. N. et al. Characterization of cetuximab Fc/2 dimers by off-line CZE-MS. Anal. Chim. Acta 908, 168–176 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Gerber, H. P., Koehn, F. E. & Abraham, R. T. The antibody–drug conjugate: an enabling modality for natural product-based cancer therapeutics. Nat. Prod. Rep. 30, 625–639 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Desnoyers, L. R. et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci. Transl Med. 5, 207ra144 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Bross, P. F. et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin. Cancer Res. 7, 1490–1496 (2001).

    CAS  PubMed  Google Scholar 

  160. Labrijn, A. F. et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat. Biotechnol. 27, 767–771 (2009).

    Article  CAS  PubMed  Google Scholar 

  161. Castaigne, S. Why is it so difficult to use gemtuzumab ozogamicin? Blood 121, 4813–4814 (2013).

    Article  CAS  Google Scholar 

  162. Lapusan, S. et al. Phase I studies of AVE9633, an anti-CD33 antibody–maytansinoid conjugate, in adult patients with relapsed/refractory acute myeloid leukemia. Invest. New Drugs 30, 1121–1131 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Tang, R. et al. P-Gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients. BMC Cancer 9, 199 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Vidriales, M. B. et al. Prognostic value of S-phase cells in AML patients. Br. J. Haematol. 89, 342–348 (1995).

    Article  CAS  PubMed  Google Scholar 

  165. Kennedy, D. A. et al. SGN-CD33A: preclinical and phase 1 interim clinical trial results of a CD33-directed PBD dimer antibody–drug conjugate for the treatment of acute myeloid leukemia (AML). Cancer Res. 75, abstr. DDT02-04 (2015).

    Article  CAS  Google Scholar 

  166. Panowski, S., Bhakta, S., Raab, H., Polakis, P. & Junutula, J. R. Site-specific antibody drug conjugates for cancer therapy. mAbs 6, 34–45 (2014).

    Article  PubMed  Google Scholar 

  167. Donaghy, H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody–drug conjugates. mAbs 8, 659–671 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wei, C. et al. Where did the linker-payload go? A quantitative investigation on the destination of the released linker-payload from an antibody–drug conjugate with a maleimide linker in plasma. Anal. Chem. 88, 4979–4986 (2016).

    Article  CAS  PubMed  Google Scholar 

  169. Geles, K. G., Gao, Y., Sapra, P. & Tchistiakova, L. G. & Zhou, B.-B. S. Anti-notch3 antibodies and antibody–drug conjugates. US Patent 2014127211 A1 (2014).

  170. Beck, A. & Reichert, J. M. Approval of the first biosimilar antibodies in Europe: a major landmark for the biopharmaceutical industry. mAbs 5, 621–623 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Li, X. et al. Site-specific dual antibody conjugation via engineered cysteine and selenocysteine residues. Bioconjug. Chem. 26, 2243–2248 (2015). This paper is one the first examples of a dual warhead ADC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Jackson, D. et al. In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody–drug conjugates. PLoS ONE 9, e83865 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Xu, Y. et al. RP-HPLC DAR characterization of site-specific antibody drug conjugates produced in a cell-free expression system. Org. Process Res. Dev. 20, 1034–1043 (2016).

    Article  CAS  Google Scholar 

  174. Dorywalska, M. et al. Effect of attachment site on stability of cleavable antibody drug conjugates. Bioconjug. Chem. 26, 650–659 (2015).

    Article  CAS  PubMed  Google Scholar 

  175. Harris, L. et al. SeriMabs: N-terminal serine modification enables modular, site-specific payload incorporation into antibody-drug conjugates (ADCs). Cancer Res. 75, abstr. 647 (2015).

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alain Beck.

Ethics declarations

Competing interests

A.B., L.G. and N.C. are employees of the Pierre Fabre Research Institute, Toulouse, France, which develops mAbs and ADCs, and has a collaboration agreement with AbbVie for the development of hepatocyte growth factor receptor (HGFR)-specific antibodies and ADCs (ABT-700 and ABBV-399). C.D. has received research funding from Pierre Fabre and Sanofi, and has worked as a consultant for Sanofi and Bristol-Myers Squibb.

Related links

PowerPoint slides

Glossary

Permeability glycoprotein 1

(PGP; also known as multidrug resistance protein 1 (MDR1), ATP-binding cassette subfamily B member 1 (ABCB1) or CD243). It is an important protein of the cell membrane that pumps many foreign substances out of cells.

Strain-promoted azide–alkyne cycloaddition

(SPAAC). A bioorthogonal non-toxic ligation reaction that allows site-specific conjugation.

Glycan remodelling

Enzymatic tailoring of the oligosaccharides of an antibody to enable the introduction of reactive groups that are exploited for the site-specific attachment of cytotoxic drugs.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beck, A., Goetsch, L., Dumontet, C. et al. Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov 16, 315–337 (2017). https://doi.org/10.1038/nrd.2016.268

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd.2016.268

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer