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Unlocking the potential of antibody–drug conjugates for cancer therapy

Abstract

Nine different antibody–drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors. Many of these drugs have impressive activity against treatment-refractory cancers, although hurdles impeding their broader use remain, including systemic toxicity, inadequate biomarkers for patient selection, acquired resistance and unknown benefit in combination with other cancer therapies. Emerging evidence indicates that the efficacy of a given ADC depends on the intricacies of how the antibody, linker and payload components interact with the tumour and its microenvironment, all of which have important clinical implications. In this Review, we discuss the current state of knowledge regarding the design, mechanism of action and clinical efficacy of ADCs as well as the apparent limitations of this treatment class. We then propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer.

Key points

  • Antibody–drug conjugates (ADCs) comprise three main components: an antibody, a linker and a payload. The clinical properties of ADCs depend on the characteristics of all three of these components.

  • The mechanism of action of ADCs is complex, often requiring drug internalization followed by intracellular processing and payload release. Unlike many standard therapies used in oncology, ADCs must be acted upon by cancer cells for optimal effectiveness.

  • The pharmacodynamic properties of ADCs make them uniquely suited for activity in treatment-refractory cancers, which is reflected in the current clinical indications for ADCs in oncology.

  • ADCs exhibit both on-target and off-target toxicities; while most toxicities seem to be related to the nature of the payload, notable examples of target-dependent toxicities exist.

  • Important and potentially practice-changing innovations in ADC design, biomarker development and combination therapies are ongoing in preclinical and clinical studies.

  • An improved understanding of the interactions between ADCs and tumours is essential for clinicians and scientists to realize the true potential of this drug class for the treatment of cancer.

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Fig. 1: Modular components of ADCs.
Fig. 2: Mechanisms of action of ADCs.
Fig. 3: Proposed mechanisms of resistance to ADCs.
Fig. 4: Rational combination therapy strategies to augment ADC activity.

References

  1. Tolcher, A. W. Antibody drug conjugates: lessons from 20 years of clinical experience. Ann. Oncol. 27, 2168–2172 (2016).

    CAS  PubMed  Google Scholar 

  2. 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).

    CAS  PubMed  Google Scholar 

  3. Carter, P. J. & Senter, P. D. Antibody-drug conjugates for cancer therapy. Cancer J. 14, 154–169 (2008).

    CAS  PubMed  Google Scholar 

  4. Sievers, E. L. & Senter, P. D. Antibody-drug conjugates in cancer therapy. Annu. Rev. Med. 64, 15–29 (2013).

    CAS  PubMed  Google Scholar 

  5. Drake, P. M. & Rabuka, D. Recent developments in ADC technology: preclinical studies signal future clinical trends. BioDrugs 31, 521–531 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  7. Beck, A., Goetsch, L., Dumontet, C. & Corvaia, N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).

    CAS  PubMed  Google Scholar 

  8. Ehrlich, P. in The Collected Papers of Paul Ehrlich 596-618 (Pergamon, 1956).

  9. Strebhardt, K. & Ullrich, A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat. Rev. Cancer 8, 473–480 (2008).

    CAS  PubMed  Google Scholar 

  10. Mathe, G., Lou, T. B. & Bernard, J. Effet sur la leucemie 1210 de la souris dune combinaison par diazotation da-methopterine et de gamma-globulines de hamsters porteurs de cette leucemie par heterogreffe. Presse Med. 66, 571–571 (1958).

    Google Scholar 

  11. Rowland, G. F., Oneill, G. J. & Davies, D. A. L. Suppression of tumor-growth in mice by a drug-antibody conjugate using a novel approach to linkage. Nature 255, 487–488 (1975).

    CAS  PubMed  Google Scholar 

  12. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    CAS  PubMed  Google Scholar 

  13. Moolten, F. L. & Cooperband, S. R. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 169, 68–70 (1970).

    CAS  PubMed  Google Scholar 

  14. Elias, D. J. et al. Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunconjugate in patients with non-small cell lung carcinoma. Cancer Res. 50, 4154–4159 (1990).

    CAS  PubMed  Google Scholar 

  15. Saleh, M. N. et al. Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-Doxorubicin in patients with Lewis Y-expressing epithelial tumors. J. Clin. Oncol. 18, 2282–2292 (2000).

    CAS  PubMed  Google Scholar 

  16. Schneck, D. et al. Disposition of a murine monoclonal antibody vinca conjugate (KS1/4-DAVLB) in patients with adenocarcinomas. Clin. Pharmacol. Ther. 47, 36–41 (1990).

    CAS  PubMed  Google Scholar 

  17. Ford, C. H. et al. Localisation and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer. Br. J. Cancer 47, 35–42 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sievers, E. L. et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J. Clin. Oncol. 19, 3244–3254 (2001).

    CAS  PubMed  Google Scholar 

  19. 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 

  20. Younes, A. et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J. Clin. Oncol. 30, 2183–2189 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Carter, P. J. & Lazar, G. A. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat. Rev. Drug Discov. 17, 197–223 (2018).

    CAS  PubMed  Google Scholar 

  24. Schuurman, J. & Parren, P. W. Editorial overview: special section: new concepts in antibody therapeutics: what’s in store for antibody therapy? Curr. Opin. Immunol. 40, Vii–Xiii (2016).

    CAS  PubMed  Google Scholar 

  25. Vidarsson, G., Dekkers, G. & Rispens, T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. https://doi.org/10.3389/fimmu.2014.00520 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tiller, K. E. & Tessier, P. M. Advances in antibody design. Annu. Rev. Biomed. Eng. 17, 191–216 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Yu, J. F., Song, Y. P. & Tian, W. How to select IgG subclasses in developing anti-tumor therapeutic antibodies. J. Hematol. Oncol. 13, 45 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  PubMed  Google Scholar 

  29. Hoffmann, R. M. et al. Antibody structure and engineering considerations for the design and function of antibody drug conjugates (ADCs). Oncoimmunology 7, e1395127 (2018).

    PubMed  Google Scholar 

  30. Hock, M. B., Thudium, K. E., Carrasco-Triguero, M. & Schwabe, N. F. Immunogenicity of Antibody drug conjugates: bioanalytical methods and monitoring strategy for a novel therapeutic modality. AAPS J. 17, 35–43 (2015).

    CAS  PubMed  Google Scholar 

  31. von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019).

    Google Scholar 

  32. Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).

    CAS  PubMed  Google Scholar 

  33. Bardia, A. et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N. Engl. J. Med. 380, 741–751 (2019).

    CAS  PubMed  Google Scholar 

  34. Rosenberg, J. E. et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J. Clin. Oncol. 37, 2592–2600 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Stepan, L. P. et al. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J. Histochem. Cytochem. 59, 701–710 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Pegram, M. D., Konecny, G. & Slamon, D. J. The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treat. Res. 103, 57–75 (2000).

    CAS  PubMed  Google Scholar 

  37. Challita-Eid, P. M. et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 76, 3003–3013 (2016).

    CAS  PubMed  Google Scholar 

  38. van der Weyden, C. A., Pileri, S. A., Feldman, A. L., Whisstock, J. & Prince, H. M. Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions. Blood Cancer J. 7, e603 (2017).

    PubMed  PubMed Central  Google Scholar 

  39. Tedder, T. F., Tuscano, J., Sato, S. & Kehrl, J. H. CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Annu. Rev. Immunol. 15, 481–504 (1997).

    CAS  PubMed  Google Scholar 

  40. Pfeifer, M. et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 29, 1578–1586 (2015).

    CAS  PubMed  Google Scholar 

  41. Gebhart, G. et al. Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial. Ann. Oncol. 27, 619–624 (2016).

    CAS  PubMed  Google Scholar 

  42. Metzger, O. et al. HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: results from a prospective clinical trial. J. Clin. Oncol. 37 (Suppl. 15), 502 (2019).

    Google Scholar 

  43. 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).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  45. Jain, N., Smith, S. W., Ghone, S. & Tomczuk, B. Current ADC linker chemistry. Pharm. Res. 32, 3526–3540 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Tsuchikama, K. & An, Z. Q. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell 9, 33–46 (2018).

    CAS  PubMed  Google Scholar 

  47. Drake, P. M. & Rabuka, D. 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, 174–180 (2015).

    CAS  PubMed  Google Scholar 

  48. Hamann, P. R. et al. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem. 13, 47–58 (2002).

    CAS  PubMed  Google Scholar 

  49. Erickson, H. K. et al. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol. Cancer Ther. 11, 1133–1142 (2012).

    CAS  PubMed  Google Scholar 

  50. 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).

    PubMed  PubMed Central  Google Scholar 

  51. Polson, A. G. et al. Antibody-drug conjugates for the treatment of non-Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 69, 2358–2364 (2009).

    CAS  PubMed  Google Scholar 

  52. Kanellos, J., Pietersz, G. A. & Mckenzie, I. F. Studies of methotrexate monoclonal-antibody conjugates for immunotherapy. J. Natl Cancer Inst. 75, 319–332 (1985).

    CAS  PubMed  Google Scholar 

  53. Starling, J. J. et al. In vivo antitumor activity of a monoclonal antibody-Vinca alkaloid immunoconjugate directed against a solid tumor membrane antigen characterized by heterogeneous expression and noninternalization of antibody-antigen complexes. Cancer Res. 51, 2965–2972 (1991).

    CAS  PubMed  Google Scholar 

  54. Trail, P. A. et al. Cure of xenografted human carcinomas by Br96-doxorubicin immunoconjugates. Science 261, 212–215 (1993).

    CAS  PubMed  Google Scholar 

  55. Teicher, B. A. & Chari, R. V. J. Antibody conjugate therapeutics: challenges and potential. Clin. Cancer Res. 17, 6389–6397 (2011).

    CAS  PubMed  Google Scholar 

  56. Sedlacek, H. H. Antibodies as Carriers of Cytotoxicity (Karger, 1992).

  57. Mach, J.-P. et al. Tumor localization of radio-labeled antibodies against carcinoembryonic antigen in patients with carcinoma: a critical evaluation. N. Engl. J. Med. 303, 5–10 (1980).

    CAS  PubMed  Google Scholar 

  58. Liu, C. N. et al. Eradication of large colon tumor xenografts by targeted delivery of maytansinoids. Proc. Natl Acad. Sci. USA 93, 8618–8623 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  60. Waight, A. B. et al. Structural basis of microtubule destabilization by potent auristatin anti-mitotics. PLoS ONE 11, e0160890 (2016).

    PubMed  PubMed Central  Google Scholar 

  61. Ricart, A. D. Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin. Clin. Cancer Res. 17, 6417–6427 (2011).

    CAS  PubMed  Google Scholar 

  62. Oroudjev, E. et al. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol. Cancer Ther. 9, 2700–2713 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. 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).

    CAS  PubMed  Google Scholar 

  65. Sun, X. X. et al. Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-maytansinoid conjugates. Bioconjugate Chem. 28, 1371–1381 (2017).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Ogitani, Y., Hagihara, K., Oitate, M., Naito, H. & Agatsuma, T. 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 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, F. et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 76, 2710–2719 (2016).

    CAS  PubMed  Google Scholar 

  69. Tolcher, A. W. The evolution of antibody-drug conjugates: a positive inflexion point. Am. Soc. Clin. Oncol. Educ. Book 40, 1–8 (2020).

    PubMed  Google Scholar 

  70. Girish, S. et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother. Pharmacol. 69, 1229–1240 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Bender, B. C. et al. 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, 591–601 (2012).

    CAS  PubMed  Google Scholar 

  72. Singh, A. P. & Shah, D. K. Application of a PK-PD modeling and simulation-based strategy for clinical translation of antibody-drug conjugates: a case study with trastuzumab emtansine (T-DM1). AAPS J. 19, 1054–1070 (2017).

    CAS  PubMed  Google Scholar 

  73. Fujimori, K., Covell, D. G., Fletcher, J. E. & Weinstein, J. N. A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J. Nucl. Med. 31, 1191–1198 (1990).

    CAS  PubMed  Google Scholar 

  74. Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumours. Nat. Rev. Cancer 6, 583–592 (2006).

    CAS  PubMed  Google Scholar 

  75. Matsumura, Y. Cancer stromal targeting therapy to overcome the pitfall of EPR effect. Adv. Drug Deliv. Rev. 154-155, 142–150 (2020).

    CAS  PubMed  Google Scholar 

  76. Thurber, G. M. & Wittrup, K. D. A mechanistic compartmental model for total antibody uptake in tumors. J. Theor. Biol. 314, 57–68 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Chari, R. V. J. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc. Chem. Res. 41, 98–107 (2008).

    CAS  PubMed  Google Scholar 

  78. Lu, G. et al. Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates. Nat. Commun. 11, 5667 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Alley, S. C. et al. The pharmacologic basis for antibody-auristatin conjugate activity. J. Pharmacol. Exp. Ther. 330, 932–938 (2009).

    CAS  PubMed  Google Scholar 

  80. Giddabasappa, A. et al. Biodistribution and targeting of Anti-5T4 antibody-drug conjugate using fluorescence molecular tomography. Mol. Cancer Ther. 15, 2530–2540 (2016).

    CAS  PubMed  Google Scholar 

  81. Juweid, M. et al. Micropharmacology of monoclonal antibodies in solid tumors: direct experimental evidence for a binding site barrier. Cancer Res. 52, 5144–5153 (1992).

    CAS  PubMed  Google Scholar 

  82. Ritchie, M., Tchistiakova, L. & Scott, N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. mAbs 5, 13–21 (2013).

    PubMed  PubMed Central  Google Scholar 

  83. Acchione, M., Kwon, H., Jochheim, C. M. & Atkins, W. M. Impact of linker and conjugation chemistry on antigen binding, Fc receptor binding and thermal stability of model antibody-drug conjugates. mAbs 4, 362–372 (2012).

    PubMed  PubMed Central  Google Scholar 

  84. Redman, J. M., Hill, E. M., AlDeghaither, D. & Weiner, L. M. Mechanisms of action of therapeutic antibodies for cancer. Mol. Immunol. 67, 28–45 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Junttila, T. T., Li, G. M., 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).

    CAS  PubMed  Google Scholar 

  86. Moasser, M. M. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26, 6469–6487 (2007).

    CAS  PubMed  PubMed Central  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  89. Jedema, I. et al. Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity. Leukemia 18, 316–325 (2004).

    CAS  PubMed  Google Scholar 

  90. Sutherland, M. S. K. et al. Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J. Biol. Chem. 281, 10540–10547 (2006).

    CAS  PubMed  Google Scholar 

  91. Erickson, H. K. et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 66, 4426–4433 (2006).

    CAS  PubMed  Google Scholar 

  92. Staudacher, A. H. & Brown, M. P. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Brit. J. Cancer 117, 1736–1742 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kovtun, Y. V. et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 66, 3214–3221 (2006).

    CAS  PubMed  Google Scholar 

  94. Dokter, W. 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, 692–7030 (2015).

    PubMed  Google Scholar 

  95. Singh, A. P., Sharma, S. & Shah, D. K. Quantitative characterization of in vitro bystander effect of antibody-drug conjugates. J. Pharmacokinet. Pharmacodyn. 43, 567–582 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Vasan, N., Baselga, J. & Hyman, D. M. A view on drug resistance in cancer. Nature 575, 299–309 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Drakaki, A. et al. Docetaxel with or without ramucirumab after immune checkpoint inhibition in platinum-refractory metastatic urothelial carcinoma (mUC): Prespecified subgroup analysis from the phase 3 RANGE trial. J. Clin. Oncol. 36 (Suppl. 6), 434 (2018).

    Google Scholar 

  98. Shitara, K. et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 382, 2419–2430 (2020).

    CAS  PubMed  Google Scholar 

  99. Barok, M., Tanner, M., Koninki, K. & Isola, J. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo. Breast Cancer Res. 13, R46 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Coley, H. M. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat. Rev. 34, 378–390 (2008).

    CAS  PubMed  Google Scholar 

  101. Perez, E. A. et al. Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J. Clin. Oncol. 22, 2849–2855 (2004).

    CAS  PubMed  Google Scholar 

  102. National Comprehensive Cancer Network. Breast cancer https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (2021).

  103. Seol, H. et al. Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance. Mod. Pathol. 25, 938–948 (2012).

    CAS  PubMed  Google Scholar 

  104. Modi, S. et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a Phase Ib study. J. Clin. Oncol. 38, 1887–1896 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Tijink, B. M. et al. 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, 6064–6072 (2006).

    CAS  PubMed  Google Scholar 

  106. Kerckhove, N. et al. Long-term effects, pathophysiological mechanisms, and risk factors of chemotherapy-induced peripheral neuropathies: a comprehensive literature review. Front. Pharmacol. 8, 86 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. Kamba, T. & McDonald, D. M. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Brit. J. Cancer 96, 1788–1795 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Sorrentino, M. F., Kim, J., Foderaro, A. E. & Truesdell, A. G. 5-fluorouracil induced cardiotoxicity: review of the literature. Cardiol. J. 19, 453–458 (2012).

    PubMed  Google Scholar 

  109. Sakamoto, S. et al. Expression of Lewisa, Lewisb, Lewisx, Lewisy, siayl-Lewisa, and sialyl-Lewisx blood group antigens in human gastric carcinoma and in normal gastric tissue. Cancer Res. 49, 745–752 (1989).

    CAS  PubMed  Google Scholar 

  110. Tolcher, A. W. et al. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17, 478–484 (1999).

    CAS  PubMed  Google Scholar 

  111. Riechelmann, H. et al. Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma. Oral. Oncol. 44, 823–829 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Banerji, U. et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 20, 1124–1135 (2019).

    CAS  PubMed  Google Scholar 

  114. Sendur, M. A., Aksoy, S. & Altundag, K. Cardiotoxicity of novel HER2-targeted therapies. Curr. Med. Res. Opin. 29, 1015–1024 (2013).

    CAS  PubMed  Google Scholar 

  115. Ponde, N. et al. Trastuzumab emtansine (T-DM1)-associated cardiotoxicity: Pooled analysis in advanced HER2-positive breast cancer. Eur. J. Cancer 126, 65–73 (2020).

    CAS  PubMed  Google Scholar 

  116. Cote, G. M., Sawyer, D. B. & Chabner, B. A. ERBB2 inhibition and heart failure. N. Engl. J. Med. 367, 2150–2153 (2012).

    CAS  PubMed  Google Scholar 

  117. Saber, H. & Leighton, J. K. An FDA oncology analysis of antibody-drug conjugates. Regul. Toxicol. Pharm. 71, 444–452 (2015).

    CAS  Google Scholar 

  118. Masters, J. C., Nickens, D. J., Xuan, D., Shazer, R. L. & Amantea, M. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest. New Drugs 36, 121–135 (2018).

    CAS  PubMed  Google Scholar 

  119. Eaton, J. S., Miller, P. E., Mannis, M. J. & Murphy, C. J. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J. Ocul. Pharmacol. Ther. 31, 589–604 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. de Goeij, B. E. & Lambert, J. M. New developments for antibody-drug conjugate-based therapeutic approaches. Curr. Opin. Immunol. 40, 14–23 (2016).

    PubMed  Google Scholar 

  121. Bardia, A. et al. 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, 2141–2148 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Cardillo, T. M., Govindan, S. V., Sharkey, R. M., Trisal, P. & Goldenberg, D. M. 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 (2011).

    CAS  PubMed  Google Scholar 

  123. Mahalingaiah, P. K. et al. Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates. Pharmacol. Ther. 200, 110–125 (2019).

    CAS  PubMed  Google Scholar 

  124. Uppal, H. et al. Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1). Clin. Cancer Res. 21, 123–133 (2015).

    CAS  PubMed  Google Scholar 

  125. Zhao, H. et al. Modulation of macropinocytosis-mediated internalization decreases ocular toxicity of antibody-drug conjugates. Cancer Res. 78, 2115–2126 (2018).

    CAS  PubMed  Google Scholar 

  126. Makawita, S. & Meric-Bernstam, F. Antibody-drug conjugates: patient and treatment selection. Am. Soc. Clin. Oncol. Educ. Book 40, 1–10 (2020).

    PubMed  Google Scholar 

  127. Ott, P. A. et al. Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma. J. Clin. Oncol. 32, 3659–3666 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 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).

    CAS  PubMed  Google Scholar 

  129. Saber, H., Simpson, N., Ricks, T. K. & Leighton, J. K. An FDA oncology analysis of toxicities associated with PBD-containing antibody-drug conjugates. Regul. Toxicol. Pharm. 107, 104429 (2019).

    CAS  Google Scholar 

  130. Drago, J. Z. et al. Inferences about drug safety in phase 3 trials in oncology: Examples from advanced prostate cancer. J. Natl Cancer Inst. https://doi.org/10.1093/jnci/djaa134 (2020).

    Article  PubMed Central  Google Scholar 

  131. Yardley, D. A. et al. Quantitative measurement of HER2 expression in breast cancers: comparison with ‘real-world’ routine HER2 testing in a multicenter collaborative biomarker Study and correlation with overall survival. Breast Cancer Res. 17, 41 (2015).

    PubMed  PubMed Central  Google Scholar 

  132. Wolff, A. C. et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch. Pathol. Lab. Med. 142, 1364–1382 (2018).

    PubMed  Google Scholar 

  133. Li, B. T. et al. Ado-trastuzumab emtansine for patients With HER2-mutant lung cancers: results from a phase II basket trial. J. Clin. Oncol. 36, 2532–2537 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Tarantino, P. et al. HER2-low breast cancer: pathological and clinical landscape. J. Clin. Oncol. 38, 1951–1962 (2020).

    CAS  PubMed  Google Scholar 

  135. Hurvitz, S. A. et al. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. https://www.abstractsonline.com/pp8/#!/9223/presentation/674 (2020).

  136. Gainor, J. F. & Shaw, A. T. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J. Clin. Oncol. 31, 3987–3996 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  138. 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).

    CAS  PubMed  Google Scholar 

  139. Li, G. M. et al. Mechanisms of acquired resistance to trastuzumab emtansine in breast cancer cells. Mol. Cancer Ther. 17, 1441–1453 (2018).

    CAS  PubMed  Google Scholar 

  140. Rios-Luci, C. et al. Resistance to the antibody-drug conjugate T-DM1 is based in a reduction in lysosomal proteolytic activity. Cancer Res. 77, 4639–4651 (2017).

    CAS  PubMed  Google Scholar 

  141. Chen, R. et al. CD30 downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin. Mol. Cancer Ther. 14, 1376–1384 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Walter, R. B. et al. CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood 109, 4168–4170 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C. & Gottesman, M. M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5, 219–234 (2006).

    CAS  PubMed  Google Scholar 

  144. Jackson, D. & Stover, D. Using the lessons learned from the clinic to improve the preclinical development of antibody drug conjugates. Pharm. Res. 32, 3458–3469 (2015).

    CAS  PubMed  Google Scholar 

  145. Takegawa, N. et al. DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance. Int. J. Cancer 141, 1682–1689 (2017).

    CAS  PubMed  Google Scholar 

  146. Chandarlapaty, S. et al. Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer. Clin. Cancer Res. 18, 6784–6791 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Baselga, J. et al. Relationship between tumor biomarkers (BM) and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC). Cancer Res. 73, LB-63 (2013).

    Google Scholar 

  148. Scheuer, W. et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 69, 9330–9336 (2009).

    CAS  PubMed  Google Scholar 

  149. Kang, J. C. et al. Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy. Nat. Biotechnol. 37, 523–526 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Li, B. T. et al. HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers. Cancer Discov. 10, 674–687 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Brevet, M., Arcila, M. & Ladanyi, M. Assessment of EGFR mutation status in lung adenocarcinoma by immunohistochemistry using antibodies specific to the two major forms of mutant EGFR. J. Mol. Diagn. 12, 169–176 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Hamblett, K. J. et al. AMG 595, an anti-EGFRvIII antibody–drug conjugate, induces potent antitumor activity against EGFRvIII-expressing glioblastoma. Mol. Cancer Ther. 14, 1614–1624 (2015).

    CAS  PubMed  Google Scholar 

  153. Comer, F., Gao, C. & Coats, S. in Innovations for Next-Generation Antibody-Drug Conjugates (ed. Damelin, M.) 267–280 (Springer International Publishing, 2018).

  154. 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 35, 948–949 (2019).

    CAS  PubMed  Google Scholar 

  155. de Goeij, B. E. et al. Efficient payload delivery by a bispecific antibody-drug conjugate targeting HER2 and CD63. Mol. Cancer Ther. 15, 2688–2697 (2016).

    PubMed  Google Scholar 

  156. Andreev, J. et al. Bispecific antibodies and antibody-drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol. Cancer Ther. 16, 681–693 (2017).

    CAS  PubMed  Google Scholar 

  157. Zhuang, C. et al. Small molecule-drug conjugates: a novel strategy for cancer-targeted treatment. Eur. J. Med. Chem. 163, 883–895 (2019).

    CAS  PubMed  Google Scholar 

  158. Casi, G. & Neri, D. Antibody-drug conjugates and small molecule-drug conjugates: opportunities and challenges for the development of selective anticancer cytotoxic agents. J. Med. Chem. 58, 8751–8761 (2015).

    CAS  PubMed  Google Scholar 

  159. Whalen, K. A. et al. Targeting the somatostatin receptor 2 with the miniaturized drug conjugate, PEN-221: a potent and novel therapeutic for the treatment of small cell lung cancer. Mol. Cancer Ther. 18, 1926–1936 (2019).

    CAS  PubMed  Google Scholar 

  160. Kumthekar, P. et al. ANG1005, a brain-penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases. Clin. Cancer Res. 26, 2789–2799 (2020).

    CAS  PubMed  Google Scholar 

  161. Gebleux, R., Stringhini, M., Casanova, R., Soltermann, A. & Neri, D. Non-internalizing antibody-drug conjugates display potent anti-cancer activity upon proteolytic release of monomethyl auristatin E in the subendothelial extracellular matrix. Int. J. Cancer 140, 1670–1679 (2017).

    CAS  PubMed  Google Scholar 

  162. Carneiro, B. A. & El-Deiry, W. S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 17, 395–417 (2020).

    PubMed  PubMed Central  Google Scholar 

  163. Mohit, E. & Rafati, S. Chemokine-based immunotherapy: delivery systems and combination therapies. Immunotherapy 4, 807–840 (2012).

    CAS  PubMed  Google Scholar 

  164. Cetinbas, N. M. et al. Tumor cell-intrinsic STING pathway is activated in the presence of cues from immune cells and contributes to the anti-tumor activity of tumor cell-targeted STING agonist antibody-drug conjugates [abstract]. J. Immunother. Cancer 8, A373 (2020).

    Google Scholar 

  165. Moyes, K. et al. A systemically administered, conditionally active TLR8 agonist for the treatment of HER2-expressing tumors. Cancer Res. 79, 3271 (2019).

    Google Scholar 

  166. Witzig, T. E. et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J. Clin. Oncol. 20, 2453–2463 (2002).

    CAS  PubMed  Google Scholar 

  167. Kaminski, M. S. et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N. Engl. J. Med. 352, 441–449 (2005).

    CAS  PubMed  Google Scholar 

  168. Leahy, M. F., Seymour, J. F., Hicks, R. J. & Turner, J. H. Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin’s lymphoma. J. Clin. Oncol. 24, 4418–4425 (2006).

    CAS  PubMed  Google Scholar 

  169. Gill, M. R., Falzone, N., Du, Y. & Vallis, K. A. Targeted radionuclide therapy in combined-modality regimens. Lancet Oncol. 18, e414–e423 (2017).

    CAS  PubMed  Google Scholar 

  170. Dovgan, I., Koniev, O., Kolodych, S. & Wagner, A. Antibody-oligonucleotide conjugates as therapeutic, imaging, and detection agents. Bioconjug Chem. 30, 2483–2501 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  172. Dornan, D. & Settleman, J. in Antibody-Drug Conjugates and Immunotoxins: From Pre-Clinical Development to Therapeutic Applications (ed. Phillips, G.L.) 77–90 (Springer, 2013).

  173. Boshuizen, J. et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat. Med. 24, 203–212 (2018).

    CAS  PubMed  Google Scholar 

  174. Yonesaka, K. et al. An HER3-targeting antibody-drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC. Oncogene 38, 1398–1409 (2019).

    CAS  PubMed  Google Scholar 

  175. Ponte, J. F. et al. Mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, potentiates the activity of standard of care therapeutics in ovarian cancer models. Neoplasia 18, 775–784 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. O’Malley, D. M. et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRalpha)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol. Oncol. 157, 379–385 (2020).

    PubMed  Google Scholar 

  177. Moore, K. N. et al. Phase 1b study of anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) in patients with platinum-sensitive recurrent ovarian cancer. Gynecol. Oncol. 158, 631–639 (2020).

    CAS  PubMed  Google Scholar 

  178. Saatci, O. et al. Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer. Oncogene 37, 2251–2269 (2018).

    CAS  PubMed  Google Scholar 

  179. Zhong, H. et al. Improved therapeutic window in BRCA-mutant tumors with antibody-linked pyrrolobenzodiazepine dimers with and without PARP inhibition. Mol. Cancer Ther. 18, 89–99 (2019).

    CAS  PubMed  Google Scholar 

  180. Cardillo, T. M. et al. Synthetic lethality exploitation by an anti-trop-2-SN-38 antibody-drug conjugate, IMMU-132, Plus PARP inhibitors in BRCA1/2-wild-type triple-negative breast cancer. Clin. Cancer Res. 23, 3405–3415 (2017).

    CAS  PubMed  Google Scholar 

  181. 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).

    CAS  PubMed  Google Scholar 

  182. Emens, L. A. et al. Results from KATE2, a randomized phase 2 study of atezolizumab (atezo) plus trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+advanced breast cancer (BC). Cancer Res. 79, PD3-01 (2019).

    Google Scholar 

  183. Rosenberg, J. E. et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J. Clin. Oncol. 38, 441–441 (2020).

    Google Scholar 

  184. Macpherson, I. R. & Cassidy, J. Challenges in combinational oncology studies. Pharm. Med. 22, 85–97 (2008).

    Google Scholar 

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Acknowledgements

All authors acknowledge support from the NCI Cancer Center Support Grant P30-CA008748. J.Z.D. acknowledges support from the Paul Calabresi Career Development Award for Clinical Oncology K12 CA184746 and a 2020 Conquer Cancer–Breast Cancer Research Foundation Young Investigator Award. S.C. acknowledges support from the Breast Cancer Research Foundation. The authors thank Linda Vahdat and Pedram Razavi of Memorial Sloan Kettering Cancer Center for editorial assistance and appreciate the helpful comments and suggestions provided by the journal editors and reviewers.

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Correspondence to Shanu Modi or Sarat Chandarlapaty.

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J.Z.D. has received Honoraria from OncLive. S.M. has received institutional research support from AstraZeneca, Daiichi Sankyo, Genentech, Novartis and Seattle Genetics; has participated in consulting/advisory boards for AstraZeneca, Daiichi Sankyo, Genentech, Macrogenics and Seattle Genetics; and has received speakers’ bureau from AstraZeneca, Daiichi Sankyo, Genentech and Seattle Genetics. S.C. has received consulting fees from Eli Lilly, Novartis and Paige.ai, and has received research support (via his institution) from Daiichi-Sankyo, Eli Lilly, Novartis and Sanofi.

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Drago, J.Z., Modi, S. & Chandarlapaty, S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol 18, 327–344 (2021). https://doi.org/10.1038/s41571-021-00470-8

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