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

Nature Reviews Drug Discovery

Volumn 16, Issue 5, 2017, Pages 315-337

  Beck, Alain ^a   Goetsch, Liliane ^a   Dumontet, Charles ^b,c,d   Corvaïa, Nathalie ^a  

^a INSTITUT DE RECHERCHE PIERRE FABRE   (France)

^b INSERM   (France)

^c UNIVERSITÉ DE LYON   (France)

^d HOSPICES CIVILS DE LYON   (France)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID DERIVATIVE; ANTIBODY; ANTIBODY DRUG CONJUGATE; AURISTATIN DERIVATIVE; BENZODIAZEPINE DERIVATIVE; CALICHEAMICIN DERIVATIVE; CAMPTOTHECIN DERIVATIVE; CD33 ANTIGEN; CYSTEINE; CYSTEINE DERIVATIVE; DOXORUBICIN; DUOCARMYCIN DERIVATIVE; GLYCAN; MAYTANSINOID DERIVATIVE; SERINE; TUBULYSIN DERIVATIVE; UNCLASSIFIED DRUG; ANTIBODY CONJUGATE; ANTINEOPLASTIC AGENT; BRENTUXIMAB VEDOTIN; MAYTANSINE; MONOCLONAL ANTIBODY; TRASTUZUMAB EMTANSINE; TUMOR ANTIGEN;

ACUTE MYELOID LEUKEMIA; AMINO TERMINAL SEQUENCE; BINDING SITE; BYSTANDER EFFECT; CANCER IMMUNOTHERAPY; DRUG CONJUGATION; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG INDICATION; DRUG POTENCY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG TARGETING; HUMAN; MULTIDRUG RESISTANCE; NONHUMAN; PHARMACEUTICAL ENGINEERING; PROCESS OPTIMIZATION; REVIEW; ANALOGS AND DERIVATIVES; ANIMAL; DRUG STABILITY; IMMUNOLOGY; NEOPLASMS; PATHOLOGY;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTIGENS, NEOPLASM; ANTINEOPLASTIC AGENTS; DRUG DESIGN; DRUG STABILITY; HUMANS; IMMUNOCONJUGATES; MAYTANSINE; NEOPLASMS;

EID: 85015612231     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2016.268     Document Type: Review

References (175)

1. Perez, H. L., et al. Antibody-drug conjugates: current status and future directions. Drug Discov. Today 19, 869-881 (2014
2. Beck, A., et al. The next generation of antibody-drug conjugates comes of age. Discov. Med. 10, 329-339 (2010
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
4. Younes, A., Yasothan, U., & Kirkpatrick, P. Brentuximab vedotin. Nat. Rev. Drug Discov. 11, 19-20 (2012
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
6. Mullard, A. Maturing antibody-drug conjugate pipeline hits 30. Nat. Rev. Drug Discov. 12, 329-332 (2013
7. Beck, A., & Reichert, J. M. Antibody-drug conjugates: present and future. mAbs 6, 15-17 (2014
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
9. Verma, V. A., et al. The cryptophycins as potent payloads for antibody drug conjugates. Bioorg. Med. Chem. Lett. 25, 864-868 (2015
10. Dumontet, C., & Jordan, M. A. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 9, 790-803 (2010
11. Dere, R., et al. PK assays for antibody-drug conjugates: case study with ado-Trastuzumab emtansine. Bioanalysis 5, 1025-1040 (2013
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
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
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
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
16. Damelin, M., Zhong, W., Myers, J., & Sapra, P. Evolving strategies for target selection for antibody-drug conjugates. Pharm. Res. 32, 3494-3507 (2015
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
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
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
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
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
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
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
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
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
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
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
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
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
30. Fauteux, F., et al. Computational selection of antibody-drug conjugate targets for breast cancer. Oncotarget 7, 2555-2571 (2016
31. Wagner-Rousset, E., et al. Antibody-drug conjugate model fast characterization by LC MS following IdeS proteolytic digestion. mAbs 6, 173-184 (2014
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
33. Maderna, A., et al. Discovery of cytotoxic dolastatin 10 analogues with N terminal modifications. J. Med. Chem. 57, 10527-10543 (2014
34. Rouleau, C., et al. Anti-endosialin antibody-drug conjugate: potential in sarcoma and other malignancies. Mol. Cancer Ther. 14, 2081-2089 (2015
35. Issell, B. F., & Crooke, S. T. Maytansine. Cancer Treat. Rev. 5, 199-207 (1978
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
37. Shor, B., Gerber, H. P., & Sapra, P. Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies. Mol. Immunol. 67, 107-116 (2015
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
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
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
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
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
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
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
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
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
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
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
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
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
52. Nakada, T., et al. Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg. Med. Chem. Lett. 26, 1542-1545 (2016
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
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
55. Govindan, S. V., et al. Milatuzumab-SN 38 conjugates for the treatment of CD74+ cancers. Mol. Cancer Ther. 12, 968-978 (2013
56. Liu, Y., et al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 520, 697-701 (2015
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
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
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
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
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
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
63. Senter, P. D. Potent antibody-drug conjugates for cancer therapy. Curr. Opin. Chem. Biol. 13, 235-244 (2009
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
65. Kovtun, Y. V., & Goldmacher, V. S. Cell killing by antibody-drug conjugates. Cancer Lett. 255, 232-240 (2007
66. Katz, J., Janik, J. E., & Younes, A. Brentuximab vedotin (SGN 35). Clin. Cancer Res. 17, 6428-6436 (2011
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
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
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
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
71. Lyon, R. P., et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat. Biotechnol. 33, 733-735 (2015
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
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
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
75. Beck, A., et al. Cutting-edge mass spectrometry characterization of originator, biosimilar and biobetter antibodies. J. Mass Spectrom. 50, 285-297 (2015
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
77. Jones, T. D., et al. The INNs and outs of antibody nonproprietary names. mAbs 8, 1-9 (2016
78. Pottier, J., Chastang, R., Dumet, C., & Watier, H. Rethinking the INN system for therapeutic antibodies. mAbs 9, 5-11 (2017
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
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
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
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
83. McDonagh, C. F., et al. Engineered anti CD70 antibody-drug conjugate with increased therapeutic index. Mol. Cancer Ther. 7, 2913-2923 (2008
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
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
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
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
88. Beck, A., & Reichert, J. M. Marketing approval of mogamulizumab: a triumph for glyco-engineering. mAbs 4, 419-425 (2012
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
90. Dennler, P. Antibody conjugates: from heterogeneous populations to defined reagents. Antibodies 4, 197-224 (2015
91. Voynov, V., et al. Design and application of antibody cysteine variants. Bioconjug. Chem. 21, 385-392 (2010
92. Beck, A., et al. 8th Annual European Antibody Congress 2012: November 27-28, 2012, Geneva, Switzerland. mAbs 5, 339-357 (2013
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
94. Kline, T., et al. Methods to make homogenous antibody drug conjugates. Pharm. Res. 32, 3480-3493 (2015
95. Tian, F., et al. A general approach to site-specific antibody drug conjugates. Proc. Natl Acad. Sci. USA 111, 1766-1771 (2014
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
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
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
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
100. Strop, P., et al. Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem. Biol. 20, 161-167 (2013
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
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
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
104. Edelman, G. M., et al. The covalent structure of an entire gammaG immunoglobulin molecule. Proc. Natl Acad. Sci. USA 63, 78-85 (1969
105. Beck, A., Wurch, T., & Corva, N. Editorial: therapeutic antibodies and derivatives: from the bench to the clinic. Curr. Pharm. Biotechnol. 9, 421-422 (2008
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
107. Okeley, N. M., et al. Metabolic engineering of monoclonal antibody carbohydrates for antibody- drug conjugation. Bioconjug. Chem. 24, 1650-1655 (2013
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
109. Zhou, Q., et al. Site-specific antibody-drug conjugation through glycoengineering. Bioconjug. Chem. 25, 510-520 (2014
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
111. Qasba, P. K. Glycans of antibodies as a specific site for drug conjugation using glycosyltransferases. Bioconjug. Chem. 26, 2170-2175 (2015
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
113. Thompson, P., et al. Hydrolytically stable site-specific conjugation at the N terminus of an engineered antibody. Bioconjug. Chem. 26, 2085-2096 (2015
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
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
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
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
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
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
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
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
122. James, C. R., et al. Stabilization of cysteine-linked antibody drug conjugates with N aryl maleimides. J. Control. Release 220, 660-670 (2015
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
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
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
126. Yurkovetskiy, A. V., et al. A polymer-based antibody-vinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res. 75, 3365-3372 (2015
127. Shefet-Carasso, L., & Benhar, I. Antibody-Targeted drugs and drug resistance - challenges and solutions. Drug Resist. Updat. 18, 36-46 (2015
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
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
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
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
132. Loganzo, F., Sung, M., & Gerber, H. P. Mechanisms of resistance to antibody-drug conjugates. Mol. Cancer Ther. 15, 2825-2834 (2016
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
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
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
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
137. Mullard, A. 2015 FDA drug approvals. Nat. Rev. Drug Discov. 15, 73-76 (2016
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
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
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
141. Le, D. T., et al. PD 1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509-2520 (2015
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
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
144. Liu, R., Wang, R. E., & Wang, F. Antibody-drug conjugates for non-oncological indications. Expert. Opin. Biol. Ther. 16, 591-593 (2016
145. Wang, R. E., et al. An immunosuppressive antibody- drug conjugate. J. Am. Chem. Soc. 137, 3229-3232 (2015
146. Lehar, S. M., et al. Novel antibody-Antibiotic conjugate eliminates intracellular S. aureus. Nature 527, 323-328 (2015
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
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
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
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
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
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
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
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
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
156. Francois, Y. N., et al. Characterization of cetuximab Fc/2 dimers by off-line CZE MS. Anal. Chim. Acta 908, 168-176 (2016
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
158. Desnoyers, L. R., et al. Tumor-specific activation of an EGFR-Targeting probody enhances therapeutic index. Sci. Transl Med. 5, 207ra144 (2013
159. Bross, P. F., et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin. Cancer Res. 7, 1490-1496 (2001
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
161. Castaigne, S. Why is it so difficult to use gemtuzumab ozogamicin?. Blood 121, 4813-4814 (2013
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
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
164. Vidriales, M. B., et al. Prognostic value of S phase cells in AML patients. Br. J. Haematol. 89, 342-348 (1995
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
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
167. Donaghy, H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. mAbs 8, 659-671 (2016
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
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
171. Li, X., et al. Site-specific dual antibody conjugation via engineered cysteine and selenocysteine residues. Bioconjug. Chem. 26, 2243-2248 (2015
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
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
174. Dorywalska, M., et al. Effect of attachment site on stability of cleavable antibody drug conjugates. Bioconjug. Chem. 26, 650-659 (2015
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