HER2-Targeted ADCs: At the Forefront of ADC Technology Development

  • Kevin J. HamblettEmail author
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Ado-trastuzumab emtansine, referred to as trastuzumab-MCC-DM1 or T-DM1, was the first antibody drug conjugate (ADC) approved for HER2 positive metastatic breast cancer. This chapter reviews the development of trastuzumab-MCC-DM1, summarizes novel anti-HER2 antibody drug conjugate technologies in clinical trials, and discusses future directions of these technologies beyond targeting HER2. In an effort to improve the efficacy of trastuzumab a panel of drug linkers were conjugated to the anti-HER2 antibody and compared in preclinical experiments. In the hallmark phase III EMILIA trial treatment with trastuzumab-MCC-DM1 led to significantly longer median survival compared to the standard of care lapatinib and capecitabine in patients with 2nd line HER2 positive metastatic breast cancer. Subsequently, multiple anti-HER2 ADCs were generated with different ADC platforms allowing a comparison of different drug linkers, drug to antibody ratios, site-specific antibody drug conjugates, and biparatopic antibody drug conjugates. Anti-HER2 antibody drug conjugates currently in clinical testing are described. Promising early clinical data are emerging from some of the ADCs employing novel technologies. Future directions including bispecific antibody drug conjugates directed against HER2 and another target are discussed. Ultimately the goal is to generate clinical candidate ADCs that can improve patient outcomes. Comparison of anti-HER2 ADCs will inform how novel ADC technologies can be applied beyond HER2 to other cancer associated antigens.


Antibody drug conjugate HER2 ERBB2 Kadcyla trastuzumab emtansine T-DM1, DM1 


  1. 1.
    Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12:553–563CrossRefPubMedGoogle Scholar
  2. 2.
    Martin V, Cappuzzo F, Mazzucchelli L, Frattini M (2014) HER2 in solid tumors: more than 10 years under the microscope; where are we now? Future Oncol 10:1469–1486CrossRefPubMedGoogle Scholar
  3. 3.
    Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317–328CrossRefPubMedGoogle Scholar
  4. 4.
    Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr et al (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin fab. Nature 421:756–760CrossRefPubMedGoogle Scholar
  5. 5.
    Hudis CA (2007) Trastuzumab — mechanism of action and use in clinical practice. N Engl J Med 357:39–51CrossRefPubMedGoogle Scholar
  6. 6.
    Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS et al (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429–440CrossRefPubMedGoogle Scholar
  7. 7.
    De Santes K, Slamon D, Anderson SK, Shepard M, Fendly B, Maneval D et al (1992) Radiolabeled antibody targeting of the HER-2/neu oncoprotein. Cancer Res 52:1916–1923PubMedGoogle Scholar
  8. 8.
    Austin CD, De Maziere AM, Pisacane PI, van Dijk SM, Eigenbrot C, Sliwkowski MX et al (2004) Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol Biol Cell 15:5268–5282CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG et al (2004) Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10:7063–7070CrossRefPubMedGoogle Scholar
  10. 10.
    Sun X, Ponte JF, Yoder NC, Laleau R, Coccia J, Lanieri L et al (2017) Effects of drug-antibody ratio on pharmacokinetics, biodistribution, efficacy, and tolerability of antibody-Maytansinoid conjugates. Bioconjug Chem 28:1371–1381CrossRefPubMedGoogle Scholar
  11. 11.
    Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF et al (2003) Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21:778–784CrossRefPubMedGoogle Scholar
  12. 12.
    Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R et al (2002) Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem 13:47–58CrossRefPubMedGoogle Scholar
  13. 13.
    Kovtun YV, Audette CA, Ye Y, Xie H, Ruberti MF, Phinney SJ et al (2006) Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res 66:3214–3221CrossRefPubMedGoogle Scholar
  14. 14.
    Flynn M, Zammarchi F, Tyrer PC, Akarca AU, Janghra N, Britten CE et al (2016) ADCT-301, a Pyrrolobenzodiazepine (PBD) dimer-containing antibody drug conjugate (ADC) targeting CD25-expressing hematological malignancies. Mol Cancer Ther 15:2709CrossRefPubMedGoogle Scholar
  15. 15.
    Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin DR, Sievers EL et al (2010) Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin Cancer Res 16:888–897CrossRefPubMedGoogle Scholar
  16. 16.
    Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL et al (2006) Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem 17:114–124CrossRefPubMedGoogle Scholar
  17. 17.
    Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K et al (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66:4426–4433CrossRefPubMedGoogle Scholar
  18. 18.
    Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX (2011) 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 128:347–356CrossRefPubMedGoogle Scholar
  19. 19.
    Maxfield FR (2014) Role of endosomes and lysosomes in human disease. Cold Spring Harb Perspect Biol 6:a016931CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Goldenberg DM (2011) Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer Xenograft models and monkeys. Clin Cancer Res 17:3157–3169CrossRefPubMedGoogle Scholar
  21. 21.
    Govindan SV, Cardillo TM, Sharkey RM, Tat F, Gold DV, Goldenberg DM (2013) Milatuzumab–SN-38 conjugates for the treatment of CD74<sup>+</sup> cancers. Mol Cancer Ther 12:968–978CrossRefPubMedGoogle Scholar
  22. 22.
    Rock BM, Tometsko ME, Patel SK, Hamblett KJ, Fanslow WC, Rock DA (2015) Intracellular catabolism of an antibody drug conjugate with a noncleavable linker. Drug Metab Dispos 43:1341–1344CrossRefPubMedGoogle Scholar
  23. 23.
    Sutherland MS, Sanderson RJ, Gordon KA, Andreyka J, Cerveny CG, Yu C et al (2006) Lysosomal trafficking and cysteine protease metabolism confer target-specific cytotoxicity by peptide-linked anti-CD30-auristatin conjugates. J Biol Chem 281:10540–10547CrossRefPubMedGoogle Scholar
  24. 24.
    Hamblett KJ, Jacob AP, Gurgel JL, Tometsko ME, Rock BM, Patel SK et al (2015) SLC46A3 is required to transport Catabolites of noncleavable antibody Maytansine conjugates from the lysosome to the cytoplasm. Cancer Res 75:5329–5340CrossRefPubMedGoogle Scholar
  25. 25.
    Jeffrey SC, Andreyka JB, Bernhardt SX, Kissler KM, Kline T, Lenox JS et al (2006) Development and properties of beta-glucuronide linkers for monoclonal antibody-drug conjugates. Bioconjug Chem 17:831–840CrossRefPubMedGoogle Scholar
  26. 26.
    Polson AG, Calemine-Fenaux J, Chan P, Chang W, Christensen E, Clark S et al (2009) Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection. Cancer Res 69:2358–2364CrossRefPubMedGoogle Scholar
  27. 27.
    Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E et al (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68:9280–9290CrossRefPubMedGoogle Scholar
  28. 28.
    Kellogg BA, Garrett L, Kovtun Y, Lai KC, Leece B, Miller M et al (2011) Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage. Bioconjug Chem 22:717–727CrossRefPubMedGoogle Scholar
  29. 29.
    Erickson HK, Lewis Phillips GD, Leipold DD, Provenzano CA, Mai E, Johnson HA et al (2012) The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther 11:1133–1142CrossRefPubMedGoogle Scholar
  30. 30.
    Barok M, Tanner M, Koninki K, Isola J (2011) Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett 306:171–179CrossRefPubMedGoogle Scholar
  31. 31.
    Poon KA, Flagella K, Beyer J, Tibbitts J, Kaur S, Saad O et al (2013) Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability. Toxicol Appl Pharmacol 273:298–313CrossRefPubMedGoogle Scholar
  32. 32.
    Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W et al (2010) Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 28:2698–2704CrossRefPubMedGoogle Scholar
  33. 33.
    Beeram M, Krop IE, Burris HA, Girish SR, Yu W, Lu MW et al (2012) A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer 118:5733–5740CrossRefPubMedGoogle Scholar
  34. 34.
    Girish S, Gupta M, Wang B, Lu D, Krop IE, Vogel CL et al (2012) Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 69:1229–1240CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S et al (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398–405CrossRefPubMedGoogle Scholar
  36. 36.
    Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lewis Phillips GD, Fields CT, Li G, Dowbenko D, Schaefer G, Miller K et al (2014) Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res 20:456–468CrossRefGoogle Scholar
  38. 38.
    Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P et al (2017) Trastuzumab Emtansine with or without Pertuzumab versus Trastuzumab plus Taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study. J Clin Oncol 35:141–148CrossRefPubMedGoogle Scholar
  39. 39.
    Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC et al (2015) HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18:476–484CrossRefPubMedGoogle Scholar
  40. 40.
    Thuss-Patience PC, Shah MA, Ohtsu A, Van Cutsem E, Ajani JA, Castro H et al (2017) Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol 18:640CrossRefPubMedGoogle Scholar
  41. 41.
    Ruschoff J, Hanna W, Bilous M, Hofmann M, Osamura RY, Penault-Llorca F et al (2012) HER2 testing in gastric cancer: a practical approach. Mod Pathol 25:637–650CrossRefPubMedGoogle Scholar
  42. 42.
    Behrens CR, Ha EH, Chinn LL, Bowers S, Probst G, Fitch-Bruhns M et al (2015) Antibody-drug conjugates (ADCs) derived from Interchain cysteine cross-linking demonstrate improved homogeneity and other pharmacological properties over conventional heterogeneous ADCs. Mol Pharm 12:3986–3998CrossRefPubMedGoogle Scholar
  43. 43.
    Bryant P, Pabst M, Badescu G, Bird M, McDowell W, Jamieson E et al (2015) In vitro and in vivo evaluation of cysteine Rebridged Trastuzumab-MMAE antibody drug conjugates with defined drug-to-antibody ratios. Mol Pharm 12:1872–1879CrossRefPubMedGoogle Scholar
  44. 44.
    Kudirka RA, Barfield RM, McFarland JM, Drake PM, Carlson A, Banas S et al (2016) Site-specific tandem Knoevenagel condensation-Michael addition to generate antibody-drug conjugates. ACS Med Chem Lett 7:994–998CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ma D, Narayanan B, Marquette K, Graziani E, Loganzo F, Charati M, Prashad N, Tumey N, Golas J, Hosselet C, Hu G, Barletta F, Betts A, Lucas J, O’Donnell C, Tchistiakova L, Gerber H, Sapra P (2016) Creating a superior, site-specific anti-HER2 antibody-drug conjugate (NG-HER2 ADC) for treatment of solid tumors. AACR Annual Meeting, New Orleans, LAGoogle Scholar
  46. 46.
    Jiang J, Dong L, Wang L, Wang L, Zhang J, Chen F et al (2016) HER2-targeted antibody drug conjugates for ovarian cancer therapy. Eur J Pharm Sci 93:274–286CrossRefPubMedGoogle Scholar
  47. 47.
    Yao X, Jiang J, Wang X, Huang C, Li D, Xie K et al (2015) A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity. Breast Cancer Res Treat 153:123–133CrossRefPubMedGoogle Scholar
  48. 48.
    Junutula JR, Flagella KM, Graham RA, Parsons KL, Ha E, Raab H et al (2010) Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer. Clin Cancer Res 16:4769–4778CrossRefPubMedGoogle Scholar
  49. 49.
    Strop P, Liu SH, Dorywalska M, Delaria K, Dushin RG, Tran TT et al (2013) Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol 20:161–167CrossRefPubMedGoogle Scholar
  50. 50.
    Shen BQ, Xu K, Liu L, Raab H, Bhakta S, Kenrick M et al (2012) Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol 30:184–189CrossRefPubMedGoogle Scholar
  51. 51.
    Liu JFM, Moore KN, Wang JS, Patel M, Birrer MJ, Hamilton E, Barroilhet L, Flanagan WM, Wang Y, Garg A, Lu X, Vaze A, Amin D, Leipold D, Commerford SR, Humke EW, Burris HA (2017) CT009 - Targeting MUC16 with the THIOMABTM-drug conjugate DMUC4064A in patients with platinum-resistant ovarian cancer: a Phase I escalation study. AACR Annual Meeting, Washington, DCGoogle Scholar
  52. 52.
    Badescu G, Bryant P, Bird M, Henseleit K, Swierkosz J, Parekh V et al (2014) Bridging disulfides for stable and defined antibody drug conjugates. Bioconjug Chem 25:1124–1136CrossRefPubMedGoogle Scholar
  53. 53.
    Tian F, Lu Y, Manibusan A, Sellers A, Tran H, Sun Y et al (2014) A general approach to site-specific antibody drug conjugates. Proc Natl Acad Sci 111:1766–1771CrossRefPubMedGoogle Scholar
  54. 54.
    Zimmerman ES, Heibeck TH, Gill A, Li X, Murray CJ, Madlansacay MR et al (2014) Production of site-specific antibody-drug conjugates using optimized non-natural amino acids in a cell-free expression system. Bioconjug Chem 25:351–361CrossRefPubMedGoogle Scholar
  55. 55.
    Humphreys RC, Kirtely J, Hewit A, Biroc S, Knudsen N, Skidmore L et al (2015) Abstract 639: site specific conjugation of ARX-788, an antibody drug conjugate (ADC) targeting HER2, generates a potent and stable targeted therapeutic for multiple cancers. Cancer Res 75:639CrossRefGoogle Scholar
  56. 56.
    Jackson D, Atkinson J, Guevara CI, Zhang C, Kery V, Moon SJ et al (2014) In vitro and in vivo evaluation of cysteine and site specific conjugated herceptin antibody-drug conjugates. PLoS One 9:e83865CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Polson AG, Yu SF, Elkins K, Zheng B, Clark S, Ingle GS et al (2007) Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma. Blood 110:616–623CrossRefPubMedGoogle Scholar
  58. 58.
    Pravin CP, Vijay S, Moses L (2015) A short review on the synthetic strategies of Duocarmycin analogs that are powerful DNA alkylating agents. Anti Cancer Agents Med Chem 15:616–630CrossRefGoogle Scholar
  59. 59.
    Elgersma RC, Coumans RG, Huijbregts T, Menge WM, Joosten JA, Spijker HJ et al (2015) Design, synthesis, and evaluation of linker-Duocarmycin payloads: toward selection of HER2-targeting antibody-drug conjugate SYD985. Mol Pharm 12:1813–1835CrossRefPubMedGoogle Scholar
  60. 60.
    Dokter W, Ubink R, van der Lee M, van der Vleuten M, van Achterberg T, Jacobs D et al (2014) Preclinical profile of the HER2-targeting ADC SYD983/SYD985: introduction of a new duocarmycin-based linker-drug platform. Mol Cancer Ther 13:2618–2629CrossRefPubMedGoogle Scholar
  61. 61.
    van der Lee MM, Groothuis PG, Ubink R, van der Vleuten MA, van Achterberg TA, Loosveld EM et al (2015) The preclinical profile of the Duocarmycin-based HER2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers. Mol Cancer Ther 14:692–703CrossRefPubMedGoogle Scholar
  62. 62.
    Koper N (2016) Development Update on SYD985, a Duocarmycin-based ADC. World ADC Summit; 2016 October 12, San Diego, CAGoogle Scholar
  63. 63.
    Cuya SM, Bjornsti M-A, van Waardenburg RCAM (2017) DNA topoisomerase-targeting chemotherapeutics: what’s new? Cancer Chemother Pharmacol 80:1–14CrossRefPubMedGoogle Scholar
  64. 64.
    Abou-Alfa GK, Letourneau R, Harker G, Modiano M, Hurwitz H, Tchekmedyian NS et al (2006) Randomized phase III study of Exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 24:4441–4447CrossRefPubMedGoogle Scholar
  65. 65.
    Soepenberg O, de Jonge MJA, Sparreboom A, de Bruin P, Eskens FALM, de Heus G et al (2005) Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors. Clin Cancer Res 11:703–711CrossRefPubMedGoogle Scholar
  66. 66.
    Kumazawa E, Ochi Y (2004) DE-310, a novel macromolecular carrier system for the camptothecin analog DX-8951f: potent antitumor activities in various murine tumor models. Cancer Sci 95:168–175CrossRefPubMedGoogle Scholar
  67. 67.
    Ochi YK, Kumazawa E, Shiose Y, Kuga H, Inoue, K (2003) DE-310, a novel macro-molecular carrier system for the camptothecin analog DX-8951f [IV]: a pos-sible drug release mechanism for antitumor activity. AACR Annual Meeting, p 395Google Scholar
  68. 68.
    Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N et al (2016) 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 22:5097–5108CrossRefPubMedGoogle Scholar
  69. 69.
    Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T (2016) Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci 107:1039–1046CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Honda T (2016) Preclinical profiles of topoisomerase I inhibitor Exatecan derivative-based HER2 targeting ADC. World ADC Summit, 2016 Ocober 12Google Scholar
  71. 71.
    Doi TI, Iwata H, Tsurutani J, Takahashi S, Park H, Redfern CH, Shitara K, Shimizu C, Taniguchi H, Iwasa T, Taira S, Lockhart AC, Fisher JM, Jikoh T, Fujisaki Y, Lee CC, Yver A, Tamura K (2017) Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors. Abstract 108. ASCO Annual Meeting, Chicago, IllinoisGoogle Scholar
  72. 72.
    Tiberghien AC, Levy J-N, Masterson LA, Patel NV, Adams LR, Corbett S et al (2016) Design and synthesis of Tesirine, a clinical antibody–drug conjugate Pyrrolobenzodiazepine dimer payload. ACS Med Chem Lett 7:983–987CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    van Berkel P (2016) Building a diversified product portfolio of PBD-based antibody drug conjugates. World ADC Summit. San Diego, CAGoogle Scholar
  74. 74.
    Bergstrom DA, Bodyak N, Yurkovetskiy A, Park PU, DeVit M, Yin M, et al (2015) A novel, highly potent HER2-targeted antibody-drug conjugate (ADC) for the treatment of low HER2-expressing tumors and combination with trastuzumab-based regimens in HER2-driven tumors. AACR Annual Meeting, 75:LB–231Google Scholar
  75. 75.
    Bodyak N, Yurkovetskiy A, Gumerov DR, Xiao D, Joshua DTDT, Poling LL, Qin LY, Yin M, DeVit MJ, et al (2016) Optimization of lead antibody selection for XMT-1522, a novel, highly potent HER2-targeted antibody-drug conjugate (ADC). AACR Annual Meeting, p 596Google Scholar
  76. 76.
    Lowinger TB (2015) Fleximer ADCs: advancing to the clinic. World ADC Summit, 21 Oct 2015, San Diego, CAGoogle Scholar
  77. 77.
    Yurkovetskiy AV, Yin M, Bodyak N, Stevenson CA, Thomas JD, Hammond CE et al (2015) A polymer-based antibody–Vinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res 75:3365–3372CrossRefPubMedGoogle Scholar
  78. 78.
    Bergstrom DA (2017) ADCs with diverse payloads of tumor-killing agents. 15th international congress on targeted anticancer therapies, March 7, 2017, Paris, FranceGoogle Scholar
  79. 79.
    Bergstrom D, Bodyak N, Park P, Yurkovetskiy A, DeVit M, Yin M, et al (2016) XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer. San Antonio Breast Cancer Symposium, San Antonio, TX. p P4–14-28Google Scholar
  80. 80.
    Bodyak N, Yurkovetskiy A, Park PU, Gumerov DR, DeVit M, Yin M, et al (2015) Abstract 641: Trastuzumab-dolaflexin, a highly potent Fleximer-based antibody-drug conjugate, demonstrates a favorable therapeutic index in exploratory toxicology studies in multiple species. AACR Annual Meeting, p 641CrossRefGoogle Scholar
  81. 81.
    Kontermann RE (2012) Dual targeting strategies with bispecific antibodies. MAbs 4:182–197CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC et al (2016) A Biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29:117–129CrossRefPubMedGoogle Scholar
  83. 83.
    Uppal H, Doudement E, Mahapatra K, Darbonne WC, Bumbaca D, Shen B-Q et al (2015) Potential mechanisms for thrombocytopenia development with Trastuzumab Emtansine (T-DM1). Clin Cancer Res 21:123–133CrossRefPubMedGoogle Scholar
  84. 84.
    Li J, Toader D, Perry SR, Muniz-Medina V, Wetzel L, Rebelatto MC, Masson Hinrichs MJ, Fleming R, Bezabeh B, Thompson P, Dimasi N, Lam B, Yu X, Gao C, Dixit R, Coats S, Osbourn J, Wu H (2016) MEDI4276, a HER2-targeting antibody tubulysin conjugate, displays potent in vitro and in vivo activity in preclinical studies. AACR Annual Meeting, New Orleans, LAGoogle Scholar
  85. 85.
    Barok M, Joensuu H, Isola J (2014) Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res 16:209CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Lewis Phillips GD (2011) Mechanisms of acquired resistance to Trastuzumab Emtansine (T-DM1). World ADC SummitGoogle Scholar
  87. 87.
    Loganzo F, Tan X, Sung M, Jin G, Myers JS, Melamud E et al (2015) Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments. Mol Cancer Ther 14:952–963CrossRefPubMedGoogle Scholar
  88. 88.
    Andreev J, Thambi N, Perez Bay AE, Delfino F, Martin J, Kelly MP et al (2017) Bispecific antibodies and antibody-drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol Cancer Ther 16:681–693CrossRefPubMedGoogle Scholar
  89. 89.
    de Goeij BE, Vink T, Ten Napel H, Breij EC, Satijn D, Wubbolts R et al (2016) Efficient payload delivery by a Bispecific antibody-drug conjugate targeting HER2 and CD63. Mol Cancer Ther 15:2688–2697CrossRefPubMedGoogle Scholar
  90. 90.
    Roopenian DC, Akilesh S (2007) FcRn: the neonatal fc receptor comes of age. Nat Rev Immunol 7:715–725CrossRefPubMedGoogle Scholar
  91. 91.
    Hamblett KJ, Le T, Rock BM, Rock DA, Siu S, Huard JN et al (2016) Altering antibody-drug conjugate binding to the neonatal fc receptor impacts efficacy and tolerability. Mol Pharm 13:2387–2396CrossRefPubMedGoogle Scholar
  92. 92.
    Beck A, Goetsch L, Dumontet C, Corvaia N (2017) Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov 16:315–337CrossRefPubMedGoogle Scholar
  93. 93.
    Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K et al (2015) A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7:302ra136CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Zymeworks Biopharmaceuticals Inc.SeattleUSA

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