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Antibody–drug conjugates for targeted anticancer drug delivery

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Abstract

Antibody–drug conjugates (ADCs) are tumor-targeted therapeutic agents that combine the specificity of monoclonal antibodies (mAbs) with the potent anti-tumor effects of cytotoxic drugs. Over the past few years, ADCs have become a powerful tool in the field of cancer chemotherapy. Recently, two ADC products, brentuximab vedotin (Adcetris®) and trastuzumab emtansine (Kadcyla®), have received FDA approval and there are more than 40 ADC candidates in clinical trials for the treatment of various cancers. Despite the success of some products, considerable interests for the next generation of ADCs have focused on the development of homogeneous conjugates because most of the current ADCs are highly heterogeneous with different drug-to-antibody ratios and drug conjugation sites. Recent studies have demonstrated that the site-specific conjugation of drugs to mAbs could produce homogeneous ADC with better pharmacokinetic properties and improved therapeutic index. A number of approaches, including the use of engineered cysteines, the insertion of unnatural amino acids, and enzymatic ligation, have addressed the challenging issues for the synthesis of homogeneous ADC. This review discusses the limitations of current ADC technologies and describes recent site-specific conjugation methods that can be used to prepare homogeneous ADCs for targeted anticancer drug delivery.

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References

  • Advani A, Coiffier B, Czuczman MS, Dreyling M, Foran J, Gine E, Gisselbrecht C, Ketterer N, Nasta S, Rohatiner A, Schmidt-Wolf IG, Schuler M, Sierra J, Smith MR, Verhoef G, Winter JN, Boni J, Vandendries E, Shapiro M, Fayad L (2010) Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol 28:2085–2093

    Article  CAS  PubMed  Google Scholar 

  • Alley SC, Benjamin DR, Jeffrey SC, Okeley NM, Meyer DL, Sanderson RJ, Senter PD (2008) Contribution of linker stability to the activities of anticancer immunoconjugates. Bioconjug Chem 19:759–765

    Article  CAS  PubMed  Google Scholar 

  • Axup JY, Bajjuri KM, Ritland M, Hutchins BM, Kim CH, Kazane SA, Halder R, Forsyth JS, Santidrian AF, Stafin K, Lu Y, Tran H, Seller AJ, Biroc SL, Szydlik A, Pinkstaff JK, Tian F, Sinha SC, Felding-Habermann B, Smider VV, Schultz PG (2012) Synthesis of site-specific antibody-drug conjugates using unnatural amino acids. Proc Natl Acad Sci USA 109:16101–16106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behrens CR, Liu B (2014) Methods for site-specific drug conjugation to antibodies. MAbs 6:46–53

    Article  PubMed  Google Scholar 

  • Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R (2001) Approval summary gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7:1490–1496

    CAS  PubMed  Google Scholar 

  • Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K (2011) Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 29:369–377

    Article  CAS  PubMed  Google Scholar 

  • Chudasama V, Maruani A, Caddick S (2016) Recent advances in the construction of antibody-drug conjugates. Nat Chem 8:114–119

    Article  CAS  PubMed  Google Scholar 

  • DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, Kunz A, Hamann PR, Gorovits B, Udata C, Moran JK, Popplewell AG, Stephens S, Frost P, Damle NK (2004) Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 103:1807–1814

    Article  CAS  PubMed  Google Scholar 

  • Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, DeBlanc RL, Gearing RP, Bovee TD, Siegall CB, Francisco JA, Wahl AF, Meyer DL, Senter PD (2003) Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21:778–784

    Article  CAS  PubMed  Google Scholar 

  • Drake PM, Albers AE, Baker J, Banas S, Barfield RM, Bhat AS, de Hart GW, Garofalo AW, Holder P, Jones LC, Kudirka R, McFarland J, Zmolek W, Rabuka D (2014) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ducry L, Stump B (2009) Antibody–drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem 21:5–13

    Article  Google Scholar 

  • Feld J, Barta SK, Schinke C, Braunschweig I, Zhou Y, Verma A (2013) Linked-in: design and efficacy of antibody drug conjugates in oncology. Oncotarget 4:397–412

    Article  PubMed  PubMed Central  Google Scholar 

  • Girish S, Gupta M, Wang B, Lu D, Krop IE, Vogel CL, Burris Iii HA, LoRusso PM, Yi JH, Saad O, Tong B, Chu YW, Holden S, Joshi A (2012) Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother Pharmacol 69:1229–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamann PR, Hinman LM, Hollander I, Beyer CF, Lindh D, Holcomb R, Hallett W, Tsou HR, Upeslacis J, Shochat D, Mountain A, Flowers DA, Bernstein I (2002) Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug Chem 13:47–58

    Article  CAS  PubMed  Google Scholar 

  • Hamblett KJ, Senter PD, Chace DF, Sun MM, Lenox J, Cerveny CG, Kissler KM, Bernhardt SX, Kopcha AK, Zabinski RF, Meyer DL, Francisco JA (2004) Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 10:7063–7070

    Article  CAS  PubMed  Google Scholar 

  • Harding FA, Stickler MM, Razo J, DuBridge R (2010) The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs 2:256–265

    Article  PubMed  PubMed Central  Google Scholar 

  • Hofer T, Skeffington LR, Chapman CM, Rader C (2009) Molecularly defined antibody conjugation through a selenocysteine interface. Biochemistry 48:12047–12057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeger S, Zimmermann K, Blanc A, Grunberg J, Honer M, Hunziker P, Struthers H, Schibli R (2010) Site-specific and stoichiometric modification of antibodies by bacterial transglutaminase. Angew Chem Int Ed Engl 49:9995–9997

    Article  CAS  PubMed  Google Scholar 

  • Junutula JR, Bhakta S, Raab H, Ervin KE, Eigenbrot C, Vandlen R, Scheller RH, Lowman HB (2008a) Rapid identification of reactive cysteine residues for site-specific labeling of antibody-Fabs. J Immunol Methods 332:41–52

    Article  CAS  PubMed  Google Scholar 

  • Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, Chen Y, Simpson M, Tsai SP, Dennis MS, Lu Y, Meng YG, Ng C, Yang J, Lee CC, Duenas E, Gorrell J, Katta V, Kim A, McDorman K, Flagella K, Venook R, Ross S, Spencer SD, Lee Wong W, Lowman HB, Vandlen R, Sliwkowski MX, Scheller RH, Polakis P, Mallet W (2008b) Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 26:925–932

    Article  CAS  PubMed  Google Scholar 

  • Katz J, Janik JE, Younes A (2011) Brentuximab vedotin (SGN-35). Clin Cancer Res 17:6428–6436

    Article  CAS  PubMed  Google Scholar 

  • Kim EG, Kim KM (2015) Strategies and advancement in antibody–drug conjugate optimization for targeted cancer therapeutics. Biomol Ther 23:493–509

    Article  CAS  Google Scholar 

  • Kitson SL, Quinn DJ, Moody TS, Speed D, Watters W, Rozzell D (2013) Antibody–drug conjugates (ADCs)—biotherapeutic bullets. Chim Oggi-Chem Today 31:30–36

    Google Scholar 

  • Kubota T, Niwa R, Satoh M, Akinaga S, Shitara K, Hanai N (2009) Engineered therapeutic antibodies with improved effector functions. Cancer Sci 100:1566–1572

    Article  CAS  PubMed  Google Scholar 

  • Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H, Stone I, Ryan MC, Sussman D, Lyon RP, Zeng W, Harrington KH, Klussman K, Westendorf L, Meyer D, Bernstein ID, Senter PD, Benjamin DR, Drachman JG, McEarchern JA (2013) SGN-CD33A: a novel CD33-targeting antibody–drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 122:1455–1463

    Article  PubMed  Google Scholar 

  • Li X, Yang J, Rader C (2014) Antibody conjugation via one and two C-terminal selenocysteines. Methods 65:133–138

    Article  CAS  PubMed  Google Scholar 

  • McCombs JR, Owen SC (2015) Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J 17:339–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McDonagh CF, Turcott E, Westendorf L, Webster JB, Alley SC, Kim K, Andreyka J, Stone I, Hamblett KJ, Francisco JA, Carter P (2006) Engineered antibody–drug conjugates with defined sites and stoichiometries of drug attachment. Protein Eng Des Sel 19:299–307

    Article  CAS  PubMed  Google Scholar 

  • Na DH, Park EJ, Kim MS, Lee HS, Lee KC (2012) Application of sodium dodecyl sulfate-capillary gel electrophoresis to the characterization of ricin A-chain immunotoxins. Chromatographia 75:679–683

    Article  CAS  Google Scholar 

  • Panowski S, Bhakta S, Raab H, Polakis P, Junutula JR (2014) Site-specific antibody drug conjugates for cancer therapy. MAbs 6:34–45

    Article  PubMed  Google Scholar 

  • Perez HL, Cardarelli PM, Deshpande S, Gangwar S, Schroeder GM, Vite GD, Borzilleri RM (2014) Antibody–drug conjugates: current status and future directions. Drug Discov Today 19:869–881

    Article  CAS  PubMed  Google Scholar 

  • Peters C, Brown S (2015) Antibody–drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep 35:e00225

    Article  PubMed  PubMed Central  Google Scholar 

  • Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A (2012) Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30:2190–2196

    Article  CAS  PubMed  Google Scholar 

  • Rabuka D, Rush JS, Wu P, Bertozzi CR (2012) Site-specific chemical protein conjugation using genetically encoded aldehyde tags. Nat Protoc 7:1052–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC (2005) Monoclonal antibody successes in the clinic. Nat Protoc 23:1073–1078

    CAS  Google Scholar 

  • Ricart AD (2011) Antibody–drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin. Clin Cancer Res 17:6417–6427

    Article  CAS  PubMed  Google Scholar 

  • Riechmann L, Clark M, Waldmann H, Winter G (1988) Reshaping human antibodies for therapy. Nature 332:323–327

    Article  CAS  PubMed  Google Scholar 

  • Schroff RW, Foon KA, Beatty SM, Oldham RK, Morgan AC (1985) Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res 45:879–885

    CAS  PubMed  Google Scholar 

  • Scott AM, Wolchok JD, Old LJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12:278–287

    Article  CAS  PubMed  Google Scholar 

  • Senter PD, Sievers EL (2012) The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 30:631–637

    Article  CAS  PubMed  Google Scholar 

  • Shen BQ, Xu K, Liu L, Raab H, Bhakta S, Kenrick M, Parsons-Reponte KL, Tien J, Yu SF, Mai E, Li D, Tibbitts J, Baudys J, Saad OM, Scales SJ, McDonald PJ, Hass PE, Eigenbrot C, Nguyen T, Solis WA, Fuji RN, Flagella KM, Patel D, Spencer SD, Khawli LA, Ebens A, Wong WL, Vandlen R, Kaur S, Sliwkowski MX, Scheller RH, Polakis P, Junutula JR (2012) Conjugation site modulates the in vivo stability and therapeutic activity of antibody–drug conjugates. Nat Biotechnol 30:184–189

    Article  CAS  PubMed  Google Scholar 

  • Sievers EL, Senter PD (2013) Antibody–drug conjugates in cancer therapy. Ann Rev Med 64:15–29

    Article  CAS  PubMed  Google Scholar 

  • Sochaj AM, Swiderska KW, Otlewski J (2015) Current methods for the synthesis of homogeneous antibody–drug conjugates. Biotechnol Adv 33:775–784

    Article  CAS  PubMed  Google Scholar 

  • Stimmel JB, Merrill BM, Kuyper LF, Moxham CP, Hutchins JT, Fling ME, Kull FC Jr (2000) Site-specific conjugation on serine right-arrow cysteine variant monoclonal antibodies. J Biol Chem 275:30445–30450

    Article  CAS  PubMed  Google Scholar 

  • Strop P, Liu SH, Dorywalska M, Delaria K, Dushin RG, Tran TT, Ho WH, Farias S, Casas MG, Abdiche Y, Zhou D, Chandrasekaran R, Samain C, Loo C, Rossi A, Rickert M, Krimm S, Wong T, Chin SM, Yu J, Dilley J, Chaparro-Riggers J, Filzen GF, O’Donnell CJ, Wang F, Myers JS, Pons J, Shelton DL, Rajpal A (2013) Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates. Chem Biol 20:161–167

    Article  CAS  PubMed  Google Scholar 

  • Sukumaran S, Gadkar K, Zhang C, Bhakta S, Liu L, Xu K, Raab H, Yu SF, Mai E, Fourie-O’Donohue A, Kozak KR, Ramanujan S, Junutula JR, Lin K (2015) Mechanism-based pharmacokinetic/pharmacodynamic model for THIOMAB™ drug conjugates. Pharm Res 32:1884–1893

    Article  CAS  PubMed  Google Scholar 

  • Sun MM, Beam KS, Cerveny CG, Hamblett KJ, Blackmore RS, Torgov MY, Handley FG, Ihle NC, Senter PD, Alley SC (2005) Reduction–alkylation strategies for the modification of specific monoclonal antibody disulfides. Bioconjug Chem 16:1282–1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takimoto JK, Adams KL, Xiang Z, Wang L (2009) Improving orthogonal tRNA-synthetase recognition for efficient unnatural amino acid incorporation and application in mammalian cells. Mol BioSyst 5:931–934

    Article  CAS  PubMed  Google Scholar 

  • Teicher BA, Chari RV (2011) Antibody conjugate therapeutics: challenges and potential. Clin Cancer Res 17:6389–6397

    Article  CAS  PubMed  Google Scholar 

  • van der Velden VH, te Marvelde JG, Hoogeveen PG, Bernstein ID, Houtsmuller AB, Berger MS, van Dongen JJ (2001) Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 97:3197–3204

    Article  Google Scholar 

  • Walker S, Landovitz R, Ding WD, Ellestad GA, Kahne D (1992) Cleavage behavior of calicheamicin gamma 1 and calicheamicin T. Proc Natl Acad Sci USA 89:4608–4612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Amphlett G, Blättler WA, Lambert JM, Zhang W (2005) Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. Protein Sci 14:2436–2446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yokoyama K, Nio N, Kikuchi Y (2004) Properties and applications of microbial transglutaminase. Appl Microbiol Biotechnol 64:447–454

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP) (NRF-2013R1A2A2A01068858).

Conflict of interest

All authors (Y. Kim, E.J. Park, and D.H. Na) declare that they have no conflict of interest.

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  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea

    Yejin Kim, Eun Ji Park & Dong Hee Na

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  1. Yejin Kim
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Correspondence to Dong Hee Na.

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Kim, Y., Park, E.J. & Na, D.H. Antibody–drug conjugates for targeted anticancer drug delivery. Journal of Pharmaceutical Investigation 46, 341–349 (2016). https://doi.org/10.1007/s40005-016-0254-z

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