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Progress in Chemistry 2014, Vol. 26 Issue (0203): 467-477 DOI: 10.7536/PC130650 Previous Articles   Next Articles

• Review •

Antibody-Drug Conjugates

Cao Gang1, Huang Zuogang1, Cheng Jiefei*2, Jiang Biao*1,3,4   

  1. 1. Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China;
    2. Otsuka Shanghai Research Institute, Shanghai 201210;
    3. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China;
    4. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 200031, China
  • Received: Revised: Online: Published:
  • Supported by:

    The work was supported by the National Natural Science Foundation of China (No.20832007)

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Over 35 monoclonal antibody drugs have been marketed since the approval of first monoclonal antibody drug in 1986, making the antibody drug development one of the most exciting fields. Antibody-drug conjugate (ADC), which combines a monoclonal antibody (mAb) with a cytotoxic (drug) molecule through a linker and thereby the name, is a new class of highly potent biopharmaceutical drugs designed as a targeted therapy. ADC takes advantage of the high binding specificity of mAbs and superior efficacy of cytotoxic molecules, while avoiding the dose-limiting toxicity of cytotoxic molecules. The first ADC, Mylotarg, was approved in 2000, which was late withdrawn by the manufacture due to the lack of appropriate stability of the linker. So far, there are two approved ADCs in the market for cancer therapy and over twenty ADCs in various stages of clinical trials. Creating a successful antibody drug conjugate requires careful selection of the drug, antibody and linker. Linker has a great influence on a conjugate's biological characteristics, such as stability in circulation and drug release at the target site. ADCs have been proven to be effective weapons against cancers and will certainly become useful therapeutics against other diseases.

Contents
1 Introduction
1.1 Approved ADC
1.2 ADC in clinical trials
2 Choose the right antibody
3 Choose the right cytotoxic small molecule
4 Choose the right linker
4.1 Chemical labile linker
4.2 Enzyme labile linker
4.3 Noncleavable linker
4.4 Other linkers
5 Conclusions and outlook

Key words: antibody-drug conjugate (ADC), linker, mAbs, cytotoxic molecules

CLC Number: 

[1] Zolot R S, Basu S, Million R P. Nat. Rev. Drug Disc., 2013, 12: 259.
[2] Goldmacher V S, Kovtun Y V. Ther. Deliv., 2011, 2 (3): 397.
[3] Teicher B A, Chari R V J. Clin. Cancer Res., 2011, 17 (20): 6389.
[4] Hamblett K J, Senter P D, Chace D F, Sun M M C, Lenox J, Cerveny C G, Kissler K M, Bernhardt S X, Kopcha A K, Zabinski R F, Meyer D L, Francisco J A. Clin. Cancer Res., 2004, 10: 7063.
[5] McDonagh C F, Turcott E, Westendorf L, Webster J B, Alley S C, Kim K, Andreyka J, Stone I, Hamblett K J, Francisco J A, Carter P. Prot. Eng. Des. Sel., 2006, 19: 299.
[6] Hamann P R, Hinman L M, Beyer C F, Lindh D, Upeslacis J, Flowers D A, Bernstein I. Bioconjugate Chem., 2002, 13: 40.
[7] Hamann P R, Hinman L M, Hollander I, Beyer C F, Lindh D, Holcomb R, Hallett W, Tsou H R, Upeslacis J, Shochat D, Mountain A, Flowers D A, Bernstein I. Bioconjugate Chem., 2002, 13: 47.
[8] Hollander I, Kunz A, Hamann P R. Bioconjugate Chem., 2008, 19: 358.
[9] de Vries J F, Zwaan C M, De Bie M, Voerman J S A, den Boer M L, van Dongen J J M, van der Velden V H J. Leukemia, 2012, 26: 255.
[10] Ritter A. Pharm. Technol., 2012, 36 (1): 42.
[11] Burris H A. Expert Opin. Biol. Ther., 2011, 11 (6): 807.
[12] Mullard A. Nat. Rev. Drug Disc., 2013, 12: 329.
[13] Ducry L, Stump B. Bioconjugate Chem., 2010, 21: 5-13.
[14] Dosio F, Brusa P, Cattel L. Toxins, 2011, 3: 848.
[15] Beck A, Haeuw J F, Wurch T, Goetsch L, Bailly C, Corvaia N. Discov. Med., 2010, 10 (53): 329.
[16] Govindan S V, Goldenberg D M. Sci. World J., 2010, 10: 2070.
[17] Hitchcock S A. J. Med. Chem., 2012, 55: 4877.
[18] Zhao R Y, Erickson H K, Leece B A, Reid E E, Goldmacher V S, Lambert J M, Chari R V J. J. Med. Chem., 2012, 55: 766.
[19] Flygare J A, Pillow T H, Aristoff P. Chem. Biol. Drug Des., 2013, 81: 113.
[20] Trail P A, Willner D, Lasch S J, Henderson A J, Hofstead S, Casazza A M, Firestone R A, Hellstrom I, Hellstrom K E. Science, 1993, 261: 212.
[21] Dubowchik G M, Firestone R A, Padilla L, Willner D, Hofstead S J, Mosure K, Knipe J O, Lasch S J, Trail P A. Bioconjugate Chem., 2002, 13: 855.
[22] Van der Velden V H J, te Marvelde J G, Hoogeveen P G, Bernstein I D, Houtsmuller A B, Berger M S, van Dongen J J M. Blood, 2001, 97: 3197.
[23] Hamann P R, Hinman L M, Beyer C F, Lindh D, Upeslacis J, Shochat D, Mountain A. Bioconjugate Chem., 2005, 16: 354.
[24] Ranson M, Sliwkowski M X. Oncology, 2002, 63: 17.
[25] Widdison W C, Wilhelm S D, Cavanagh E E, Whiteman K R, Leece B A, Kovtun Y, Goldmacher V S, Xie H, Steeves R M, Lutz R J, Zhao R, Wang L, Blattler W A, Chari R V J. J. Med. Chem., 2006, 49: 4392.
[26] Erickson H K, Park P U, Widdison W C, Kovtun Y V, Garrett L M, Hoffman K, Lutz R J, Goldmacher V S, Blattler W A. Cancer Res., 2006, 66: 4426.
[27] Kovtun Y V, Audette C A, Ye Y, Xie H, Ruberti M F, Phinney S J, Leece B A, Chittenden T, Blättler W A, Goldmacher V S. Cancer Res., 2006, 66: 3214.
[28] Xie H, Audette C, Hoffee M, Lambert J M, Blattler W A. J. Pharmacol. Exp. Ther., 2004, 308: 1073.
[29] Koblinski J E, Ahram M, Sloane B F. Clin. Chim. Acta, 2000, 291: 113.
[30] Doronina S O, Toki B E, Torgov M Y, Mendelsohn B A, Cerveny C G, Chace D F, DeBlanc R L, Gearing R P, Bovee T D, Siegall C B, Francisco J A, Wahl A F, Meyer D L, Senter P D. Nat. Biotechnol., 2003, 21: 778.
[31] Toki B E, Cerveny C G, Wahl A F, Senter P D. J. Org. Chem., 2002, 67: 1866.
[32] Sanderson R J, Hering M A, James S F, Sun M M C, Doronina S O, Siadak A W, Senter P D, Wahl A F. Clin. Cancer Res., 2005, 11: 843.
[33] Doronina S O, Bovee T D, Meyer D W, Miyamoto J B, Anderson M E, Morris-Tilden C A, Senter P D. Bioconjugate Chem., 2008, 19: 1960.
[34] Jeffrey S C, Nguyen M T, Andreyka J B, Meyer D L, Doronina S O, Senter P D. Bioorg. Med. Chem. Lett., 2006, 16: 358.
[35] Chari R V J. Acc. Chem. Res., 2008, 41: 98.
[36] Polson A G, Calemine-Fenaux J, Chan P, Chang W, Christensen E, Clark S, de Sauvage F J, Eaton D, Elkins K, Elliott J M, Frantz G, Fuji R N, Gray A, Harden K, Ingle G S, Kljavin N M, Koeppen H, Nelson C, Prabhu S, Raab H, Ross S, Stephan J P, Scales S J, Spencer S D, Vandlen R, Wranik B, Yu S F, Zheng B, Ebens A. Cancer Res., 2009, 69: 2358.
[37] Doronina S O, Mendelsohn B A, Bovee T D, Cerveny C G, Alley S C, Meyer D L, Oflazoglu E, Toki B E, Sanderson R J, Zabinski R F, Wahl A F, Senter P D. Bioconjugate Chem., 2006, 17: 114.
[38] Alley S C, Benjamin D R, Jeffrey S C, Okeley N M, Meyer D L, Sanderson R J, Senter P D. Bioconjugate Chem., 2008, 19: 759.
[39] Jeffrey S C, Brabander J D, Miyamoto J, Senter P D. ACS Med. Chem. Lett., 2010, 1: 277.
[40] Ban H, Nagano M, Gavrilyuk J, Hakamata W, Inokuma T, Barbas C F. Bioconjugate Chem., 2013, 24: 520.
[41] Sato S, Inokuma T, Otsubo N, Burton D R, Barbas C F. ACS Med. Chem. Lett., 2013, 4: 460.
[42] Cal P M S D, Vicente J B, Pires E, Coelho A V, Veiros L F, Cordeiro C, Gois P M P. J. Am. Chem. Soc., 2012, 134: 10299.
[43] Casi G, Huguenin-Dezot N, Zuberbühler K, Scheuermann J, Neri D. J. Am. Chem. Soc., 2012, 134: 5887.
[44] Li L S, Rader C, Matsushita M, Das S, Barbas C F, Lerner R A, Sinha S C. J. Med. Chem., 2004, 47: 5630.
[45] Voynov V, Chennamsetty N, Kayser V, Wallny H J, Helk B, Trout B L. Bioconjug. Chem., 2010, 21: 385.
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Abstract

Antibody-Drug Conjugates