Emerging Role of Antibody Drug Conjugates (ADCs) in Therapeutics: An Appraisal
European Journal of Clinical and Biomedical Sciences
Volume 3, Issue 1, February 2017, Pages: 7-12
Received: Oct. 15, 2016; Accepted: Jan. 12, 2017; Published: Feb. 9, 2017
Views 3155      Downloads 120
Raja Chakraverty, Department of Pharmaceutical Technology, Bengal School of Technology (A College of Pharmacy) Hooghly, West Bengal, India
Tatini Debnath, Department of Quality Control, Abate Medicaments, Barasat, West Bengal, India
Article Tools
Follow on us
Antibody drug conjugates intends to pursue the monoclonal antibodies (mAbs) as the potent source of delivering cytotoxic drugs to more specific site which binds selectively to the antigen expressing tumor cells. Inspite of the facts, various other safety profile must be considered while designing and optimizing ADC such as selecting congruous target antigen and method of conjugation. Each and every component of the ADC i.e antibody, linker and the drug should be optimized to the extent of desirable targeted therapy which will ameliorate as well as enhance tolerability. The past decade had witnessed advances in newer cancer treatments with extremely selective small molecules targeting the specific genetic abnormality causing the disease. The approach of traditional cytotoxic agents in the treatment of cancer, unlike the target specificity, they affect both healthy as well as cancer cells. In order to build a powerful and more specific cytotoxic agent with target oriented mAb’s designing attributes would lead to pertinent and potential breakthrough in cancer treatments. Therefore ADC’s were developed with the intention that antibody would target the specific antigen of the tumor wherein the drug attached to it would induce its cytotoxicity. Developement of new techniques and methods in implementing new generation ADC’s in the past decades incorporated non-immunogenic monoclonal antibodies comprising linkers having equitable stability and distinctly potent cytotoxic agents. Newer challenges although remain but comprehensive clinical accomplishment is generating increased interest in this therapeutic class of drugs.
ADC, Monoclonal Antibodies, Bioconjugation, Linker
To cite this article
Raja Chakraverty, Tatini Debnath, Emerging Role of Antibody Drug Conjugates (ADCs) in Therapeutics: An Appraisal, European Journal of Clinical and Biomedical Sciences. Vol. 3, No. 1, 2017, pp. 7-12. doi: 10.11648/j.ejcbs.20170301.12
Copyright © 2017 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
N. Stephanopoulos and M. B. Francis, Nat. Chem. Biol., 2011, 7, 876–883.
Qi-Ying Hu, F. Bertib and R. Adamo, Chem. Soc. Rev., 2016, DOI: 10.1039/c4cs00388h
C. H. Fu and K. M. Sakamoto, Exp. Opin. Pharmacother., 2007, 8, 1977–1984.
P. Agarwal and C. R. Bertozzi, Bioconjugate Chem., 2015, 26, 176–192.
G. Li, S. Wang, X. Xue, X. Qu and H. Liu, Drug Discoveries Ther., 2013, 7, 178–184.
R. V. J. Chari, M. L. Miller and W. C. Widdison, Angew. Chem., Int. Ed., 2014, 53, 3796–3827.
P. Strop, K. Delaria, D. Foletti, J. M. Witt, A. Hasa-Moreno, K. Poulsen, et al., Nat. Biotechnol., 2015, 33, 694–696.
F. Tian, Y. Lu, A. Manibusan, A. Sellers, H. Tran, Y. Sun, et al., Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 1766–1771.
J. R. Junutula, K. M. Flagella, R. A. Graham, K. L. Parsons, E. Ha, H. Raab, et al., Clin. Cancer Res., 2010, 16, 4769–4778.
P. Strop, S. H. Liu, M. Dorywalska, K. Delaria, R. G. Dushin, T. T. Tran, et al., Chem. Biol., 2013, 20, 161–167.
T. V. Jerjian, A. E. Glode, L. A. Thompson, C. L. O'Bryant, Pharmacother., 2016, 36, 99116. H. P. Gerber, P. Sapra, F. Loganzo, C. May, Biochem. Pharmacol., 2015, http://dx.doi.org/10.1016/j.bcp.2015.12.008.
S. C. Alley, D. R. Benjamin, S. C. Jeffrey, N. M. Okeley, D. L. Meyer, R. J. Sanderson, and P. D. Senter, Biocon¬jug. Chem., 2008, 19, 759-765.
B. Goeij, and J. M. Lambert, Curr. Opinion in Immunol.., 2016, 40, 14–23.
J. R. Junutula, H. Raab, S. Clark, S. Bhakta, D. D. Leipold, S. Weir, et al., Nat. Biotechnol., 2008, 26, 925–932.
A. Beck, P. Senter, and R. Chari, World Antibody Drug Conju¬gate Summit Europe: February 21-23, 2011; Frankfurt, Germany. MAbs 3, 331-337.
I. Melero, D. M. Berman, M. A. Aznar, A. J. Korman, J. L. Gracia, and J. Haanen, Nat. Rev. Cancer., 2015, 15, 457–472.
R. P. Lyon, T. D. Bovee, S. O. Doronina, P. J. Burke, J. H. Hunter, H. D. Neff-LaFord, et al., Nat. Biotechnol., 2015, 33, 733–735.
K. M. Mahoney, P. D. Rennert, and G. J. Freeman, Nat. Rev. Drug Discov., 2015, 14, 561–584.
C. Dumontet, and M. A. Jordan, Nat. Rev. Drug. Discov., 2010, 9, 790-803.
E. Oroudjev, M. Lopus, L. Wilson, C. Audette, C. Provenzano, H. Erickson, Y. Kovtun, R. Chari, and M. A. Jordan, Mol. Cancer Ther., 2010, 9, 2700-2713.
Eunhee G. Kim and Kristine M. Kim, Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics, Biomol Ther 23 (6), 493-509 (2015).
Satish K. Singh, Donna L. Luisi, Roger H. Pak, Antibody-Drug Conjugates: Design, Formulation and Physicochemical Stability, Pharm Res, 2015, DOI 10.1007/s11095-015-1704-4.
Alexander-Bryant AA, Vanden Berg-Foels WS, Wen X. Bioengineering strategies for designing targeted cancer therapies. Adv Cancer Res. 2013;118:1–59.
Panowksi S, Bhakta S, Raab H, Polakis P, Junutula JR. Sitespecific antibody drug conjugates for cancer therapy. mAbs. 2014; 6 (1): 34–45.
Arias JL. Drug delivery strategies in targeting cancer: current concepts and future developments. Curr Drug Targets. 2011;12(8):1094–5.
Goldmacher VS, Kovtun YV. Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells. Ther Deliv. 2011; 2 (3): 397–416.
Basile L, Pignatello R, Passirani C. Active targeting strategies for anticancer drug nanocarriers. Curr Drug Deliv. 2012; 9 (3): 255–68.
Salfeld JG. Isotype selection in antibody engineering. Nat Biotechnol. 2007; 25 (12): 1369–72.
McDonagh, C. F., Kim, K. M., Turcott, E., Brown, L. L., Westendorf, L., Feist, T., Sussman, D., Stone, I., Anderson, M., Miyamoto, J., Lyon, R., Alley, S. C., Gerber, H. P. and Carter, P. J. (2008) Engineered anti-CD70 antibody-drug conjugate with increased therapeutic in¬dex. Mol. Cancer Ther. 7, 2913-2923.
Gerber HP, Koehn FE, Abraham RT. The antibody-drug conjugate: an enabling modality for natural product-based cancer therapeutics. Nat Prod Rep. 2013; 30 (5): 625–39.
Bai RL, Pettit GR, Hamel E. Structure-activity studies with chiral isomers and with segments of the antimitotic marine peptide dolastatin 10. Biochem Pharmacol. 1990; 40 (8): 1859–64.
Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, ChaceDF, et al. Development of potentmonoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003; 21 (7): 778–84.
Bai R, Roach MC, Jayaram SK, Barkoczy J, Pettit GR, Luduena RF, et al. Differential effects of active isomers, segments, and analogs of dolastatin 10 on ligand interactions with tubulin. Correlation with cytotoxicity. Biochem Pharmacol. 1993; 45 (7): 1503–15.
Smith AL, Nicolaou KC. The enediyne antibiotics. J Med Chem. 1996; 39 (11): 2103–17.
Hinman LM, Hamann PR, Wallace R, Menendez AT, Durr FE, Upeslacis J. Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics. Cancer Res. 1993; 53 (14): 3336–42.
Dosio F, Brusa P, Cattel L. Immunotoxins and anticancer drug conjugate assemblies: the role of the linkage between components. Toxins. 2011; 3 (7): 848–83.
Hamann PR, Hinman LM, Beyer CF, Lindh D, Upeslacis J, Flowers DA, et al. An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker. Bioconjug Chem. 2002; 13 (1): 40–6.
Takahashi I, Takahashi K, Ichimura M, Morimoto M, Asano K, Kawamoto I, et al. Duocarmycin A, a new antitumor antibiotic from Streptomyces. J Antibiot. 1988; 41 (12): 1915–7.
Wolfe AL, Duncan KK, Lajiness JP, Zhu K, Duerfeldt AS, Boger DL. A fundamental relationship between hydrophobic properties and biological activity for the duocarmycin class of DNA alkylating antitumor drugs: hydrophobic-binding-driven bonding. J Med Chem. 2013; 56 (17): 6845–57.
Boger DL. The duocarmycins: synthetic and mechanistic studies. Acc Chem Res. 1995; 28 (1): 20–9.
Kupchan SM, Komoda Y, Court WA, Thomas GJ, Smith RM, Karim A, et al. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J Am Chem Soc. 1972; 94 (4): 1354–6.
Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, Kovtun Y, et al. Semisynthetic maytansine analogues for the targeted treatment of cancer. J Med Chem. 2006; 49 (14): 4392–408.
Remillard S, Rebhun LI, Howie GA, Kupchan SM. Antimitotic activity of the potent tumor inhibitor maytansine. Science. 1975; 189 (4207): 1002–5.
Kupchan SM, Sneden AT, Branfman AR, Howie GA, Rebhun LI, McIvor WE, et al. Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids. J Med Chem. 1978; 21 (1): 31–7.
Higashide E, Asai M, Ootsu K, Tanida S, Kozai Y, Hasegawa T, et al. Ansamitocin, a group of novel maytansinoid antibiotics with antitumour properties from Nocardia. Nature. 1977; 270 (5639): 721–2.
Beck, A., Senter, P. and Chari, R. (2011) World Antibody Drug Conju¬gate Summit Europe: February 21-23, 2011; Frankfurt, Germany. MAbs 3, 331-337.
Sapra, P., Stein, R., Pickett, J., Qu, Z., Govindan, S. V., Cardillo, T. M., Hansen, H. J., Horak, I. D., Griffiths, G. L. and Goldenberg, D. M. (2005) Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in ahuman multiple myeloma xenograft and in monkeys. Clin. Cancer Res. 11, 5257-5264.
Sujiet Puthenveetil, Sylvia Musto, Frank Loganzo, L. Nathan Tumey, Christopher J. O'Donnell, and Edmund Idris Graziani. Development of solid-phase site-specific conjugation and its application towards generation of dual labeled antibody and Fab drug conjugates. 2016. DOI: 10.1021/acs.bioconjchem.6b00054.
Kendall Morrison, Pia M. Challita-Eid, Arthur Raitano, Zili An, Peng Yang, Joseph D. Abad, Wendy Liu, Dawn Ratay Lortie, Josh T. Snyder, Linnette Capo, Alla Verlinsky, Hector Aviña, Fernando Doñate, Ingrid B. J. Joseph, Daniel S. Pereira, Karen Morrison, David R. Stover. 2016, DOI: 10.1158/1535-7163.MCT-15-0570.
Yusuke Ogitani, Tetsuo Aida, Katsunobu Hagihara, 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. doi:10.1158/1078-0432.CCR-15-2822.
Antibody Drug Conjugates Currently in Clinical Evaluations: Angew. Chem. Int. Ed.,2014,53,3796.
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
Tel: (001)347-983-5186