title: Linked-in: design and efficacy of antibody drug conjugates in oncology.
abstract: The use of antibody drug conjugates (ADCs) as targeted chemotherapies has successfully entered clinical practice and holds great promise. ADCs consist of an antibody and toxin-drug combined together via a chemical linker. While the antibody and drug are of vital importance in the direct elimination of cancer cells, more advanced linker technology was instrumental in the delivery of more potent drugs with fewer side effects. Here, we discuss the preclinical experience as well as clinical trials, with a specific emphasis on the clinical outcomes and side effects, in addition to linker strategies for five different ADCs, in order to describe different approaches in the development of this new class of anticancer agents. Brentuximab vedotin is approved for use in Hodgkin's lymphoma and Trastuzumab emtansine is approved for breast cancer. Combotox, Inotuzumab Ozogamicin, and Moxetumomab Pasudotox are in various stages of clinical development and are showing significant efficacy in lymphoid malignancies. These ADCs illustrate the promise and future potential of targeted therapy for presently incurable malignancies.
authors: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors: Jonathan
authors: J
authors: Feld
authors: Stefan K
authors: SK
authors: Barta
authors: Carolina
authors: C
authors: Schinke
authors: Ira
authors: I
authors: Braunschweig
authors: Yiyu
authors: Y
authors: Zhou
authors: Amit K
authors: AK
authors: Verma
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical / Q000379:methods / Q000639:trends; D002986:Clinical Trials as Topic; D015195:Drug Design; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D018448:Models, Immunological; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D018796:Immunoconjugates
references: Clin Cancer Res. 2000 Apr;6(4):1302-13
references: 10778955
references: Clin Cancer Res. 2006 Jan 1;12(1):242-9
references: 16397048
references: Leukemia. 2000 May;14(5):853-8
references: 10803517
references: Cancer. 2012 Dec 1;118(23):5733-40
references: 22648179
references: Nat Biotechnol. 2008 Aug;26(8):925-32
references: 18641636
references: J Clin Oncol. 2012 Sep 10;30(26):3234-41
references: 22649126
references: Leukemia. 2003 Feb;17(2):334-8
references: 12592332
references: Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):843-52
references: 15701875
references: Clin Cancer Res. 2000 Apr;6(4):1476-87
references: 10778980
references: Clin Cancer Res. 2005 Feb 15;11(4):1545-50
references: 15746059
references: Oncoimmunology. 2012 Dec 1;1(9):1469-1475
references: 23264893
references: J Biol Chem. 2006 Apr 14;281(15):10540-7
references: 16484228
references: Cancer Sci. 2010 Aug;101(8):1840-5
references: 20491780
references: Biochim Biophys Acta. 1994 Dec 30;1198(2-3):165-84
references: 7819273
references: JAMA. 1984 May 4;251(17):2255-61
references: 6368885
references: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5742-7
references: 21436054
references: Blood. 2003 Aug 15;102(4):1458-65
references: 12714494
references: Cancer Immunol Immunother. 2005 Jan;54(1):11-24
references: 15693135
references: N Engl J Med. 2001 Jul 26;345(4):241-7
references: 11474661
references: Cancer Chemother Pharmacol. 2011 Apr;67(4):741-9
references: 20521053
references: Breast Cancer Res Treat. 2011 Jul;128(2):347-56
references: 20730488
references: J Clin Oncol. 2012 May 20;30(15):1822-8
references: 22355053
references: Br J Haematol. 2010 Jan;148(1):99-109
references: 19821820
references: J Clin Oncol. 2013 Mar 20;31(9):1157-63
references: 23382472
references: Cancer Sci. 2012 May;103(5):933-8
references: 22335424
references: Bioconjug Chem. 2008 Mar;19(3):759-65
references: 18314937
references: MAbs. 2009 Nov-Dec;1(6):563-71
references: 20068389
references: Proc Natl Acad Sci U S A. 2012 May 1;109(18):6898-903
references: 22509046
references: N Engl J Med. 2010 Nov 4;363(19):1812-21
references: 21047225
references: Oncotarget. 2012 Apr;3(4):395-8
references: 22565037
references: Br J Haematol. 2011 Aug;154(4):471-6
references: 21732928
references: Mol Cancer Ther. 2012 May;11(5):1133-42
references: 22408268
references: Oncotarget. 2012 Sep;3(9):907-8
references: 23006938
references: Br J Haematol. 2008 Jul;142(1):69-73
references: 18477046
references: Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11782-7
references: 22753489
references: Bioconjug Chem. 1996 Sep-Oct;7(5):557-63
references: 8889017
references: Clin Cancer Res. 2010 Mar 15;16(6):1894-903
references: 20215554
references: Cancer Res. 2008 Aug 1;68(15):6300-5
references: 18676854
references: Leukemia. 2009 Jul;23(7):1329-36
references: 19369961
references: Clin Cancer Res. 2001 Jun;7(6):1490-6
references: 11410481
references: Blood. 1992 Nov 1;80(9):2315-20
references: 1384801
references: J Clin Oncol. 2013 Feb 10;31(5):573-83
references: 23295790
references: Ann Oncol. 2012 Jan;23(1):93-97
references: 21531783
references: Cancer Res. 2008 Nov 15;68(22):9280-90
references: 19010901
references: Int J Cancer. 2000 Jul 1;87(1):86-94
references: 10861457
references: Bioconjug Chem. 2010 Jan;21(1):84-92
references: 19891424
references: J Clin Oncol. 2012 Jun 20;30(18):2190-6
references: 22614995
references: Clin Cancer Res. 2002 Apr;8(4):995-1002
references: 11948105
references: Oncotarget. 2012 Jan;3(1):22-30
references: 22289880
references: Ann N Y Acad Sci. 2012 Apr;1253:102-11
references: 22352893
references: Br J Haematol. 2010 Aug;150(3):352-8
references: 20528877
references: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11311-6
references: 18678888
references: Haematologica. 2012 May;97(5):771-9
references: 22180432
references: Leukemia. 2007 Nov;21(11):2240-5
references: 17657218
references: C R Hebd Seances Acad Sci. 1958 Mar 10;246(10):1626-8
references: 13537412
references: Blood. 1997 Sep 1;90(5):2020-6
references: 9292538
references: J Clin Oncol. 2012 Nov 10;30(32):3924-31
references: 22851554
references: J Biol Chem. 2005 Jan 7;280(1):607-17
references: 15491997
references: Blood. 2009 Apr 16;113(16):3792-800
references: 18988862
references: Clin Cancer Res. 2004 Dec 15;10(24):8620-9
references: 15623646
references: J Clin Oncol. 2009 Jun 20;27(18):2983-90
references: 19414673
references: Blood. 2012 Sep 6;120(10):1975-84
references: 22665936
references: Br J Haematol. 2009 Jun;146(1):34-43
references: 19388933
references: Leuk Lymphoma. 2011 Sep;52(9):1641-54
references: 21619423
references: Leuk Lymphoma. 2012 Nov;53(11):2283-6
references: 22424602
references: J Immunol. 1989 Jul 15;143(2):712-7
references: 2472450
references: Int J Cancer. 1999 Mar 31;81(1):148-55
references: 10077166
references: Oncotarget. 2012 Feb;3(2):158-71
references: 22374986
references: J Am Pharm Assoc (Wash). 1999 Jul-Aug;39(4):571-2
references: 10467825
references: Nat Rev Cancer. 2008 Jun;8(6):473-80
references: 18469827
references: Clin Cancer Res. 2004 Oct 15;10(20):7063-70
references: 15501986
references: Leuk Lymphoma. 2012 Oct;53(10):1999-2003
references: 22448921
references: Clin Cancer Res. 2010 Oct 1;16(19):4769-78
references: 20805300
references: Blood. 2004 Apr 1;103(7):2718-26
references: 14525789
references: J Clin Oncol. 2005 Sep 20;23(27):6719-29
references: 16061911
references: Lancet. 2012 Apr 21;379(9825):1508-16
references: 22482940
references: Nat Rev Drug Discov. 2012 Jan 03;11(1):19-20
references: 22212672
references: N Engl J Med. 2012 Nov 8;367(19):1783-91
references: 23020162
references: J Clin Oncol. 2012 Jun 20;30(18):2183-9
references: 22454421
references: Adv Drug Deliv Rev. 2000 Sep 30;43(2-3):95-100
references: 10967223
references: J Pediatr Hematol Oncol. 2009 Dec;31(12):936-41
references: 19875969
references: Expert Rev Mol Med. 2009 Sep 30;11:e29
references: 19788782
references: Clin Cancer Res. 2009 Feb 1;15(3):832-9
references: 19188153
references: Cancer Res. 2006 Nov 1;66(21):10586-93
references: 17079483
references: J Clin Oncol. 2011 Feb 1;29(4):398-405
references: 21172893
references: Oncotarget. 2012 Aug;3(8):744-58
references: 22889873
references: Clin Cancer Res. 2012 Jan 1;18(1):248-55
references: 22080439
references: Lancet Oncol. 2012 Apr;13(4):403-11
references: 22357140
references: Leukemia. 2012 Feb;26(2):255-64
references: 21869836
references: Lancet. 2012 Apr 21;379(9825):1468-9
references: 22482941
references: Int J Immunopharmacol. 1992 Feb;14(2):281-91
references: 1624227
references: J Clin Oncol. 2010 Jun 1;28(16):2698-704
references: 20421541
references: Cancer Res. 2009 Mar 15;69(6):2358-64
references: 19258515
references: J Clin Oncol. 2010 Apr 20;28(12):2085-93
references: 20308665
references: Curr Opin Oncol. 1998 Nov;10(6):548-51
references: 9818234
references: Blood. 2004 Mar 1;103(5):1807-14
references: 14615373
references: J Exp Med. 1991 Jan 1;173(1):137-46
references: 1985119
references: Breast Cancer Res. 2011 Apr 21;13(2):R46
references: 21510863