Self-immolative Linkers in Prodrugs and Antibody Drug Conjugates in Cancer Treatment

Veera V. Shivaji    R.    Edupuganti; Joel    D.A.    Tyndall; Allan    B.   Gamble

Abstract

Background: The design of anti-cancer therapies with high anti-tumour efficacy and reduced toxicity continues to be challenging. Anti-cancer prodrug and antibody-drug-conjugate (ADC) strategies that can specifically and efficiently deliver cytotoxic compounds to cancer cells have been used to overcome some of the challenges. The key to the success of many of these strategies is a self-immolative linker, which after activation can release the drug payload. Various types of triggerable self-immolative linkers are used in prodrugs and ADCs to improve their efficacy and safety.

Objective: Numerous patents have reported the significance of self-immolative linkers in prodrugs and ADCs in cancer treatment. Based on the recent patent literature, we summarise methods for designing the site-specific activation of non-toxic prodrugs and ADCs in order to improve selectivity for killing cancer cells.

Methods: In this review, an integrated view of the potential use of prodrugs and ADCs in cancer treatment are provided. This review presents recent patents and related publications over the past ten years uptill 2020.

Results: The recent patent literature has been summarised for a wide variety of self-immolative PABC linkers, which are cleaved by factors including responding to the difference between the extracellular and intracellular environments (pH, ROS, glutathione) through over-expressed enzymes (cathepsin, plasmin, β-glucuronidase) or bioorthogonal activation. The mechanism for self-immolation involves the linker undergoing a 1,4- or 1,6-elimination (via electron cascade) or intramolecular cyclisation to release cytotoxic drug at the targeted site.

Conclusion: This review provides the commonly used strategies from recent patent literature in the development of prodrugs based on targeted cancer therapy and antibody-drug conjugates, which show promise in therapeutic applications.

Keywords: Self-immolative linkers, cancer, prodrugs, antibody-drug-conjugate, 1, 4- elimination, 1, 6-elimination, Intramolecular cyclisation.

[1] 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin  2020; 70(1): 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902] 
[2] 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin  2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593] 
[3] 
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell  2011; 144(5): 646-74.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230] 
[4] 
Anand P, Kunnumakkara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res  2008; 25(9): 2097-116.
[http://dx.doi.org/10.1007/s11095-008-9661-9] [PMID: 18626751] 
[5] 
Sanai N, Berger MS. Surgical oncology for gliomas: The state of the art. Nat Rev Clin Oncol  2018; 15(2): 112-25.
[http://dx.doi.org/10.1038/nrclinonc.2017.171] [PMID: 29158591] 
[6] 
Kułakowski A. The contribution of Marie Skłodowska-Curie to the development of modern oncology. Anal Bioanal Chem  2011; 400: 1583-6.
[http://dx.doi.org/10.1007/s00216-011-4712-1] 
[7] 
Papaioannou NE, Beniata OV, Vitsos P, Tsitsilonis O, Samara P. Harnessing the immune system to improve cancer therapy. Ann Transl Med  2016; 4(14): 261.
[http://dx.doi.org/10.21037/atm.2016.04.01] [PMID: 27563648] 
[8] 
Agostinis P, Berg K, Cengel KA, et al. Photodynamic therapy of cancer: An update. CA Cancer J Clin  2011; 61(4): 250-81.
[http://dx.doi.org/10.3322/caac.20114] [PMID: 21617154] 
[9] 
Bunnell BA, Morgan RA. Gene therapy for infectious diseases. Clin Microbiol Rev  1998; 11(1): 42-56.
[http://dx.doi.org/10.1128/CMR.11.1.42] [PMID: 9457428] 
[10] 
DeVita VT Jr, Chu E. A history of cancer chemotherapy. Cancer Res  2008; 68(21): 8643-53.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-6611] [PMID: 18974103] 
[11] 
Albert A. Chemical aspects of selective toxicity. Nature  1958; 182(4633): 421-2.
[http://dx.doi.org/10.1038/182421a0] [PMID: 13577867] 
[12] 
Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: Design and clinical applications. Nat Rev Drug Discov  2008; 7(3): 255-70.
[http://dx.doi.org/10.1038/nrd2468] [PMID: 18219308] 
[13] 
Rautio J, Meanwell NA, Di L, Hageman MJ. The expanding role of prodrugs in contemporary drug design and development. Nat Rev Drug Discov  2018; 17(8): 559-87.
[http://dx.doi.org/10.1038/nrd.2018.46] [PMID: 29700501] 
[14] 
Zawilska JB, Wojcieszak J, Olejniczak AB. Prodrugs: A challenge for the drug development. Pharmacol Rep  2013; 65(1): 1-14.
[http://dx.doi.org/10.1016/S1734-1140(13)70959-9] [PMID: 23563019] 
[15] 
Dan N, Setua S, Kashyap VK, et al. Antibody-drug conjugates for cancer therapy: Chemistry to clinical implications. Pharmaceuticals (Basel)  2018; 11(2): 32.
[http://dx.doi.org/10.3390/ph11020032] [PMID: 29642542] 
[16] 
Keam SJ. Trastuzumab deruxtecan: First approval. Drugs  2020; 80(5): 501-8.
[http://dx.doi.org/10.1007/s40265-020-01281-4] [PMID: 32144719] 
[17] 
Bargh JD, Isidro-Llobet A, Parker JS, Spring DR. Cleavable linkers in antibody-drug conjugates. Chem Soc Rev  2019; 48(16): 4361-74.
[http://dx.doi.org/10.1039/C8CS00676H] [PMID: 31294429] 
[18] 
Deeks ED. Polatuzumab vedotin: First global approval. Drugs  2019; 79(13): 1467-75.
[http://dx.doi.org/10.1007/s40265-019-01175-0] [PMID: 31352604] 
[19] 
Chang E, Weinstock C, Zhang L, et al. FDA approval summary: Enfortumab vedotin for locally advanced or metastatic urothelial carcinoma. Clin Cancer Res  2020; 27(4): 922-7.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-2275] [PMID: 32962979] 
[20] 
Syed YY. Sacituzumab govitecan: First approval. Drugs  2020; 80(10): 1019-25.
[http://dx.doi.org/10.1007/s40265-020-01337-5] [PMID: 32529410] 
[21] 
Markham A. Belantamab mafodotin: First approval. Drugs  2020; 80(15): 1607-13.
[http://dx.doi.org/10.1007/s40265-020-01404-x] [PMID: 32936437] 
[22] 
Yang X, Pan Z, Choudhury MR, et al. Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery. Med Res Rev  2020; 40(6): 2682-713.
[http://dx.doi.org/10.1002/med.21720] [PMID: 32803765] 
[23] 
Frigerio M, Kyle AF. The chemical design and synthesis of linkers used in antibody drug conjugates. Curr Top Med Chem  2017; 17(32): 3393-424.
[http://dx.doi.org/10.2174/1568026618666180118155847] [PMID: 29357801] 
[24] 
Jain N, Smith SW, Ghone S, Tomczuk B. Current ADC linker chemistry. Pharm Res  2015; 32(11): 3526-40.
[http://dx.doi.org/10.1007/s11095-015-1657-7] [PMID: 25759187] 
[25] 
Leriche G, Chisholm L, Wagner A. Cleavable linkers in chemical biology. Bioorg Med Chem  2012; 20(2): 571-82.
[http://dx.doi.org/10.1016/j.bmc.2011.07.048] [PMID: 21880494] 
[26] 
Nakada T, Masuda T, Naito H, et al. Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett  2016; 26(6): 1542-5.
[http://dx.doi.org/10.1016/j.bmcl.2016.02.020] [PMID: 26898815] 
[27] 
Carl PL, Chakravarty PK, Katzenellenbogen JA. A novel connector linkage applicable in prodrug design. J Med Chem  1981; 24(5): 479-80.
[http://dx.doi.org/10.1021/jm00137a001] [PMID: 7241503] 
[28] 
Kratz F, Müller IA, Ryppa C, Warnecke A. Prodrug strategies in anticancer chemotherapy. ChemMedChem  2008; 3(1): 20-53.
[http://dx.doi.org/10.1002/cmdc.200700159] [PMID: 17963208] 
[29] 
Dubowchik GM, Walker MA. Receptor-mediated and enzyme-dependent targeting of cytotoxic anticancer drugs. Pharmacol Ther  1999; 83(2): 67-123.
[http://dx.doi.org/10.1016/S0163-7258(99)00018-2] [PMID: 10511457] 
[30] 
Blencowe CA, Russell AT, Greco F, Hayes W, Thornthwaite DW. Self-immolative linkers in polymeric delivery systems. Polym Chem  2011; 2(4): 773-90.
[http://dx.doi.org/10.1039/C0PY00324G] 
[31] 
Hettiarachchi SU, Prasai B, McCarley RL. Detection and cellular imaging of human cancer enzyme using a turn-on, wavelength-shiftable, self-immolative profluorophore. J Am Chem Soc  2014; 136(21): 7575-8.
[http://dx.doi.org/10.1021/ja5030707] [PMID: 24813575] 
[32] 
Louise-Leriche L, Paunescu E, Saint-André G, et al. A HTS assay for the detection of organophosphorus nerve agent scavengers. Chem Eur J  2010; 16(11): 3510-23.
[http://dx.doi.org/10.1002/chem.200902986] [PMID: 20143367] 
[33] 
Ho NH, Weissleder R, Tung CH. A self-immolative reporter for β-galactosidase sensing. ChemBioChem  2007; 8(5): 560-6.
[http://dx.doi.org/10.1002/cbic.200600386] [PMID: 17300128] 
[34] 
Phillips ST, Robbins JS, DiLauro AM, Olah MG. Amplified responses in materials using linear polymers that depolymerize from end-to-end when exposed to specific stimuli. J Appl Polym Sci  2014; 131(19): 40992.
[http://dx.doi.org/10.1002/app.40992] 
[35] 
Dal Corso A, Borlandelli V, Corno C, et al. Fast cyclization of a proline-derived self-immolative spacer improves the efficacy of carbamate prodrugs. Angew Chem Int Ed Engl  2020; 59(10): 4176-81.
[http://dx.doi.org/10.1002/anie.201916394] [PMID: 31881115] 
[36] 
Alouane A, Labruère R, Le Saux T, Schmidt F, Jullien L. Self-immolative spacers: Kinetic aspects, structure-property relationships, and applications. Angew Chem Int Ed Engl  2015; 54(26): 7492-509.
[http://dx.doi.org/10.1002/anie.201500088] [PMID: 26053475] 
[37] 
Gnaim S, Shabat D. Quinone-methide species, a gateway to functional molecular systems: From self-immolative dendrimers to long-wavelength fluorescent dyes. Acc Chem Res  2014; 47(10): 2970-84.
[http://dx.doi.org/10.1021/ar500179y] [PMID: 25181456] 
[38] 
Herrlinger EM, Hau M, Redhaber DM, et al. Nitroreductase-mediated release of inhibitors of Lysine-Specific Demethylase 1 (LSD1) from prodrugs in transfected acute myeloid Leukaemia Cells. ChemBioChem  2020; 21(16): 2329-47.
[http://dx.doi.org/10.1002/cbic.202000138] [PMID: 32227662] 
[39] 
Wang Q, Guan J, Wan J, Li Z. Disulfide based prodrugs for cancer therapy. RSC Adv  2020; 10(41): 24397-409.
[http://dx.doi.org/10.1039/D0RA04155F] 
[40] 
Song C, Ji R, Du F, Li Z. Oxidation-responsive poly(amino ester)s containing arylboronic ester and self-immolative motif: Synthesis and degradation study. Macromolecules  2013; 46(21): 8416-25.
[http://dx.doi.org/10.1021/ma401656t] 
[41] 
Ji X, Pan Z, Yu B, et al. Click and release: Bioorthogonal approaches to “on-demand” activation of prodrugs. Chem Soc Rev  2019; 48(4): 1077-94.
[http://dx.doi.org/10.1039/C8CS00395E] [PMID: 30724944] 
[42] 
Avital-Shmilovici M, Shabat D. Self-immolative dendrimers: A distinctive approach to molecular amplification. Soft Matter  2010; 6(6): 1073-80.
[http://dx.doi.org/10.1039/b922341j] 
[43] 
Papot S, Tranoy I, Tillequin F, Florent JC, Gesson JP. Design of selectively activated anticancer prodrugs: Elimination and cyclization strategies. Curr Med Chem Anticancer Agents  2002; 2(2): 155-85.
[http://dx.doi.org/10.2174/1568011023354173] [PMID: 12678742] 
[44] 
Tranoy-Opalinski I, Fernandes A, Thomas M, Gesson JP, Papot S. Design of self-immolative linkers for tumour-activated prodrug therapy. Anticancer Agents Med Chem  2008; 8(6): 618-37.
[http://dx.doi.org/10.2174/187152008785133065] [PMID: 18690826] 
[45] 
Ponziani S, Di Vittorio G, Pitari G, et al. Antibody-drug conjugates: The new frontier of chemotherapy. Int J Mol Sci  2020; 21(15): E5510.
[http://dx.doi.org/10.3390/ijms21155510] [PMID: 32752132] 
[46] 
Tang H, Liu Y, Yu Z, et al. The analysis of key factors related to ADCs structural design. Front Pharmacol  2019; 10: 373.
[http://dx.doi.org/10.3389/fphar.2019.00373] [PMID: 31068807] 
[47] 
Poreba M. Protease-activated prodrugs: Strategies, challenges, and future directions. FEBS J  2020; 287(10): 1936-69.
[http://dx.doi.org/10.1111/febs.15227] [PMID: 31991521] 
[48] 
Dal Corso A, Pignataro L, Belvisi L, Gennari C. Innovative linker strategies for tumor-targeted drug conjugates. Chem Eur J  2019; 25(65): 14740-57.
[http://dx.doi.org/10.1002/chem.201903127] [PMID: 31418970] 
[49] 
Kratz F, Haag R, Calderon M. Drug conjugates with polyglycerols.  US20110117009, 2011.
[50] 
Kratz F, Warnecke A, Elsadek B. Prodrugs.  US20120094892, 2012.
[51] 
Kratz F, Warnecke A, Elsadek B. Prodrugs.  US8642555, 2014.
[52] 
Kratz F, Hochdoerffer K. Bisphosphonate-prodrugs.  US8778914, 2014.
[53] 
Kratz F, Hochdoerffer K. Bisphosphonate-prodrugs.  US9320803, 2016.
[54] 
Hochdörffer K, Abu Ajaj K, Schäfer-Obodozie C, Kratz F. Development of novel bisphosphonate prodrugs of doxorubicin for targeting bone metastases that are cleaved pH dependently or by cathepsin B: Synthesis, cleavage properties, and binding properties to hydroxyapatite as well as bone matrix. J Med Chem  2012; 55(17): 7502-15.
[http://dx.doi.org/10.1021/jm300493m] [PMID: 22882004] 
[55] 
Warnecke A, Müller I. Acid-labile trigger units.  US8609860, 2013.
[56] 
Leamon CP, Vlahov IR, Low PS. Folate receptor binding conjugates of antifolates.  US8546425, 2013.
[57] 
Cohen SM, Jourden JLM. Stimulus-triggered prodrugs.  US8889638, 2014.
[58] 
He MK, Le Y, Zhang YF, et al. Matrix metalloproteinase 12 expression is associated with tumor FOXP3+ regulatory T cell infiltration and poor prognosis in hepatocellular carcinoma. Oncol Lett  2018; 16(1): 475-82.
[http://dx.doi.org/10.3892/ol.2018.8642] [PMID: 29928435] 
[59] 
Major Jourden JL, Cohen SM. Hydrogen peroxide activated matrix metalloproteinase inhibitors: A prodrug approach. Angew Chem Int Ed Engl  2010; 49(38): 6795-7.
[http://dx.doi.org/10.1002/anie.201003819] [PMID: 20715043] 
[60] 
Peiró Cadahía J, Previtali V, Troelsen NS, Clausen MH. Prodrug strategies for targeted therapy triggered by reactive oxygen species. MedChemComm  2019; 10(9): 1531-49.
[http://dx.doi.org/10.1039/C9MD00169G] [PMID: 31673314] 
[61] 
Bierbach U, Ding S. Targeted delivery and prodrug designs for platinum-acridine anti-cancer compounds and methods thereof.  US9090640, 2015.
[62] 
Ding S, Pickard AJ, Kucera GL, Bierbach U. Design of enzymatically cleavable prodrugs of a potent platinum-containing anticancer agent. Chem Eur J  2014; 20(49): 16164-73.
[http://dx.doi.org/10.1002/chem.201404675] [PMID: 25303639] 
[63] 
Versteegen RM, Rossin R, ten Hoeve W, Janssen HM, Robillard MS. Click to release: Instantaneous doxorubicin elimination upon tetrazine ligation. Angew Chem Int Ed Engl  2013; 52(52): 14112-6.
[http://dx.doi.org/10.1002/anie.201305969] [PMID: 24281986] 
[64] 
Robillard MS. Bio-orthogonal drug activation.  US20150297741, 2015.
[65] 
van Onzen AHAM, Versteegen RM, Hoeben FJM, et al. Bioorthogonal tetrazine carbamate cleavage by highly reactive trans-cyclooctene. J Am Chem Soc  2020; 142(25): 10955-63.
[http://dx.doi.org/10.1021/jacs.0c00531] [PMID: 32453557] 
[66] 
Papot S, Thomas M. Self-reactive arms and prodrugs comprising same.  US9000135, 2015.
[67] 
Prijovic ZM, Leu Y-L, Roffler SR. BQC-G, a tumor-selective anti-cancer prodrug.  US9353140, 2016.
[68] 
Prijovich ZM, Burnouf PA, Chou HC, et al. Synthesis and antitumor properties of BQC-glucuronide, a camptothecin prodrug for selective tumor activation. Mol Pharm  2016; 13(4): 1242-50.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00771] [PMID: 26824303] 
[69] 
Beria I, Caruso M, Lupi V, Orsini P, Salsa M. Functionalized thieno-indole derivatives for the treatment of cancer.  US9561290, 2017.
[70] 
Kim S-Y, Byun Y, Chung SW. Prodrugs activated by caspase.  US9775914, 2017.
[71] 
Feng B. Heterocyclic self-immolative linkers and conjugates.  US7754681, 2010.
[72] 
Beria I, Caruso M, Flygare JA, et al. Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds. US8389697, 2013.
[73] 
Boyd SE, Chen L, Gangwar S, et al. Antibody-drug conjugates and methods of use. CA2623652, 2013.
[74] 
Dushin R, Feyfant E, Sapra P, Tchistiakova LG, Tian F. Antibody-drug conjugates.  WO2013068874, 2013.
[75] 
Tian F, Lu Y, Manibusan A, et al. A general approach to site-specific antibody drug conjugates. Proc Natl Acad Sci USA  2014; 111(5): 1766-71.
[http://dx.doi.org/10.1073/pnas.1321237111] [PMID: 24443552] 
[76] 
Lin R-H, Lin S-Y, Hsieh Y-C, Huang C-C. Hydrophilic self-immolative linkers and conjugates thereof.  WO2014100762, 2014.
[77] 
Lin R-H, Lin S-Y, Hsieh Y-C, Huang C-C. Hydrophilic self-immolative linkers and conjugates thereof.  US9408923, 2016.
[78] 
Morrison RK, An Z, Morrison KJM, Snyder J, Jia X-C. Antibody Drug Conjugates (ADC) that bind to 158P1D7 proteins.  US8968742, 2015.
[79] 
Lyon R, Burke P, Hunter J. Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics.  US20160310612, 2016.
[80] 
Burke PJ, Hamilton JZ, Jeffrey SC, et al. Optimization of a PEGylated glucuronide-monomethylauristatin E linker for antibody-drug conjugates. Mol Cancer Ther  2017; 16(1): 116-23.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0343] [PMID: 28062707] 
[81] 
Jeffrey S. β-glucuronide-linker drug conjugates.  USRE45272, 2014.
[82] 
Jeffrey SC, De Brabander J, Miyamoto J, Senter PD. Expanded utility of the β-glucuronide linker: ADCs that deliver phenolic cytotoxic agents. ACS Med Chem Lett  2010; 1(6): 277-80.
[http://dx.doi.org/10.1021/ml100039h] [PMID: 24900208] 
[83] 
Jeffrey SC, Nguyen MT, Andreyka JB, Meyer DL, Doronina SO, Senter PD. Dipeptide-based highly potent doxorubicin antibody conjugates. Bioorg Med Chem Lett  2006; 16(2): 358-62.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.081] [PMID: 16275070] 
[84] 
An D, Han N, Di Z, et al. Tridentate connexon and use thereof.  US20160015832, 2016.
[85] 
An D, Han N, Di Z, et al. Tridentate connexon and use thereof.  EP2949343, 2020.
[86] 
Han N, An D, Di Z, et al. Trimaleimide linkers and uses thereof.  WO2016192528, 2016.
[87] 
Han N, An D, Di Z, et al. Trimaleimide linkers and uses thereof. US10314922, 2019.
[88] 
Steinkuhler MC, Gallinari MP, Osswald B, et al. Cryptophycin-based antibody-drug conjugates with novel self-immolative linkers.  WO2016146638, 2016.
[89] 
Steinkuhler MC, Gallinari MP, Osswald B, et al. Cryptophycin-based antibody-drug conjugates with novel self-immolative linkers.  US20180078656, 2018.
[90] 
Miao Z, Chen G, Zhu T, et al. Antibody drug conjugates.  US20170224835, 2017.
[91] 
Van Berkel PHC, Howard PW. Pyrrolobenzodiazepine-antibody conjugates.  US9931415, 2018.
[92] 
Dragovich P, Pei Z, Pillow T, Sadowsky J, Verma V, Zhang D. Pyrrolobenzodiazepine prodrugs and antibody conjugates thereof.  WO2018031662, 2018.
[93] 
Dragovich P, Pei Z, Pillow T, Sadowsky J, Verma V, Zhang D. Pyrrolobenzodiazepine prodrugs and antibody conjugates thereof.  US10532108, 2020.
[94] 
Pei Z, Chen C, Chen J, et al. Pyrrolobenzodiazepine (PBD)-dimers containing disulfide-based prodrugs as payloads for antibody-drug conjugates. Mol Pharm  2018; 15(9): 3979-96.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00431] [PMID: 30040421] 
[95] 
Zhang D, Pillow TH, Ma Y, et al. Linker immolation determines cell killing activity of disulfide-linked pyrrolobenzodiazepine antibody-drug conjugates. ACS Med Chem Lett  2016; 7(11): 988-93.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00233] [PMID: 27882196] 
[96] 
Robillard MS, Janssen HM, Ten Hoeve W, Versteegen RM, Rossin R. Bio-orthogonal drug activation.  US20190336612, 2019.
[97] 
Robillard MS, Versteegen RM, Rossin R, Hoeben FJM, Van Kasteren SI, Van De Graaf MJ. Tetrazines for high click conjugation yield in vivo and high click release yield.  WO2019212356, 2019.
[98] 
Robillard MS, Rossin R, Versteegen RM. Compounds comprising a linker for increasing transcyclooctene stability. WO2019212357, 2019.
[99] 
Rossin R, Versteegen RM, Wu J, et al. Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice. Nat Commun  2018; 9(1): 1484.
[http://dx.doi.org/10.1038/s41467-018-03880-y] [PMID: 29728559] 
[100] 
Agatsuma T, Takahashi S, Hasegawa J, Okajima D, Hamada H, Yamaguchi M. Anti-TROP2 antibody-drug conjugate.  US10227417, 2019.
[101] 
Staudacher AH, Brown MP. Antibody drug conjugates and bystander killing: Is antigen-dependent internalisation required? Br J Cancer  2017; 117(12): 1736-42.
[http://dx.doi.org/10.1038/bjc.2017.367] [PMID: 29065110] 
[102] 
Dorywalska M, Dushin R, Moine L, et al. Molecular basis of valine-citrulline-PABC linker instability in site-specific ADCs and its mitigation by linker design. Mol Cancer Ther  2016; 15(5): 958-70.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-1004] [PMID: 26944918] 
[103] 
Newman DJ. The “utility” of highly toxic marine-sourced compounds. Mar Drugs  2019; 17(6): E324.
[http://dx.doi.org/10.3390/md17060324] [PMID: 31159276] 
[104] 
Theocharopoulos C, Lialios PP, Gogas H, Ziogas DC. An overview of antibody-drug conjugates in oncological practice. Ther Adv Med Oncol  2020; 12: 1758835920962997.
[http://dx.doi.org/10.1177/1758835920962997] [PMID: 33088347] 

Cite As

Recent Patents on Anti-Cancer Drug Discovery

Self-immolative Linkers in Prodrugs and Antibody Drug Conjugates in Cancer Treatment

Abstract