- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
A Review on Antibody-Drug Conjugates Components for the Treatment of Cancer
Zubair Ishtiaque1 and Uzair Ishtiaq2*
1Department of Analytical, Biopharmaceutical and Medical Sciences, Atlantic Technological University, Galway, Ireland
2Department of Computer Science, COMSATS University Islamabad, Vehari Campus, Pakistan
Submission: June 08, 2023;Published:June 14, 2023
*Corresponding author: Uzair Ishtiaq, Department of Computer Science, COMSATS University Islamabad, Vehari Campus, Pakistan
How to cite this article: Zubair I, Uzair I. A Review on Antibody-Drug Conjugates Components for the Treatment of Cancer. JOJ Ophthalmol. 2023; 10(1): 555779. DOI: 10.19080/JOJO.2023.10.555779
- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
Abstract
Cytotoxic drugs are generally utilized as chemotherapeutic agents for the therapy of different sorts of tumors. The disadvantage of utilizing cytotoxic medications is their non-explicitness, which might prompt harming healthy human cells alongside the cancerous cells. Thus, it can cause various damaging effects on human health. However, anticancer drugs and antibody-drug conjugates (ADCs) are used to avoid the aforementioned harmful effects. This review presents the components of antibody-drug conjugates and the effect of Maytansinoids for the treatment of cancer. Moreover, this review also presents the formation and mechanism of action of Antibody-Maytansinoid Conjugates. In addition, it summarizes the Antibody-Maytansinoid Conjugate Products that may be helpful for the researchers working in the field of cancer treatment through Antibody-Maytansinoid Conjugate.
Keywords: Conjugates Components; Anticancer Drugs; Cancerous Cells
- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
Introduction to Antibody-Drug Conjugates
Cytotoxic drugs are traditionally used as chemotherapeutic agents for the treatment of various types of cancers. One of the major disadvantages of using cytotoxic drugs alone is their non-specificity, which may lead to damaging healthy cells along with the cancer cells. Consequently, numerous adverse effects are associated with the use of such agents. In order to avoid these adverse effects, and to enhance the specificity, safety and efficacy of anticancer drugs, antibody-drug conjugates (ADCs) are used. ADCs are composed of a monoclonal antibody (mAb) as well as a cytotoxic payload, joined together through a linker group, where the cancer cell targeting ability of antibody and the cancer cell killing potential of cytotoxic payload are combined [1]. Considering the specificity of antibodies, targeting only the disease-causing agents, without damaging the healthy cells, the German scientist Paul Ehrlich regarded them as “zauberkugel” which means “magic bullet” [2]. The first clinical trial of ADCs on human body was conducted in 1983 [3]. Later on, further advances in this field lead to generation of more efficacious, target specific and less immunogenic ADCs [4].
Components of Antibody-Drug Conjugates
There are three components of ADCs, a monoclonal antibody, a linker molecule and a cytotoxic drug [5].
Antibody: Selection of a suitable antibody, with high specificity for the target cells, is the most vital aspect of ADC design [6]. There are five types of immunoglobulins, i.e., IgG, IgA, IgM, IgE and IgD, among which IgG is the most widely used for manufacturing ADC [7].
Linker molecule: Linkers are the chemical agents which are used to bind the antibody with the cytotoxic drug. The efficacy, specificity and safety of ADC depend upon the linker molecule because it aids the antibody to deliver the cytotoxic ayload to the site of tumour [8]. Linkers are of two types, cleavable and non-cleavable linkers. As the name indicates, cleavable linkers cleave on the tumour site, due to pH change or enzymatic effect, and release the cytotoxic payload for killing the cancer cells. On the contrary, non-cleavable linkers do not cleave, rather the ADC enters the lysosome of tumour cell, where the antibody and linker are destroyed, and the cytotoxic payload is released and kills the tumour cell. Hence, non-cleavable linkers are considered to be safer and more target specific than cleavable linkers [9].
Cytotoxic payload: Another vital component of ADC is the cytotoxic drug, attached to the antibody, also known as cytotoxic payload or warhead, having the ability to kill the tumour cells [10]. The cytotoxic payload should be highly efficacious, that it may kill the tumour cells even in less quantity [11]. Generally, cytotoxic payloads or warheads have two types, i.e., microtubule disrupting agents and DNA damaging agents. Microtubule disrupting agents interfere with the mitosis step during the cell division of tumour cells and hence seize the cells from dividing [12]. Examples of microtubule disrupting agents are Auristatin [13] and Maytansinoids [14]. Conversely, the DNA damaging agents target the DNA of tumour cells and cause breakage of DNA double strand, leading to death of tumour cells [15]. Examples of DNA damaging agents include Calicheamicins [16], Duocarmycin [17] and Doxorubicin [18].
Maytansinoids
Maytansine was discovered by Kupchan and his colleagues in 1972 from the bark of plant Maytenus ovatus [19]. It is a benzoansamacrolide, with highly potent anti-mitotic activity [20]. Maytansinol also has a similar chemical structure as of maytansine, and both are Maytansinoids, included in the class of microtubule disrupting agents [21]. Maytansinoids stop the mitotic phase of cell division by interacting with the tubulin at the binding sites of Vinca alkaloids [22]. However, the cytotoxic potency of Maytansinoids is 100 times higher than the Vinca alkaloids [23]. Hence, by interacting with the tubulin, maytansinoids disrupt the formation of microtubules, causing arrest of cell in G2/M phase of cell division and eventually cause death of the affected cell [14]. However, when used alone for the treatment of cancer, in certain human trials, maytansinoids failed to exhibit desired therapeutic efficacy [24].
Formation of Antibody-Maytansinoid Conjugates
In order to enhance the therapeutic efficacy and targeted cytotoxic effect of maytansinoids, for the treatment of cancer, they are used as Adtibody-Drug Conjugates (ADCs). The ADCs having maytansinoids as cytotoxic payload are also known as Antibody-Maytansinoid Conjugates (AMCs). Ado-Trastuzumab emtansine is an AMC that has been approved for therapeutic use [25]. This AMC is composed of an anti-HER2 antibody, which is attached to maytansinoid, through a non-cleavable linker, and used for the therapy of breast cancer [26]. Among the AMCs, two thiol-based maytansinoids are being used as cytotoxic payloads for killing cancer cells, i.e., DM1 [N2′‐deacetyl‐N2′‐ (3‐mercapto‐1‐oxopropyl) ‐maytansine] and DM4 [N2′‐deacetyl‐N2′‐ (4‐mercapto‐4‐methyl‐1‐oxopentyl) ‐maytansine] [27,28].
AMCs are produced chemically by joining the amino group of lysine amino acid of antibody with the thiol group of a maytansinoid, either DM1 or DM4, through a cleavable or non-cleavable linker molecule [29]. The cleavable linkers are disulfide-based linkers, whereas the non-cleavable linkers are thioether based linkers. Moreover, depending upon the various combinations of linkers and cytotoxic payloads, AMCs can be classified into four groups, i.e., emtansines, mertansines, ravtansines and soravtansines [30].
Mechanism of Action of Antibody-Maytansinoid Conjugates
AMC is a targeted mode of treatment for various cancers and tumours, in which the cytotoxic payload is transported to the tumour cell by the attached antibody and the linker molecule, to ensure the safety and efficacy of the treatment [31]. Upon reaching the target site, the AMC is internalized in the target tumour cell, where the antibody and linker molecule are degraded by the lysosomal enzymes and active cytotoxic payload (maytansinoid) is released into the cytoplasm of tumour cell [32]. Consequently, maytansinoid interferes with the microtubule formation of the cell and hence causes cell death [33].
Antibody-Maytansinoid Conjugate Products
Maytansine
Maytansine has been teted in various clinical trials for treatment of cancer, and when tested on human, it caused rise in SGOT (AST) levels with increased doses, hence produced dose limiting toxicity [34]. Moreover, increased levels of bilirubin and transaminases were also observed in another trial on maytansine [35]. Furthermore, in animal models, on monkeys, dogs and mice, hepatotoxicity was observed with raised liver enzymes [36].
- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
4.1. Ado-Trastuzumab Emtasine (T-DM1, Status: FDA approved)
T-DM1 with brand name Kadcyla ®, with payload class Maytansinoid DM1, is the first FDA approved AMC, in which HER2 humanized IgG1 antibody is bound to DM1, using non-cleavable thioether linker SMCC [37]. It was approved in February 2013 after successful phase III clinical trials [26]. T-DM1 (Kadcyla ®) is used for the treatment of breast cancer [38]. The most significant adverse effect associated with T-DM1 (Kadcyla ®) is onset of liver toxicity, especially in patients with raised liver enzymes (AST and ALT) [25].
- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
Mertansines (DM1 linked with cleavable disulfide linker SPP)
According to current data, there is no approved mertansine AMC in the market, as all of them have been discontinued due to adverse effects. A few of the AMCs of this class include Lorvotuzumab mertansine (status: discontinued), Cantuzumab mertansine (status: discontinued), Bivatuzumab mertansine (status: discontinued), MLN 2704 (status: discontinued).
- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
Currently, there are no approved ravtansine AMCs in the market, because many of them are under clinical trial phase and some have been discontinued. Some of the ravtansines include Coltuximab ravtansine (status: currently in phase II), Indatuximab ravtansine (status: currently in phase II), Anatumab ravtansine (status: currently in phase II), Cantuzumab ravtansine (status: discontinued).
- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
Mirvetuximab soravtansine (IMGN853, Status: FDA approved)
Mirvetuximab soravtansine (IMGN853), with payload class Maytansinoid DM4, is an FDA approved AMC, which is available in market with brand name ELAHERE, comprising of humanized IgG1 antibody M9346A against FOLR1 (folate receptor 1), attached with DM4 maytansinoid, using cleavable disulfide linker sulfo-SPDB [39]. It is indicated for the treatment of platinum-resistant ovarian cancer [40]. The adverse effects associated with this AMC is slightly raised AST and ALT levels during the treatment [41].
- Research Article
- Abstract
- Introduction
- Emtansines (DM1 linked with non-cleavable thioether linker SMCC)
- Mertansines (DM1 linked with cleavable disulfide linker SPP)
- Ravtansines (DM4 linked with cleavable disulfide linker SPDB)
- Soravtansines (DM4 linked with cleavable disulfide linker sulfo-SPDB)
- References
References
- Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nature reviews Molecular cell biology 2(2): 127-137.
- Schwartz RS (2004) Paul Ehrlich's magic bullets. New England Journal of Medicine 350(11): 1079-1080.
- Ford C, Newman C, Johnson J, Woodhouse C, Reeder T, et al. (1983) Localisation and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer. British journal of cancer 47(1): 35-42.
- Tsuchikama K, An Z (2018) Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein & cell 9(1): 33-46.
- Baah S, Laws M, Rahman KM (2021) Antibody-drug conjugates-A tutorial review. Molecules 26(10): 2943.
- Panowski S, Bhakta S, Raab H, Polakis P, Junutula JR (2014) Site-specific antibody drug conjugates for cancer therapy. MAbs 6(1): 34-45.
- Pysz I, Jackson PJ, Thurston DE (2019) Introduction to antibody-drug conjugates (ADCs).
- Jain N, Smith SW, Ghone S, Tomczuk B (2015) Current ADC linker chemistry. Pharmaceutical research 32(11): 3526-3540.
- Lu J, Jiang F, Lu A, Zhang G (2016) Linkers having a crucial role in antibody-drug conjugates. International journal of molecular sciences 17(4): 561.
- Mclaughlin J, Lorusso P (2016) Antibody-drug conjugates (ADCs) in clinical development. Antibody‐Drug Conjugates: Fundamentals, Drug Development, and Clinical Outcomes to Target Cancer pp. 321-344.
- Shefet-carasso L, Benhar I (2015) Antibody-targeted drugs and drug resistance-challenges and solutions. Drug Resistance Updates 18: 36-46.
- Calligaris D, Verdier-Pinard P, Devred F, Villard C, Braguer D, et al (2010) Microtubule targeting agents: from biophysics to proteomics. Cellular and molecular life sciences 67(7): 1089-1104.
- Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, et al. (2013) MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood, The Journal of the American Society of Hematology 121(11): 2051-2058.
- Lopus M, Oroudjev E, Wilson L, Wilhelm S, Widdison W, et al. (2010) Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Molecular cancer therapeutics 9(10): 2689-2699.
- Nicolaou K, Pitsinos E, Theodorakis EA, Saimoto H, Wrasidlo W (1994) Synthetic calicheamicin mimics with novel initiation mechanisms: DNA cleavage, cytotoxicity, and apoptosis. Chemistry & biology 1(1): 57-66.
- Maiese W, Lechevalier M, Lechevalier H, Korshalla J, Kuck N, et al. (1989) Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties. The Journal of antibiotics 42(4): 558-563.
- Crane EA, Gademann K (2016) Capturing biological activity in natural product fragments by chemical synthesis. Angewandte Chemie International Edition 55(12): 3882-3902.
- Tacar O, Sriamornsak P, Dass CR (2013) Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. Journal of pharmacy and pharmacology 65(2): 157-170.
- Kupchan SM, Komoda Y, Court W, Thomas G, Smith R, et al. (1972) Tumor inhibitors. LXXIII. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. Journal of the American Chemical Society 94(4): 1354-1356.
- Kupchan S, Komoda Y, Branfman AR, Sneden AT, Court WA, et al. (1977) Tumor inhibitors. 122. The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides. The Journal of organic chemistry 42(14): 2349-2357.
- Čermák, V., Dostál, V., Jelínek, M., Libusová, L., Kovář, J, et al. (2020) Microtubule-targeting agents and their impact on cancer treatment. European journal of cell biology 99(4): 151075.
- Bhattacharyya B, Wolff J (1977) Maytansine binding to the vinblastine sites of tubulin. FEBS letters 75(1): 159-162.
- Issell BF, Crooke ST (1978) Maytansine. Cancer treatment reviews 5(4): 199-207.
- Blum RH, Kahlert T (1978) Maytansine: A Phase Study of an Ansa Macrolide with Antitumor. Cancer treatment reports 62(3): 435-438.
- Amiri-Kordestani L, Blumenthal GM, Xu QC, Zhang L, Tang SW, et al. (2014) FDA Approval: Ado-Trastuzumab Emtansine for the Treatment of Patients with HER2-Positive Metastatic Breast Cancer FDA Approval Summary for T-DM1 for HER2+ MBC. Clinical cancer research 20(17): 4436-4441.
- Ballantyne A, Dhillon S (2013) Trastuzumab emtansine: first global approval. Drugs 73(7): 755-765.
- Chari RV, Martell BA, Gross JL, Cook SB, Shah SA, et al. (1992) Immunoconjugates containing novel maytansinoids: promising anticancer drugs. Cancer research 52(1): 127-131.
- Widdison WC, Wilhelm SD, Cavanagh EE, Whiteman KR, Leece BA, (2006) Semisynthetic maytansine analogues for the targeted treatment of cancer. Journal of medicinal chemistry 49(14): 4392-4408.
- Junttila TT, Li, G, Parsons K, Phillips GL, Sliwkowski MX (2011) Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast cancer research and treatment 128(2): 347-356.
- A Beck, Thierry W, Christian B, Nathalie C (2017) Strategies and challenges for the next generation of antibody-drug conjugates. Nature reviews Drug discovery 10(5): 345-52.
- Girish S, Gupta M, Wang B, Lu D, Krop IE, et al. (2012) Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer chemotherapy and pharmacology 69(5): 1229-1240.
- Widdison WC, Ponte JF, Coccia JA, Lanieri L, Setiady Y, et al. (2015) Development of anilino-maytansinoid ADCs that efficiently release cytotoxic metabolites in cancer cells and induce high levels of bystander killing. Bioconjugate Chemistry 26(11): 2261-2278.
- Chen X, Bai Y, Zaro JL, Shen WC (2010) Design of an in vivo cleavable disulfide linker in recombinant fusion proteins. Biotechniques 49(1): 513-518.
- Eagan R, Ingle J, Rubin J, Frytak S, M Oertel C (1978) Early clinical study of an intermittent schedule for maytansine (NSC-153858): brief communication. Journal of the National Cancer Institute 60(1): 93-96.
- Blum RH, Wittenberg BK, Canellos GP, Mayer RJ, Skarin AT, et al. (1978) A therapeutic trial of maytansine. Cancer clinical trials 1(2): 113-117.
- Cabanillas F, Rodriguez V, Hall SW, Burgess MA, Bodey GP (1978) Phase I Study of Maytansine Using a 3-Day Schedule 1, 2, 3. Cancer treatment reports 62(3): 425-428.
- Verma S, Miles D, Gianni L, Krop IE, Welslau M, et al. (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. New England journal of medicine 367(19): 1783-1791.
- Guerin M, Sabatier R, Goncalves A (2015) Trastuzumab emtansine (Kadcyla (®)) approval in HER2-positive metastatic breast cancers. Bulletin du cancer 102(4): 390-397.
- Ponte JF, Ab O, Lanieri L, Lee J, Coccia J, et al. (2016) Mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, potentiates the activity of standard of care therapeutics in ovarian cancer models. Neoplasia 18(12): 775-784.
- Moore KN, Martin LP, O'Malley DM, Matulonis UA, Konner JA, et al. (2018) A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncology 14(2): 123-136.
- Moore KN, Martin LP, O’Malley DM, Matulonis UA, Konner JA, et al (2017) Safety and activity of mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, in platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a phase I expansion study. Journal of Clinical Oncology 35(10): 1112-1118.