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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by Daiichi Sankyo and licensed by AstraZeneca trastuzumab deruxtecan (Enhertu™) is approved for the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have received two or more previous anti-HER2 therapies. This ADC consists of a HER2-targeted antibody joined to a topoisomerase I inhibiting payload (i.e., deruxtecan, a derivative of exatecan) through a cleavable peptidic linker (Figure 7.36). Structure of trastuzumab deruxtecan (Enhertu™) which consists of a HER2-targeted antibody joined to a topoisomerase I inhibiting payload (i.e., deruxtecan, a derivative of exatecan) through a cleavable peptidic linker (Figure reprinted with permission from Daiichi Sankyo. References: [1] Doi et al., Lancet Oncol. 2017;18:1512-1522; [2] Ogitani et al. Cancer Sci. 2016;107:1039–46; [3] Poon et al. Toxicol Appl Pharmacol. 2013;273:298–313; [4] Mitsui et al. Jpn J Cancer Res. 1995; 86: 776–782).
Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
Three other campotothecin derivatives contain anticancer activities which include belotecan, lurtotecan, and exatecan. Belotecan has been tested by Choi et al. (2010) in a phase II trialalong with carboplatin (combination therapy) to assess its anticancer effect on patients that suffer from recurrent ovarian cancer. The clinical trial included 38 patients and became successful with an overall response rate of 57.1% and comprehensive response rate of 20%. Lurtotecan is highly water-soluble and due to this most research conducted on it focused on delivering the drug through liposomal formulation, NX211. Studies (Desjardins et al., 2001) on mice-bearing KB cancer cells determined that lurtotecan delivered in NX211 could improve the chances of drug-to-tumor contract. Exatecan, another analog of camptothecin, has a useful anticancer effect on advanced peritoneal, ovarian, and tubal cancer when novel anticancer agents such as topotecan, taxane, and cis-platin failed (Verschraegen et al., 2004). The phase II clinical study demonstrated its effectiveness when patients administered a daily dose in 5 times a day continuously every 3 weeks. Figure 5.6 provides the structure of anticancer campotothecin. Anticancer effect of a few significant natural and semi-synthetic drugs is summarized in Table 5.1.
Application of Phytodrug Delivery in Anticancer Therapy
Published in Madhu Gupta, Durgesh Nandini Chauhan, Vikas Sharma, Nagendra Singh Chauhan, Novel Drug Delivery Systems for Phytoconstituents, 2020
Camptothecins (CPTs), which are derived from the bark and stem of Chinese ornamental tree Camptotheca accuminata with broad-spectrum anticancer activity, have become the third largest anticancer drugs worldwide (Han, 1994).They are characterized by their specific inhibition of enzyme topoisomerase I, which would lead to the separation of DNA strands prior to transcription and replication (Berti et al., 2013, Chaudhuri et al., 2012, Huang et al., 2012, Tomicic and Kaina, 2013). CPT was first recognized in the mid-1960s by Wall et al. (1966); however, its early promise was blighted by poor solubility as well as unpredictable side effects, preventing CPT from being approved (Venditto and Simanek, 2010). Therefore, a series of CPT derivatives have been developed subsequently via chemical manipulation, mainly including topotecan, irinotecan, belotecan, exatecan, gimatecan, and karenitecan, which have been proverbially applied in the treatment of numerous tumors, including ovarian cancer, lung cancer, breast cancer, pancreatic cancer, metastatic colorectal cancer, glioblastoma, small cell carcinoma, etc. (Bissinger et al., 2015, Cremolini et al., 2015, Kamisawa et al., 2016, Kim et al., 2013, Liu et al., 2015a, Mulholland and Wu, 2016, Wan et al., 2012, Wang-Gillam et al., 2016). The plant source of CPTs, the chemical structure of camptothecin, and representative anticancer alkaloids derived from CPT are shown in Figure 9.3c. It was found that chemotherapy with oral topotecan achieved prolonged survival and improved quality of life for patients with relapsed small-cell lung cancer (SCLC) (O’Brien et al., 2006). It was also shown that, as the first-line therapy for patients with metastatic colorectal cancer, the combination of irinotecan/5-FU/LV prevailed over 5-FU/LV alone, accompanied by enhanced tumor control as well as prolonged survival (Saltz et al., 2001). Besides, it has been shown that belotecan combined with etoposide presented significant activity for platinum-resistant or heavily pretreated ovarian cancer patients (Hwang et al., 2012), and similar activity has also been demonstrated via the combination of belotecan and carboplatin (Choi et al., 2011). Moreover, belotecan showed promising efficacy for glioblastoma combined with cliengitide (Kim et al., 2013), also prospective for small-cell lung cancer as the second-line therapy (Chan and Coward, 2013, Rhee et al., 2011) or as the first-line chemotherapy when combined with cisplatin (Hong et al., 2012).
Current trends in the use of human serum albumin for drug delivery in cancer
Published in Expert Opinion on Drug Delivery, 2022
Milan Paul, Asif Mohd Itoo, Balaram Ghosh, Swati Biswas
Albumin-based prodrugs have gained attention in cancer therapy, especially the stimuli-sensitive ones responding to the tumor microenvironment-specific enzymes or pathological conditions. An albumin-binding prodrug of Dox was developed strategically to contain maleimide functionality and an acid-sensitive hydrazone linker connected to Dox [126–128]. The prodrug, Doxo-EMCH, gets attached covalently to the cysteine (Cys-34) residue of albumin in circulation, eventually accumulating in the tumor environment. Doxo-EMCH is the first albumin-binding prodrug of doxorubicin entering a clinical trial, which increased the Dox-dosing by 4.5–340 mg/m2 compared to 75 mg/m2 for free Dox, associated with typical side effects, including myelotoxicity and mucositis, as concluded in the phase-I clinical study [126]. A recent study reported a prodrug system of exatecan modified by a hypoxia-activated linker, 1-methyl-2-nitro-5-hydroxymethylimidazole, terminally functionalized with maleimide [129]. The maleimide could bind to HSA systemically, and the prodrug system could release the drug in a hypoxic tumor environment. Albumin-binding caspase-cleavable prodrug system has been prepared in a study, where the prodrug of Dox binds to circulatory albumin and gets activated in the presence of caspase-3 overexpressed in the tumor microenvironment [130].
Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Alberto Zambelli, Riccardo Sgarra, Rita De Sanctis, Elisa Agostinetto, Armando Santoro, Guidalberto Manfioletti
Another ADC that could potentially revolutionize the classical therapeutic strategies of mBC, not only mTNBC, is trastuzumab deruxtecan (T-DXd). It is composed of an antiHER2 (human epidermal growth factor receptor 2) mAb linked to a topoisomerase I inhibitor, an exatecan derivative. In HER2-low BC (HER2 IHC score 1+ or 2+ and FISH test negative, corresponding to the HER2-negative disease as defined by ASCO/CAP guidelines), its peculiar mechanism of action is mainly based on the bystander effect. In detail, T-DXd binds to HER2 expressed on the surface of HER2-positive tumor cells (even HER2-low), then it is internalized and DXd is released into the cytoplasm, thus inducing apoptosis. DXd is then transferred to and induces apoptosis in neighboring HER2-negative cells. Indeed, T-DXd showed an ORR of 14% in patients with HER2-low TNBC in a phase I trial. Its toxicity profile is well known and mainly characterized by nausea and the rarer interstitial lung disease [73,74] More data are expected from the DESTINY Breast 04 phase III trial, which enrolled mTNBC HER2 low to receive T-DXd or TPC; the enrollment has been recently completed (NCT03734029).
Antibody-drug conjugates in metastatic triple negative breast cancer: a spotlight on sacituzumab govitecan, ladiratuzumab vedotin, and trastuzumab deruxtecan
Published in Expert Opinion on Biological Therapy, 2021
Julia E. McGuinness, Kevin Kalinsky
Trastuzumab deruxtecan (T-DXd), or DS-8201, comprises an anti-HER2 human monoclonal IgG1 conjugated to the payload DXd via an enzymatically cleavable peptide linker [53]. DXd is a derivative of exatecan mesylate, a synthetic camptothecin analog and potent topoisomerase I inhibitor. Exatecan mesylate, like irinotecan, has moderate activity in patients with metastatic breast cancer refractory to anthracyclines and taxanes, and DXd has been shown in xenograft models of multiple tumors, including breast cancers [54,55]. HER2 is a member of the epidermal growth factor receptor (EGFR) family, that is overexpressed in 15–20% of breast cancers. As TNBC is ‘negative’ for HER2 overexpression and/or amplification, defined as HER2 staining of 3+ by IHC and FISH HER2/CEP17 ratio of 2.0 or higher [56], HER2-targeting therapies are considered ineffective in this subtype of breast cancer. However, T-DXd showed efficacy in mouse xenograft models of low-HER2 expressing breast and gastric cancer, defined as FISH negative but IHC 1+ or 2+; this was compared with the anti-HER2 ADC T-DM1, which had no efficacy in these cell lines [53]. One potential explanation is that T-DXd has a high DAR of 8, enabling the delivery of sufficient payload even at low HER2 level on the cell surface. DXd is also cell membrane permeable and can induce a greater bystander cytotoxic effect on cells in close proximity to the targeted HER2-expressing tumor cells, regardless of their HER2-status.