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Current and Future Perspectives of Marine Drugs for Cancer Disorders: A Critical Review
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Bhaskaran Mahendran, Thirumalaraju Vaishnavi, Vishakante Gowda, Johurul Islam, Narahari Rishitha, Arunachalam Muthuraman, Rajavel Varatharajan
Various marine-derived products are identified as potential therapeutic efficacy in vitro and in vivo. Some of the marine-derived products are under clinical trials use to treat cancer disorders. The ongoing marine drugs in clinical trials are plinabulin, plitidepsin, glembatumumabvedotin, and lurbinectedin at phase III levels; mafodotin, depatuxizumab, polatuzumab vedotin, tisotumab AGS-16C3F, PM184, vedotin, enfortumabvedotin, and monomethyl auristatin F at phase II levels; GSK2857916, ABBV-085, ABBV-399, ABBV-221, ASG-67E, ASG-15ME, bryostatin, marizomib, and SGN-LIV1A at phase I levels (Dyshlovoy and Honecker, 2018; Mayer, 2017; Doronina et al., 2018). Furthermore, the additional marine-derived products are pipelines for the clinical trials. Some of newer molecules are identified in different marine sources. These molecules proved their potency and efficacy in various ailments in laboratory animals. Therefore, marine-derived natural molecules are expected to manage multiple cancer disorders.
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
At the time of writing, the two most commonly used payloads for ADCs are the auristatins and the maytansines, both of which inhibit tubulin polymerization. Overall, the auristatins are the most common, with over 50% of ADCs in clinical development using it as a payload. For example, Seattle Genetics, the developer and manufacturer of AdcetrisTM, use mainly the synthetic auristatins monomethylauristatin E (MMAE) and monomethylauristatin F (MMAF). The International Nonproprietary Names (INN) nomenclature for the MMAE component within MMAE-MAB-conjugates is “vedotin”. Both MMAE and MMAF are based on the natural product Dolastatin 10 which is a pentapeptide originally isolated from the marine mollusk Dolabella auricularia (Figure 7.15 B). This agent was originally investigated as a potential stand-alone anticancer agent but was found to be too toxic. Dolastatin exerts its biological effect by binding to tubulin and inhibiting microtubule assembly causing G2/M cell-cycle arrest, and resulting in the formation of tubulin aggregates, thus inhibiting mitosis and subsequently leading to apoptosis. It also induces tumor cell apoptosis through a mechanism involving bcl-2 which is overexpressed in some cancers.A. The parent antitubulin agent Dolastatin 10 isolated from the Indian Ocean sea hare Dolabella ariculara (shown in B) (Image from Wikipedia, “Blunt-End Seahare (Dolabella auricularia) (41145635260)” by Rickard Zerpe, shared under the Creative Commons Attribution 2.0 Generic license (https://creativecommons.org/licenses/by/2.0/deed.en)); C. The synthetic Dolastatin 10 analogues monomethylauristatin E (MMAE) and monomethylauristatin F (MMAF) used as payloads for ADCs.
Clinical development of an anti-GPC-1 antibody for the treatment of cancer
Published in Expert Opinion on Biological Therapy, 2022
Saikat Ghosh, Pie Huda, Nicholas Fletcher, Douglas Campbell, Kristofer J. Thurecht, Bradley Walsh
The therapeutic benefits of ADCs in GPC-1 over-expressing solid tumors were realized by Naka and colleagues in a few of their recent studies. In 2017, they reported the design and biological testing of a novel anti-GPC-1-ADC carrying a toxic ‘payload’ of monomethyl auristatin F (MMAF), a microtubule-destabilizing agent that prevents cancer cell division [25]. Initially, the GPC-1-ADC was shown to be effective against cervical carcinoma, but subsequently its applications were expanded toward successful treatment of pancreatic ductal adenocarcinoma (PDAC), esophageal squamous cell carcinoma (ESCC) and cholangiocarcinoma (CCA) tumors in pre-clinical models [27,42,47]. In addition to triggering cell-cycle arrest, the GPC-1-ADC was able to inhibit tumor angiogenesis by blocking VEGF activity and inhibiting vascular endothelial cells [47]. Moreover, the heparan sulfate chains of glypicans can cross-link and cause caveolar internalization [48]. This mechanism of receptor-mediated endocytosis was exploited by Naka and colleagues to deliver GPC-1-ADCs inside cancer cells [25,42,49]. In these studies, both unconjugated anti-GPC1 mAb and GPC-1-ADCs demonstrate rapid internalization into GPC1-expressing cells in vitro in a time- and temperature-dependent manner [5].
Antibody-drug conjugates, immune-checkpoint inhibitors, and their combination in breast cancer therapeutics
Published in Expert Opinion on Biological Therapy, 2021
Kamal S Saini, Kevin Punie, Chris Twelves, Stefanella Bortini, Evandro de Azambuja, Steven Anderson, Carmen Criscitiello, Ahmad Awada, Sherene Loi
Only a limited quantity of payload molecules can be linked to each mAb molecule [16]. For example, the mean drug–antibody ratio (DAR) is 3.5, 7.6, and 7.7 for T-DM1, sacituzumab govitecan, and trastuzumab deruxtecan, respectively. These payloads are, therefore, usually highly potent cytotoxics, such as auristatin, maytansinoids or tubulysins that target microtubules, and calicheamicins or duocarmicins that bind to the DNA minor groove [17,18]. Auristatins include monomethyl auristatin E (MMAE, used in the anti-CD30 ADC brentuximab vedotin) and monomethyl auristatin F (MMAF, used in the anti-BCMA ADC belantamab mafodotin), while maytansinoids include DM1 (used in the anti-HER2 ADC T-DM1). Deruxtecan and SN38, the payloads of trastuzumab deruxtecan and sacituzumab govitecan, respectively, are both topoisomerase inhibitors [19]. Additional examples of different payloads used in ADCs are provided in Tables 1 and 2.
A new decade: novel immunotherapies on the horizon for relapsed/refractory multiple myeloma
Published in Expert Review of Hematology, 2021
Marc Braunstein, Jonathan Weltz, Faith Davies
Belantamab mafodotin (belamaf, GSK2857916), is a first-in-class BCMA humanized IgG1 monoclonal ADC with a monomethyl auristatin F (MMAF). Once the auristatin F payload is internalized it disrupts microtubules and leads to MM death in a multifunctional manner including the induction of apoptosis, ADCC, ADCP, and immunogenic cell death. Single agent belamaf demonstrated clinically meaningful activity in patients with heavily pretreated R/R MM (median 7 lines of prior therapy) refractory to an IMiD, a PI, and refractory and/or intolerant to an anti-CD38 mAb in the pivotal phase II DREAMM-2 study [51,52]. At 13 months follow-up, the ORR was 32% and the median duration of response was 11.0 months in the belamaf 2.5 mg/kg arm [53]. A unique safety signal in this study included keratopathy related to the monomethyl auristatin F conjugate, which was observed in 21% and 27% in different dosing cohorts and was the most common reason for treatment discontinuation. Based upon these impressive initial results as a single agent, a number of studies are exploring belamaf in combinations and in earlier lines of therapy. Interim reports suggest predictable safety profiles with good response rates. For example, in DREAMM-6, the combination of belamaf, bortezomib, dexamethasone for eight cycles, followed by single-agent belamaf maintenance, resulted in an impressive ORR of 78%, and very good partial response (VGPR) rate of 50% [54].