Natural Products in Clinical Trials: Volume 1 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Natural Products in Clinical Trials
- Sprache: Englisch
Natural products continue to play a key role in drug development. A recent analysis of the drug market in the developed world revealed that 40% of total clinically approved drugs were either unmodified natural products or their semi-synthetic derivatives.
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Veröffentlichungsjahr: 2018
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Natural Products in Clinical Trials
(Volume 1)
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PREFACE
Natural products continue to play a key role in drug development. A recent analysis of the drug market in the developed world revealed that 40% of total clinically approved drugs were either unmodified natural products or their semi-synthetic derivatives. This new series of e-books focuses on exciting new bioactive natural products that have huge potential as drugs.
Gomes et al. in chapter 1 review the wide range of natural products derived from marine invertebrates that stand out as an important class of natural products with therapeutic potential, some of which are undergoing clinical studies. Moorthy et al. discuss those natural products that are under clinical trials for immunological and inflammatory diseases in chapter 2. Subramani et al. in chapter 3 discuss the clinical trials of curcumin, camptothecin, astaxanthin, and biochanin for various diseases ranging from inflammation to infection. The chapter also deals with lead optimization, formulations and improved delivery systems of these natural products.
Currently, there is a substantial decline in new drug development for anti-microbial activities, as many microbes are developing resistance and becoming superbugs. Sangshetti et al. in chapter 4 review new antibacterial and antifungal drugs under clinical trials that are mainly derived from natural sources. Numerous natural product based anti-HIV drugs, such as Robustaflavone, Chamaeflavone A, Longipedunins A, Binankadsurin A, Schisanlactone A, Anibamine, Altertoxine, Betulinic acid, Baicalin, and Hinokiflavone are undergoing clinical trials. These are reviewed in the 5th chapter by Parveen et al.
We hope that the readers will enjoy the comprehensive and explicit reviews written by eminent authorities in the field. We are also grateful to the editorial staff of Bentham Science Publishers, particularly Dr. Faryal Sami, Mr. Shehzad Naqvi and Mr. Mahmood Alam for their continued support.
List of Contributors
Clinical Trials for Deriving Bioactive Compounds from Marine Invertebrates
Ana R. Gomes1,*,Ana C. Freitas1,2,3,Armando C. Duarte1,2,Teresa A.P. Rocha-Santos1,2Abstract
Natural products have been the greatest source of novel medicines currently used in the treatment of several human diseases. In past decades, a notable quantity of natural molecules has been obtained from several marine sources. The huge biodiversity existing in the marine environment, from among which marine invertebrates stand out as a major contributors to the discovery of new molecules, has encouraged investigators from all over the world to identify new marine natural compounds with therapeutic potential. With the discovery of cytarabine and vidarabine in 1974 promising natural products isolated from marine invertebrates became part of the pharmacopeia used in human therapeutic. In 2004, ziconotide was approved for moderate to severe pain treatment and in 2007, trabectedin received European approval to treat patients with soft tissue sarcoma, and finally in 2009 it was approved for treatment of ovarian carcinoma. The largely unexplored marine world harbors a great biodiversity and provides a unique and rich source of natural products with interesting pharmaceutical activities and potential therapeutic applications. In this context, this chapter focuses on the marine invertebrates and reviews marine natural products that are currently being assessed in clinical trials and provides a glimpse of these compounds' potential to expand the pharmacopeia in the treatment of diverse human diseases.
INTRODUCTION
Nature is a powerful olden pharmacy that harbors a vast source of biodiversity and provides a wide abundance of organisms from which to discover structurally unique bioactive compounds (BC) [1]. Although the oceans and seas harbor an abundant biodiversity of organisms, efforts to explore marine life diversity through the isolation of novel molecules has just begun (Fig. 1) [1-3]. The largely unexplored marine environment offers a variety of organisms with unique metabolic characteristics due to an incredible variety of hostile environments, such as sunlight presence/absence, nutrient availability, salinity, pressure and oxygen levels, resulting in the production of an assortment of secondary metabolites with particular and interesting properties [4].
Fig. (1)) Percentage (%) of new marine natural products discovered from marine invertebrates sources. A) Porifera (48.3%); B) Annelida (0.3%); C) Bryozoa (1.2%); D) Chordata (6,6%), E) Cnidaria (29.3%); F) Echinodermata (7.9%); G) Hemichordata (0.1%) and H) Mollusca (6.4%). Arthropoda, Nematoda and Platyhelminthes (0.0%) [1].Covering most of the earth's surface, seas and oceans offer unexploited sources of promising agents with interesting activities for health improvement. With the constant survey of the marine habitat, marine invertebrates, which include around 60% of all marine animals, were put on the spotlight as resources for new drugs since they were reported as the source of more than 11,000 new natural compounds over the last decade [3, 4].
Although aquatic ecosystems cover most of the earth’s surface, their modern exploration only began with the appearance of modern snorkeling, scuba and the use of remotely operated vehicles (ROVs). Study of marine organisms began with the isolation of the most reachable and big animals, such as sponges, soft corals and red algae, which revealed a wide variety of molecules with peculiar chemical structures [4]. Enhancements in exploration technology, mainly scuba diving and remotely operated vehicles, allowing the collection of a greater diversity of source organisms, allied with improvements in analytical technology, spectroscopy and high-throughput screening, allowed the isolation of novel bioactive marine natural products with unique chemical structures [4-6]. The increasing effort in uncovering the chemistry and pharmacology of new natural molecules over the years has fueled marine-based drug discovery [1, 6].
Marine natural products (MNP) have long been used in medicines, with more than 5 new molecules discovered and approved for clinical use and at least 22 additional compounds derived from marine invertebrates that are in clinical trials, 17 of which are antibody-drug conjugate (ADC) [7, 8]. ADCs are composed by an antibody connected to a drug via a labile linker. After binding of the antibody to the targeted cell antigen, the ADC is taken up by the cell and the cytotoxic agent is released in its active form, thus killing the target cell. ADC has the ability to discriminate between healthy and diseased tissue, attacking only the cancer cells. The idea behind ADC is not new, and their use in vivo was already described in the literature in 1970, as well as clinical trials conducted in 1980, however with restricted success [9]. Nonetheless, a significant increase of these biopharmaceutical agents has been observed over the last 5 years, most likely due to a better understanding of the mechanism of action, a better target selection and more appropriate dosing procedures. These natural bioactive compounds show curious properties and exceptionally interesting pharmaceutical and therapeutic applications, due to their large spectrum of bioactivities, such as anti-tumor, anti-proliferative, anti-microtubule, antibiotic and anti-infective [4].
The diversity of marine life uncovered until now indicates a high potential for new pharmaceutical developments, and there is still much to be discovered in the unexplored ocean depths [3, 10]. This chapter summarizes the current status of bioactive compounds isolated from marine invertebrates that are presently in clinical trials and gives the prospect that marine natural products with a broad spectrum of biological activity represent an added value in the treatment of diverse human diseases.
MARINE BIOACTIVE COMPOUNDS
As shown in Table 1, there are currently five drugs approved by Food and Drug Administration (FDA), namely cytarabine (Cytosar-U®, Depocyt®), vidarabine (Vira-A®), ziconotide (Prialt®), eribulin mesylate (Halaven®) and brentuximab vedotin (Adcetris®). Trabectedin (Yondelis®) has been approved by the European Agency for the Evaluation of Medicinal Products (EMEA), and is finishing relevant phase III trials for approval in the US.
Currently, there are 24 marine natural compounds in clinical trials. Those that are in phase III development include Plitidepsin (Aplidin®), in phase II trials: ABT-414, PM00104 (Zalypsis®), DMXBA, glembatumumab vedotin, PM01183, PSMA-ADC, phase I/II trials: DNIB0600A, pinatuzumab vedotin, polatuzumab vedotin, and in phase I trials, include AGS-16C3F, ASG-67E, ASG-15ME, ASG-22ME, bryostatin, DEDN6526A, DMUC5754A, DSTP3086S, HuMax®-TF-ADC, marizomib, MLN-0264, PM060184, SGN-CD19A, SGN-LIV1A.
These compounds are described in more detail (e.g., discovery, mode of action, clinical application) in the following section. The corresponding chemical structures of each compound are provided and noted with boldface numbers in parentheses following each compound name.
Marine Compounds: Approved Drugs
Cytarabine
Cytarabine (1), also known as cytosine arabinoside, arabinosylcytosine, Ara-C and Cytosar-U® is a chemotherapy agent approved in 1969 by Food and Drug Administration (FDA) [11]. Initially isolated from the Caribbean sponge Tethya crypta, this pyrimidine nucleoside obtained from spongothymidine (2), is currently synthesized and used in the treatment of acute myeloid leukemia, acute lymphocytic leukemia, and blast crisis phase of chronic myelogenous leukemia, meningeal leukemia and non-Hodgkin lymphoma [12-14].
Cytarabine acts by rapidly converting into cytosine arabinoside triphosphate, which competes with DNA polymerase's natural substrate, deoxycitidine triphosphate, leading to DNA damages during the S phase cell cycle. Ara-C is also responsible for inhibiting RNA polymerase and nucleotide reductase enzymes, both needed for DNA synthesis [15, 16]. Cytarabine is currently developed by Bedford Laboratories as plain cytarabine (Cytosar-U®) and by Enzon Pharmaceuticals as liposomal formulations (Depocyt®).
Vidarabine
Vidarabine (3), also named arabinofuranosyladenine, adenine arabinoside, Ara-A and Vira-A® is an antibiotic obtained from Streptomyces antibioticus, and approved in 1976 by FDA. Developed from spongouridine (4) (initially isolated from the Caribbean sponge Tethya crypta), this synthetic nucleoside was used to treat patients with superficial keratitis caused by herpes simplex virus, recurrent epithelial keratitis caused by herpes simplex virus type 1 and 2 and acute keratoconjunctivitis [17-19]. In in vitro studies, Vira-A® shows broad spectrum action against DNA viruses and antineoplastic activity [20]. Vidarabine is rapidly phosphorylated into adenine arabinoside triphosphate, which is its active form, and inhibits replication of herpes viral DNA by both competitive inhibition of viral DNA polymerase and incorporation into the DNA strand by substitution of some adenosine bases, thus destabilizing it [20]. Vira-A® was marketed by King Pharmaceuticals.
Ziconotide
Ziconotide (5), (SNX-111 and Prialt®) is a strong analgesic agent only approved by FDA in 2004. Ziconotide is a synthetic form of ω-conotoxin MVIIA (6), obtained from the venom of the marine snail Conus magus and is currently considered for treatment of severe chronic pain in patients with cancer or AIDS [21-23].
Ziconotide is a selective N-type calcium channel blocker. The binding of this neurotoxic drug to calcium channels, located in the dorsal horn of the spinal cord, inhibits the release of pro-nociceptive neurotransmitters, resulting in pain mitigation [24-26]. Prialt® is marketed by Jazz Pharmaceuticals.
Trabectedin
Trabectedin (7), also recognized as ET-743, ecteinascidin 743 and Yondelis® is an anticancer agent approved in 2007 by European Commission to treat patients with advanced soft tissue sarcoma after anthracyclines and ifosfamide failure [27, 28]. In 2009, trabectedin associated with pegylated liposomal doxorubicin was approved for the treatment of relapsed platinum-sensitive ovarian cancer [29, 30]. Yondelis® is also being evaluated in other tumor types, such as breast and prostate cancer [30-32]. Trabectedin is a tetrahydroisoquinoline alkaloid found in the tunicate Ecteinascidia turbinata (collected in the Caribbean and Mediterranean Sea), and it is currently prepared synthetically [33, 34].
Trabectedin is characterized by its peculiar chemical structure composed by three fused tetrahydroisoquinoline rings, named subunits A, B and C. Both subunits A and B allow the interaction with the minor groove of the double-stranded DNA, while subunit C overhangs from the DNA double helix, promoting interactions with neighboring nuclear proteins. The drug prompts a cascade of events that disturbs numerous transcription factors, DNA repair pathways, and DNA binding proteins. Trabectedin is also capable of modifying tumor microenvironment by altering the synthesis of cytokines, as well as chemokines by aberrant and normal cells [35]. Yondelis® is being developed and marketed by Pharmamar.
Eribulin Mesylate
Eribulin mesylate (8), (E7389, Halaven®) is an anticancer drug approved in 2010 by FDA for treatment of metastatic breast cancer patients after receiving at least two prior anthracycline- and taxane-based therapeutics [36, 37]. Halaven® is being marketed by Eisai Inc. to treat several other solid tumors, such as prostate cancer, non-small cell lung cancer, and sarcoma [38, 39]. Eribulin mesylate is a synthetic equivalent of halichondrin B (9), a natural compound, originally isolated from the marine sponge Halichondria okadai [40]. Halaven® is a microtubule inhibitor. It inhibits microtubule growth, although without affect microtubule shortening during the mitosis. This mode of action leads to G2/M phase arrest, promoting cell death as a result of prolonged mitotic blockage [36].
Brentuximab Vedotin
Brentuximab vedotin (10) also named as INN-brentuximab vedotin, SGN-35 and Adcetris® is an antibody-drug conjugate (ADC) targeting cluster of differentiation 30 (CD30) which proved effective in the treatment of anaplastic large cell lymphoma and relapsed or refractory Hodgkin lymphoma [41, 42]. Approved by FDA in 2011, this interesting ADC combines an anti-CD30 monoclonal (cAC10) to a potent microtubule disrupting agent, called monomethyl auristatin E (MMAE) via valine-citrulline peptide linker (11). MMAE is a synthetic antimitotic agent derived from dolastatin 10 (12), a natural antineoplastic drug derived from peptides initially isolated from the marine shell-less mollusk Dorabella auricularia and currently also from a marine cyanobacterium Symploca sp. [43, 44]. Adcetris® rapidly initiates internalization after binding to CD30 on cell surface. MMAE is transported to lysosomes, where is released and binds to tubulin, inhibiting microtubule polymerization, inducing G2/M-phase growth arrest and cell death by apoptosis of the CD30 expressing cells [45-47]. Brentuximab vedotin is marketed as Adcetris® by Seattle Genetics.
Marine Compounds: Phase III Trials
Plitidepsin
Plitidepsin (13) (dehydrodidemnin B and Aplidin®) is a chemical natural cyclic depsipeptide identified from Mediterranean tunicate Aplidium albicans, and presently produced by chemical synthesis. Plitidepsin induces early oxidative stress and the inhibition of protein phosphatases causing apoptosis by activating c-Jun N-terminal protein kinases (JNK) and p38 MAPK which lead to mitochondrial cytochrome C release and subsequently initiates the apoptosis cascade. Plitidepsin is also capable of inducing G1 and G2 arrest by interfering with protein synthesis [48-50]. Preclinical studies have demonstrated strong anticancer activity against several human cancer cells (MDA-MB-231, ACHN, and A-498) and in xenografts mice. Plitidepsin phase I/II clinical trials revealed encouraging results in patients as an anticancer agent [51, 52]. Currently, plitidepsin is in phase III trials for multiple myeloma, lymphoma and leukemia. Aplidin® is being developed by Pharmamar.
Marine Compounds: Phase II Trials
ABT-414
ABT-414 is an ADC containing an anti- epidermal growth factor receptor (anti-EGFR) antibody attached to the cytotoxic monomethyl auristatin F (MMAF) (14). ABT-414 was prepared to be stable in the bloodstream and release the MMFA only into targeted tumor cells. Preclinical studies demonstrated high efficiency in mice xenografts using human mutant and wild-type EGFR-positive cells [53]. ABT-414 is currently in phase II trials for the treatment of glioblastoma multiforme, as well as for the squamous cell tumors [53, 54]. ABT-414 is developed by Abbott Pharmaceutical.
DMXBA
DMXBA (15) also called 3-(2,4-dimethoxybenzylidene)-anabaseine and GTS-21, is a synthetic analogue of anabaseine, an alkaloid found in marine worms, belonging the Phylum Nemertea [55]. DMXBA is a nicotinic agonist described to selectively activate α7 nicotinic acetylcholine receptors (AChRs), which are produced on central nervous system neurons and astrocytes, as well as on peripheral macrophages [56, 57]. Preclinical in vitro studies demonstrated neuroprotective activity, thwarting the harmful effects of beta-amyloid in cerebral cortex neuron cells. In vivo studies, DMXBA displays anti-inflammatory activity, mediated through macrophage α7 receptors [57]. Currently in phase II trials, DMXBA is also in clinical studies to treat patients with cognitive disorders in schizophrenia, Parkinsonism and Alzheimer’s disease [58-61]. GTS-21 is registered by Comentis Inc., an entity conducting treatments for Alzheimer’s disease.
Lurbinectedin
Lurbinectedin (16) also known as PM01183 is a synthetic tetrahydroisoquinoline alkaloid, containing a pentacyclic skeleton made of two rings (subunits A and B) and an additional module, named ring C. In this marine-compound, the ring C binds covalently to the DNA minor groove, prompting mostly double-strand breaks (DSBs) in DNA and transcription blockage. DNA damage accumulation, leads to S/G2 phase arrest and causes cell death by apoptosis [62]. Preclinical in vitro studies showed anticancer activity against human cell lines. In vivo studies, PM01183 also revealed cytotoxicity against a wide variety of human cancer xenografts in athymic mice [63]. Lurbinectedin is developed by PharmaMar, and is currently in phase II clinical studies to treat patients with solid tumors, such as ovarian, breast and lung cancer [64, 65].
Glembatumumab Vedotin
Glembatumumab vedotin (CDX-011) is a human monoclonal ADC targeting cancer cells expressing glycoprotein nonmetastatic B (GPNMB), a protein overexpressed by several tumors, such as melanoma and breast cancer [66-68]. The complex GPNMB-targeting antibody (CR011) is attached to a cytotoxic MMAE. After the internalization into a GPNMB-expressing tumor cell, glembatumumab vedotin breaks the linkage and MMAE is released, killing cancer cells [69]. Preclinical in vitro tests showed anticancer activity, killing melanoma and breast cancer cells expressing GPNMB. In vivo studies revealed regression of tumors expressing GPNMB [70]. Currently, glembatumumab vedotin is in phase II trials to treat patients with locally advanced or metastatic breast cancer, with an initial focus in triple negative disease. This investigation is also in progress for the treatment of melanoma [71, 72]. CDX-011 is being developed by Celldex Therapeutics.
PM00104
PM00104 (17) with a trade name Zalypsis® is a synthetic tetrahydroisoquinolone alkaloid associated to jorumycin obtained from the mucus and skin of the Pacific nudibranch Joruna funebris and renieramiycins usually found in sponges and tunicates [73].
PM00104 binds to DNA, triggering transcription and cell cycle inhibition, leading to DNA double helix breaks, cell cycle stop in the S-phase and cell death by apoptosis [73, 74]. Preclinical in vivo studies revealed encouraging results in colon, renal, prostate and breast cancer [75, 76]. Currently in phase II trials, Zalypsis® is a potential chemotherapeutic drug to treat patients with hematological malignancies and solid human tumors [77, 78]. Zalypsis® is investigated by Pharmamar.
PSMA-ADC
PSMA-ADC is an ADC that consists of a human anti- prostate-specific membrane antigen (PSMA) monoclonal antibody conjugated to MMAE through a valine-citrulline linker. PSMA is overexpressed on most of the tumor cells in prostate cancer, as well as on blood vessels supplying other solid tumors [79, 80]. The monoclonal antibody conjugate of the PSMA-ADC selectively binds PSMA. PSMA-ADC is devised to be stable in the bloodstream and only release the potent cytotoxic chemical MMAE once inside targeted tumor cells, disrupting the microtubule filaments causing cell cycle arrest and apoptosis [81]. Preclinical studies demonstrated anti-cancer activity in prostate tumor cells and in xenografts models [82]. PSMA-ADC is presently in phase II trials to treat patients with prostate cancer and is investigated by Progenics Pharmaceuticals [83].
Marine Compounds: Phase I/II Trials
DNIB0600A
DNIB0600A is an ADC comprising a humanized IgG1 anti-NaPi2b monoclonal antibody linked to an anti-mitotic agent MMAE that showed anti-proliferative activity in xenograft models. Information on the linkage method is scarce, however, NaPi2b is a multi-transmembrane, sodium-dependent phosphate transporter that is expressed in human lung, ovarian, and thyroid cancers [8, 84]. DNIB0600A is currently in phase I/II clinical trials against non-small cell lung cancer and platinum resistant ovarian cancer according to the NIH database and is studied by Genentech/Roche [83].
Pinatuzumam Vedotin
Pinatuzumab vedotin (DCDT-2980S) is an ADC, composed of a monoclonal IgG1 antibody targeting CD22, a human B-lymphocyte antigen, linked to an anti-mitotic agent MMAE via a protease-cleavable linker. Upon binding, pinatuzumab vedotin is internalized into the target cell after which the MMAE drug is released, causing microtubule disruptions and cell death. Preclinical trials using cynomolgus monkeys revealed both effective safety in primates and efficacy in xenografts [8, 85]. DCDT-2980S is in phase I/II trials for non-Hodgkin lymphoma, melanoma and leukemia, not solid tumors [83, 85]. This compound was identified and developed by Genentech/Roche.
Polatuzumab Vedotin
Polatuzumab vedotin (DCDS-4501A) is an ADC consisting of a MMAE covalently linked to a CD79b-targeting antibody which is designed to maximize toxin delivery to B-cells. The majority of B-cell disorders express the molecule CD79b as part of the B-cell receptor complex. Upon binding, the ADC is internalized into the target cell and the cytotoxic agent is released, which may lead to microtubule disruptions and cell death [86, 87]. According to the NIH database, DCDT-2980S is presently in phase II trials to treat follicular B cell lymphoma, as well as in phase I/II trials to treat several lymphomas [83]. This compound is also investigated by Genentech/Roche.
Marine Compounds: Phase I Trials
AGS-16C3F
AGS-16C3F also known as AGS-16M8F is an ADC composed by a human IgG2k monoclonal antibody (AGS-16) linked to monomethyl auristatin F (MMAF), a potent microtubule inhibitor with potential antineoplastic activity. After administration, AGS-16C3F binds to ectonucleotide pyrophosphatase/ phosphodiesterase family member 3 (ENPP3), and once internalized, it suffers proteolytic cleavage and MMAF is released. MMAF inhibits tubulin polymerization, causing G2/M phase arrest and cell death by apoptosis [8]. AGS-16C3F is in phase I clinical trials focused on the treatment of renal and liver carcinomas (NIH database), and it is developed by Agensys and Astellas Pharma [83].
ASG-15ME
ASG-15ME also named AGS-15E is an ADC containing a human antibody IgG2 targeted to SLITRK6, an antigen expressed in several human cancers, such as bladder, lung and breast cancer as well as glioblastoma. The antibody is conjugated to a cytotoxic agent MMAE, via a maleimidocaproyl-valine-citrulline linker. Created to be stable in the bloodstream, this ADC releases the MMAE inside SLITRK6 expressing cancer cells, causing cell death [8]. Preclinical trials with ASG-15ME have demonstrated antitumor activity in vivo against bladder and lung cancer [88]. Phase I trials with ASG-15ME have investigated for metastatic urothelial cancer according NIH database [83]. ASG-15ME is investigated by Seattle Genetics.
Bryostatin
Bryostatin (18) is an antineoplastic agent obtained from the bryozoan Bugula neritina. Bryostatin-1 binds with high affinity to enzyme protein kinase C (PKC) modulating its activity, which leads to angiogenesis and cell growth inhibition, as well as induction of cell differentiation and apoptosis. In vivo studies showed that bryostatin repairs hippocampal synapses, memory and spatial learning, making it a prospective drug to treat Alzheimer’s disease and strokes. Other preclinical tests showed its potential to help eradicate human immunodeficiency virus (HIV) [89, 90]. Bryostatin is currently in phase I studies and is being considered as an anti-Alzheimer’s agent by National Cancer Institute.
Enfortumab Vedotin
Enfortumab vedotin (ASG-22ME) is an ADC targeting the cell adhesion molecule Nectin-4, which can be found overexpressed on multiple tumor types, such as lung, breast, pancreatic and bladder cancer. The antibody is conjugated to MMAE, via an enzyme-cleavable linker. After internalization, MMAE is released from ASG-22ME by proteolytic cleavage, and binds to tubulin inhibiting its polymerization, which results in G2/M phase arrest and apoptosis in the target cells [8]. Currently, ASG-22ME is in phase I for metastatic urothelial cancer and is developed by Seattle Genetics [83].
DEDN6526A
DEDN6526A (RG-7636) is an ADC with the anti-mitotic agent MMAE linked to the humanized IgG1 anti–endothelin B receptor (ETBR) monoclonal antibody by a protease-cleavable linker. ETBR is a G-protein coupled receptor that can activate RAF/MEK signaling, and is overexpressed in metastatic melanoma. After administration, the monoclonal antibody moiety of DEDN6526A selectively binds to ETBR. The antibody-drug complex is taken into the cells, where MMAE is released, killing the melanoma cancer cells [91]. DEDN6526A is in phase I clinical studies for the treatment of metastatic or unresectable melanoma (NHI database) and it is investigated by Genentech/Roche [83].
DMUC5754A
DMUC5754A (RG-7458) is an ADC composed by a humanized IgG1 anti-MUC16 monoclonal antibody, linked to the agent MMAE, via a cleavable linker. MUC16 is a transmembrane glycoprotein overexpressed on ovarian cancer cells. When DMUC5754A binds to MUC16, a linker molecule releases MMAE into the ovarian cancer cells and kills them [92]. A phase I study developed by Genentech/Roche in order to evaluate the efficacy, safety and pharmacokinetics of DMUC5754A in the treatment of patients with platinum-resistant ovarian cancer is in progress [83].
DSTP3086S
DSTP3086S also known as RG-7450 is an ADC containing a human IgG1 against six-transmembrane epithelial antigen of the prostate 1 (STEAP1) protein coupled to MMAE via a protease labile peptide linker. STEAP1 protein is a cell-surface protein frequently overexpressed in prostate cancer [93]. Currently, DSTP3086S is in phase I trial developed by Genentech/Roche for treatment of metastatic castration-resistant prostate cancer and ovarian cancer according NHI database [83].
HuMax®-TF-ADC
HuMax®-TF-ADC is an ADC composed of a human antibody against tissue factor (TF), conjugated to MMAE via a protease-cleavable valine-citrulline linker. TF is highly expressed in several solid tumors, such as pancreatic, lung, cervical, prostate, bladder, ovarian, breast, and colon cancer, making it an appropriate target for HuMax®-TF-ADC [94]. Preclinical trials demonstrated strong capacity of HuMax-TF-ADC to bind to TF, release MMAE in the target cells and, consequently, inhibit tumor cell proliferation [94, 95]. A phase I trial of HuMax-TF-ADC to treat several solid tumors, such as prostate, ovary and lung is underway in collaboration with both Genmab and Seattle Genetics organizations [83].
MLN-0264
MLN-0264 contains the agent MMAE conjugated to a human monoclonal IgG antibody (5F9), that recognizes guanylyl cyclase C (GCC) via a cleavable linker. GCC is a receptor expressed on the epithelial cell in healthy intestinal tissue, and overexpressed in multiple tumors, including metastatic colorectal, pancreatic and gastric cancer. The monoclonal antibody moiety of this conjugate selectively binds to protein GCC, leading to internalization of the drug. Once inside the tumor cells, the linkage is broken and MMAE is released, killing cancer cells exposed to its cytotoxic activity [96, 97]. The activity of MLN0264 in phase I trials has been evaluated in xenograft models of cancers to express GCC, such as metastatic colorectal cancer, gastric and pancreatic cancer [83].
PM060184
PM060184 (19) is a synthetic compound derived from a marine chemical initially isolated from the Madagascan sponge Lithoplocamia lithistoides [98]. PM060184 promotes disorder of the microtubules, chromosome missegregation and aberrant mitotic spindle multipolarization, causing prometaphase arrest and formation of multinucleated cells, leading to programmed cell death by apoptosis. This compound demonstrated potent in vivo anti-cancer activity [99, 100]. PM060184 is developed by PharmaMar in Phase I clinical trials for treatment of advanced solid tumors [83].
SGN-CD19A
SGN-CD19A is an ADC consisting of a human anti-CD19 monoclonal antibody attached to the agent MMAF via a maleimidocaproyl linker. CD19 is a B-cell specific marker expressed in most B-lineage acute lymphocytic leukemia. After administration of SGN-CD19A, the monoclonal antibody portion of this conjugate selectively binds to CD19. Then, it is internalized and MMAF is released, which induces G2/M arrest and tumor cell death by apoptosis [101]. Currently, SGN-CD19A is developed by Seattle Genetics and is in phase I clinical trials for CD19-positive acute lymphoblastic leukemia and B-cell lymphoma [83].
SGN-LIV1A
SGN-LIV1A is an ADC consisting of an anti-zinc transporter SLC39A6 (LIV-1) monoclonal antibody conjugated to a MMAE via an enzyme-labile linker. Upon internalization into tumor cells expressing LIV-1, such as the majority of metastatic breast cancers, this ADC releases its high cytotoxic agent MMAE, leading to tumor cell apoptosis. Preclinical in vitro and in vivo studies revealed significant delay of tumor proliferation when SGN-LIV1A is administered [102, 103]. SGN-LIV1A is developed by Seattle Genetics, and is currently in phase I clinical trial for treatment of LIV-1-positive metastatic breast cancer patients [83].
CONCLUSION
Throughout the years, pharmaceutical research was mainly dedicated to terrestrial plants and microorganisms, not only because they were more easily accessible organisms, but also because popular traditions associated their use to beneficial effects. However, recently there has been a shift in the focus of researchers towards exploring the huge biodiversity of oceans and seas in the hope of identifying and taking advantage of new and unique biological compounds produced by marine organisms.
About 28 natural compounds from marine invertebrates have been submitted to clinical trials in last 50 years and described in this chapter. All of these natural compounds showed interesting bioactivities with complex mechanisms of action and with potential exploration by the pharmaceutical industries. As a result of these research endeavors, it is evident that the marine environment most likely harbors many currently unknown natural molecules that could be an important source of new pharmaceutical developments. This is just the beginning, as there is still much to be learned from the oceans’ depths. Chemical structure, origin and isolation of BC are poorly represented in the literature and should also be clarified in further studies. Furthermore, in many other bioactive compounds, such as elisidepsin (Irvalec®), hemiasterilin (E7974), plinabulin (NPI 2358), pseudopterosin, soblidotin (TZT1027), synthadotin (ILX-651) and tasidotin little information is available, leaving doubt whether the clinical trials were completed or discontinued.
The largely unexplored marine environment is a valuable source for discovering new substances with interesting and complex mechanisms of action. However, when it comes to bioactive compounds, several challenges, such as bioprospection, collection, preservation, extraction and fractionation of marine invertebrate must be taken into account, in order to discover unique molecules with therapeutic potential. Developments in tools and procedures, including sampling approaches, structure determination, and chemical synthesis are fundamental to the successful exploration of marine natural compounds as potential bases for new pharmaceuticals.
Although improving survivability, recently approved therapies for advanced diseases are far from a cure, therefore, it is opportune and imperative to discover novel therapeutic options and develop more efficient treatment methodologies. Encouraging results from clinical trials have been showing that research on marine natural products should continue in order to further develop new cures and improve current treatments.
Consent for Publication
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
Declared none.
