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Vadastuximab Talirine (SGN-CD33A)
Vadastuximab talirine is an antibody-drug conjugate (ADC) directed to CD33 (siglec-3) which is a transmembrane receptor expressed on cells of myeloid lineage. The experimental drug, being developed by Seattle Genetics, was in clinical trials for the treatment of acute myeloid leukemia (AML). Development of vadastuximab talirine was discontinued in 2017 after a pivotal phase III clinical trial. Target, mAb, linker, and cytotoxin The drug target, CD33, is expressed on most AML cells. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer (SGD-1882), via a proprietary site-specific conjugation chemistry via a cleavable (valine-alanine dipeptide as cathepsin B cleavage site) maleimidocaproyl type linker, to a monoclonal antibody with engineered cysteines (EC-mAb). Vadastuximab talirine contains two site-specific drug attachment engineered cysteines. This use of engineered cysteine residues at the sites of drug linker attachment results ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
CD33
CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. It binds sialic acids, therefore is a member of the SIGLEC family of lectins. Structure The extracellular portion of this receptor contains two immunoglobulin domains (one IgV and one IgC2 domain), placing CD33 within the immunoglobulin superfamily. The intracellular portion of CD33 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that are implicated in inhibition of cellular activity. Function CD33 can be stimulated by any molecule with sialic acid residues such as glycoproteins or glycolipids. Upon binding, the immunoreceptor tyrosine-based inhibition motif (ITIM) of CD33, present on the cytosolic portion of the protein, is phosphorylated and acts as a docking site for Src homology 2 (SH2) domain-containing protei ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Antibody-drug Conjugate
Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs. ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic (anticancer) payload or drug. Antibody-drug conjugates are an example of bioconjugates and immunoconjugates. ADCs combine the targeting properties of Monoclonal antibody, monoclonal antibodies with the cancer-killing capabilities of cytotoxic drugs, designed to discriminate between healthy and diseased tissue. Mechanism of action An anticancer drug is coupled to an antibody that targets a specific tumor antigen (or protein) that, ideally, is only found in or on tumor cells. Antibodies attach themselves to the antigens on the surface of cancerous cells. The biochemical reaction that occurs upon attaching ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Seattle Genetics
SeaGen was the world's first large scale commercial tidal stream generator. It was four times more powerful than any other tidal stream generator in the world at the time of installation. It was successfully decommissioned by SIMEC Atlantis Energy Limited in summer 2019, having exported 11.6GWh to the grid since 2008. The first SeaGen generator was installed in Strangford Narrows between Strangford and Portaferry in Northern Ireland. Strangford Lough was also the site of the first known tide mill in the world, the Nendrum Monastery mill where remains dating from 787 have been excavated. History Marine Current Turbines, the developer of SeaGen, demonstrated first prototype of tidal stream generator in 1994 with a 15 kilowatt system in Loch Linnhe, off the west coast of Scotland. In May 2003, the prototype for SeaGen, '', was installed off the coast of Lynmouth, North Devon, England. Seaflow was a single rotor turbine which generated 300 kW but was not co ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Clinical Trials
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted. Depending on product type and development stage, investigators initially enroll volunteers or patients into small pilot studies, and subsequently conduct progressively larger scale comparative studies. Clinical trials can vary i ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated. Risk factors include smoking, previous chemotherapy or radiation therapy, myelodysplastic syndrome, and exposure to the chemical benzene. The underlying mechanism involves replacement of normal bone marrow with leukemia cells, which results in a drop in red blood cells, platelets, and normal white blood cells. Diagnosis is generally based on bone marrow aspiration and specific blood tests. AML has several subtypes for which treatments and outcomes may vary. The fir ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Pyrrolobenzodiazepine
Pyrrolobenzodiazepines, (PBD) are a class of compound that may have antibiotic or anti-tumor properties. Some dimeric pyrrolobenzodiazepines are used as the cytotoxic drug payloads in antibody-drug conjugate Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 phar ...s, for example in loncastuximab tesirine. History Anthramycin, the first PBD monomer, was first synthesized in the 1960s.From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs) Angew Chem Int Ed Engl. 2017 Jan 9; 56(2): 462–488. Published online 2016 Nov 15. doi: 10.1002/anie.201510610 References Antibiotics {{heterocyclic-stub ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Cathepsin B
Cathepsin B belongs to a family of lysosomal cysteine proteases known as the cysteine cathepsins and plays an important role in intracellular proteolysis. In humans, cathepsin B is encoded by the ''CTSB'' gene. Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions. Structure Gene The ''CTSB'' gene is located at chromosome 8p22, consisting of 13 exons. The promoter of CTSB gene contains a GC-rich region including many SP1 sites, which is similar to housekeeping genes. At least five transcript variants encoding the same protein have been found for this gene. Protein Cathepsin B is synthesized on the rough endoplasmic reticulum as a preproenzyme of 339 amino acids with a signal peptide of 17 amino acids. Procathepsin B of 43/46 kDa is then transported to the Golgi apparatus, where cathepsin B is formed. Mature cathepsin B is composed of a heavy chain of 25-26 kDa and a light chain of 5kDa, which are linked by a dime ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
American Society Of Hematology
The American Society of Hematology (ASH) is a professional organization representing hematologists. It was founded in 1958. Its annual meeting is held in December of every year and has attracted more than 30,000 attendees. The society publishes the medical journal ''Blood'', the most cited peer-reviewed publication in the field, and ''Blood Advances'', an online, peer-reviewed open-access journal. The first official ASH meeting was held in Atlantic City, New Jersey, in April 1958. More than 300 hematologists met together to discuss the key research and clinical issues related to blood and blood diseases. Since the first gathering, ASH has been an important member in the development of hematology as a discipline. For more than six decades, ASH has sponsored its annual meeting. Today, ASH has more than 17,000 members, many of whom have made major advancements in understanding and treating blood diseases. Annual meeting Held each year in December, the annual meeting brings together ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Hypomethylating Agent
A hypomethylating agent (or demethylating agent) is a drug that inhibits DNA methylation: the modification of DNA nucleotides by addition of a methyl group. Because DNA methylation affects cellular function through successive generations of cells without changing the underlying DNA sequence, treatment with a hypomethylating agent is considered a type of epigenetic therapy. Currently available hypomethylating agents block the activity of DNA methyltransferase (DNA methyltransferase inhibitors / DNMT inhibitors). Currently two members of the class, azacitidine and decitabine, are FDA-approved for use in the United States in myelodysplastic syndrome and are being investigated for use in a number of tumors. Clinical use Two hypomethylating agents are approved for the treatment of myelodysplastic syndrome by the United States FDA * decitabine Also has EU approval for acute myeloid leukemia (AML). * azacitidine Mechanism of action DNA methylation is the modification of DNA nucleotides ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Azacitidine
Azacitidine, sold under the brand name Vidaza among others, is used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine (also known as 5-aza-2′-deoxycytidine) were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer. The most common adverse reactions in children with juvenile myelomonocytic leukemia include pyrexia, rash, upper respiratory tract infection, and anemia. Medical uses Azacitidine is indicated for the treatment of myelodysplastic syndrome, for which it received approval by the U.S. Food and Drug Administration (FDA) on May 19, 2004. In two randomized controlled trials comparing azacitidine to supportive treatment, 16% of subjects with myelodysplastic syndrome who were randomized to receive azacitidine had a complete or partial normalization of blood cell counts and bo ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Decitabine
Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog. Medical uses Decitabine is used to treat myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes ( refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System groups. In patients with chronic kidney disease, Batty and colleagues reported the first case series on the feasibility of therapy with hypomethylating agents in patients with chronic kidney disease. It also h ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Myelodysplastic Syndrome
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include feeling tired, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia. Risk factors include previous chemotherapy or radiation therapy, exposure to certain chemicals such as tobacco smoke, pesticides, and benzene, and exposure to heavy metals such as mercury or lead. Problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts. Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood. The types of MDS are based on specific changes in the blood cells and bone marrow. Treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantati ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
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