标题: First Specific (Rather Than Symptomatic) Treatment for Ebola Virus [打印本页] 作者: choi 时间: 10-31-2019 15:37 标题: First Specific (Rather Than Symptomatic) Treatment for Ebola Virus Betsy McKay, From War Zone Came an Unexpected Cure for Ebola; A clinical trial om Congo proved two new drugs can reduce deaths. Wall Street Journal, Oct 31, 2019 (front page). https://www.wsj.com/articles/ebo ... ar-zone-11572446873
Quote:
(a) "the disease that emerged in 1976 from a remote village near the Ebola River.
(b) "In the [clinical] trial, patients given a single-antibody drug had a 35% mortality rate, according to results presented at an infectious-diseases conference this month in Washington, DC, compared with as high as 90% without treatment. The NIAID [National Institute of Allergy and Infectious Diseases, part of US National Institute of Health] - led drug, mAB114, was developed from an antibody of an Ebola survivor found [not 'treated'] by Dr Muyembe.
"Dr Muyembe set out on his path to an Ebola treatment during the 1995 outbreak. He transferred blood from five survivors to eight patients, hoping that the antibodies that kept some people alive would keep others from dying. Seven of the patients who received the blood transfusion recovered. He published the result in a scientific journal in 1999. Other researchers said the study was small and had failed to include a control group, a comparison set of patients who weren't given the treatment [and received placebo instead]. * * *
"In 2005 Dr Muyembe met with NIAID scientist Barney Graham, and their conversation turned to Ebola. Dr Muyembe suggested theNIAID study one of the survivors who had donated blood [presumably in 1995]. The survivor, Cyprien Mubiala, lost 15 members of his family to Ebola in the 1995 outbreak. He and his family members were infected caring for a brother who was a hospital technician and had contracted the illness at work. As family members died one by one, Mr Mubiala developed a fever and grew weak. Only he and a sister lived. After recovering, he donated blood t Dr Muyembe for the study, and, assuming he was immune to Ebola, spent the next months caring for others with the disease. Scientists suspect Mr Mubiala has potent antibodies because he had been exposed again to the virus as he helped Ebola patients ['potent' is the key, but suspicions may not be correct, as some people react strongly, some others little, in terms of immunity]. In late 2006, Mr Mubiala traveled to the NIAID's vaccine Research Centerin Bethesda, Md and gave blood samples. * * * they developed mAb114.
(c) "Among patients treated with a drug made of three antibodies by Regeneron Pharmaceuticals Inc, called REGN-EB3, 34% died [ie, similar efficacy as mAb114].
"Regeneron, a Tarrytown ['about 25 miles (40 km) north of midtown Manhattan': Wikipedia], NY-based company, started developing an Ebola drug in October 2014. Years earlier, the company had developed a technology to create treatments against viruses using human antibodies produced in a genetically-modified mouse. It identified three antibodies to attack the Ebola virus and created REGN-EB3.
(d) "Mr Mubiala, 52 years old, * ** now has a wife and three children. 'When I heard there [is] now a cure from my blood,' he said, 'I was very, very happy.' 作者: choi 时间: 10-31-2019 15:38
Note: The report is locked behind paywall. There is no need to read the rest.
(a)
(i) "It is roughly 250 km in length. The name Ebola is a French corruption of Legbala, its name in the Ngbandi language which means 'white water.' * * * In 1976, Ebola virus (EBOV) was first identified in [Village of] Yambuku, 60 miles from the Ebola River, but Professor Peter Piot [Belgian, 1949- ] decided to name it after the river so that the town would not be associated with the disease's stigma." en.wikipedia.org for "Ebola River."
(ii) Jean-Jacques Muyembe-Tamfum https://en.wikipedia.org/wiki/Jean-Jacques_Muyembe-Tamfum
("was educated in schools run by Jesuits. He studied medicine at the Lovanium University in the Democratic Republic of the Congo where he became interested in microbiology and graduated in 1962. He earned a PhD in virology at the University of Leuven in Belgium, working on viral infections with mouse models")
was born in 1942 (age 77).
(iii) University of Leuven, or
Université catholique de Louvain https://en.wikipedia.org/wiki/Université_catholique_de_Louvain
(1425- (the first university in Belgium and the Netherlands); table: state funded, Religious affiliation Roman Catholicism, Location: Louvain-la-Neuve; "In 1968 the Catholic University of Leuven split into the Dutch-language Katholieke Universiteit Leuven, which stayed in Leuven, and the French-language Université catholique de Louvain, which moved to Louvain-la-Neuve in Wallonia, 30 km southeast of Brussels")
, whose acronym Us ICL. See next.
(iv) Louvain, Leuven and Louvain-la-Neuve. Tourism Ottignies Louvain-la-Neuven, undated www.tourisme-olln.be/en/for-prac ... uvain-la-neuve.html
("Leuven is a city located in the Flemish Brabant, in the west of Brussels at about 30 km from Louvain-la-Neuve. It is commonly called 'Louvain' by the french speaking people of Belgium, a translation that often leads to confusion with the name of Louvain-la-Neuve. For more information about the origin of the name Louvain-la-Neuve, refer to its history")
(b)
(i) All four antibodies (mAb114 and EB-3, where EB comes from the first two letters of Ebola) are monoclonal antibodies. A monoclonal antibody is shortened to mAb. They are all in aqueous (ie, water) solution, not solid, and will drip via an intravenous line (medical term: infusion). They are not vaccine, because the four will be administered (as soon as possible) after a person got infected and shows symptoms.
(ii) They were in phase I of clinical trials, given to a small number of patients to observe side effects, not efficacy of the treatment (which is the goal of Phases II and III, with more patients in III than in II). In other words, the goal of phase I is to ascertain the drug is "safe" to patients. The WSJ report says that in June 2018 there was an outbreak in Congo. So both drugs were rushed there to test on patients with their consent. Both drugs succeeded. So both Regeneron and Miami-based Ridgeback Biotherapeutics LP that licensed mAb114 from NIAID, will soon seek FDA for approval, the WSJ report says.
(iii) Rhodesian Ridgeback https://en.wikipedia.org/wiki/Rhodesian_Ridgeback
(view a photo whose caption reads: "Rhodesian Ridgeback showing his back")
(c) Regeneron "had developed a technology to create treatments against viruses using human antibodies produced in a genetically-modified mouse."
Velocisuite.® Regeneron, undated (in the "Technology" tab in the top horizontal bar) https://www.regeneron.com/technology
("VelociMab® is a group of technologies that allow us to move with unprecedented speed from identification of a therapeutic antibody into clinical studies. VelociMab enables the high-throughput screening of potential therapeutic antibodies and the rapid generation of cell lines for recombinant human antibodies. It allows researchers to go from mouse immunization to production cell line bioreactor harvest within eight months")
The Mab in VelociMab® is same as mAb -- monoclonal antibody.
(d)
(i) "Ebola viruses belong to a family of viruses termed Filoviridae. Filovirus particles form long, sometimes branched, filaments of varying shapes, as well as shorter filaments, and may measure up to 14,000 nanometers in length with a diameter of 80 nanometers. Viral particles contain one molecule of single-stranded negative-sense RNA, enveloped in a lipid (fatty) membrane." Baylor College of Medicine, undated.
The prefix filo- or fili- (as in filiform) means "thread" and is derived from Latin noun neuter fīlum thread, string, filament, fiber. https://en.wiktionary.org/wiki/filum
(ii) How mAb 114 was produced.
Corti D et al, Protective Monotherapy Against Lethal Ebola Virus Infection by a Potently Neutralizing Antibody. Science, 351: 1339 (2016; citations omitted)). https://science.sciencemag.org/content/351/6279/1339
two consecutive paragraphs:
"We obtained blood from two survivors of the 1995 EVD [Ebola virus disease] outbreak in Kikwit, Democratic Republic of the Congo, 11 years after infection. To determine whether the subjects retained circulating antibodies against Ebola virus (EBOV) glycoprotein (GP), we assessed GP-specific antibodies by enzyme-linked immunosorbent assay (ELISA) (Fig 1A). The reciprocal 10% maximal binding EC90 titer (the reciprocal dilution at which there is a 90% decrease in antigen binding) for subject 1 (S1) was 2326, higher than control sera by more than a factor of 10. Moreover, serum from the more severely ill subject, S1, displayed potent virus-neutralizing activity (Fig 1B); this finding indicates that S1 maintained serologic memory against EBOV GP more than a decade after infection and suggested the potential for cloning immunoglobulins with potent neutralizing activity from S1's memory B cells.
"Therefore, we sorted memory B cells from S1's peripheral blood mononuclear cells and immortalized individual clones with Epstein-Barr virus [this virus makes B lymphoblasts live forever, and therefore carcinogenic with regard to PRECURSORS -- that is what lymphoblasts mean -- of B lymphocytes ONLY]. Forty clone supernatants displayed a range of GP binding (Fig 1C); two of them, 100 and 114, expressed antibodies with markedly higher neutralizing activity than all others (Fig. 1D). A second immortalization yielded 21 clones, from which the GP-specific clones 165 and 166 were rescued (fig S1 [where S stands for supplemental]).
(e) Because neither drugs is on sale, so both companies does not say much about the two treatments. So Wikipedia provides an excellent source. (there is no information about REGN-EB3) whatsoever.
(i) mAb114 https://en.wikipedia.org/wiki/MAb114
(section 2 Mechanism of action, section 2.1 Neutralization)
(ii) in normal situation:
Figure 1 is color-coded and the top is the inside -- the lumen, that is -- of lysosome, cytoplasm (or cytosol) is at the bottom, separated by the membrane of lysosome. The 13 transmembrane domains (brown, all in alpha-helix) cross the membrane of lysosome. Figure 1A shows NPC2 (green) with cholesterol (purple). There is no need to read beyond Figure 1, whose C contain PTCH (abbreviation from Patch) protein, which is unrelated to cholesterol (transportation) -- C merely shows "PTCH is closely related to NPC1" as the text following Figure 1 states.
(iii) West VR et al, Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody. Nature Structural and Molecular Biology, 26: 204 (2019). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402988/
("All Ab [antibody] therapeutics currently under development for Ebola virus disease target the ebolavirus surface glycoprotein, GP, which mediates viral entry into host cells by catalyzing viral membrane fusion in host cell endosomes. During biogenesis, GP is post-translationally processed [split by an enzyme] to yield GP1 and GP2 subunits (Fig 1a), held together by a single disulfide bond, which associate into a trimer of GP1,2 heterodimers")
Figure 1(a) is space-filling model, showing three (3) GP1 (dark green) and three GP2 (light green) and two (2) front part (Fab, where f and ab stand for fraction and antigen-binding -- so Fab means antigen-binding fraction or portion of the antibody) of monoclonal antibody. One Fab binds to one side of the green balls and the other, the other side. Fan is composed of light chain (light brown) and heavy chain (dark brown) wrapping around each other. Figure 3(a) at the bottom shows the same, but in ribbon model.
(iv) Presently, there is no three-dimensional structure how Ebola virus's glycoprotein 1 and 2 interact with NPC 1 and 2.