BREAKING! Narsoplimab May Prevent And Treat COVID-19 Severity By Halting Complement Cascade Says Researchers
Narsoplimab And COVID-19
: Researchers are now saying that treatments for COVID-19 may be focusing on at the wrong elements of the disease based on emerging data from Bergamo, Italy, the epicenter of the pandemic in Europe.
Italian researchers realized, as they combed through the data, that COVID-19 is an endothelia injury rather than a pulmonary event and that stopping the complement cascade can have a significant effect on the escalation of symptoms during a patient’s illness. https://www.sciencedirect.com/science/article/pii/S0171298520304459?via%3Dihub
Dr Jeffrey Conrad Lawrence, M.D., professor of medicine at Cornell Medical College
, noted immunohistochemistry analysis of pulmonary autopsy tissue showed “striking depositions of C5b-9 in the microvasculature of the interalveolar septa, including areas of normal appearing lung, which is suggestive of systemic complement activation.” C4 and MASP2 deposition also were seen in the septa.
Dr Lawrence told Thailand Medical News, “This was the first time we showed clotting in the small blood vessels, leading to lung damage. Chinese researchers also found it in the kidneys, and we’ve found it in the skin, which shows the deposition of MASP2 is a systemic problem. The presence of MASP2 activates the inflammatory system and clotting and, with D-dimers, involves complement, coagulation, and inflammation.”
Studies showed co-deposition of virus spike points along with complement in the damaged vessels, which leads to activation of MASP2.
Consequently, the SARS-CoV-2 coronavirus can directly activate MASP2. This is a very important finding Dr Lawrence stressed, because it emphasizes the role of complement in COVID-19.
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system, which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system.
The complement system consists of a number of small proteins that are synthesized by the liver, and circulate in the blood as inactive precursors.
When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end result of this complement activation or complement fixation cascade is stimulation of phagocytes to clear foreign and damaged material, inflammation to attract additional phagocytes, and
activation of the cell-killing membrane attack complex. Over 30 proteins and protein fragments make up the complement system, including serum proteins, and cell membrane receptors. They account for about 10% of the globulin fraction of blood serum
Activation of any of the three complement pathways (classical, alternative, or lectin) results in the formation of the terminal complement complex, also called the membrane attack complex, or MAC. The MAC is composed of the complement proteins C5b, C6, C7, C8, and multiple copies of C9 (C5b-9)
Mannan-binding lectin serine protease 2 also known as mannose-binding protein-associated serine protease 2 (MASP-2) is an enzyme that in humans is encoded by the MASP2 gene. MASP-2 is involved in the complement system. MASP-2 is very similar to the C1s molecule, of the classical complement pathway, and they are thought to have a common evolutionary ancestor. When the carbohydrate-recognizing heads of MBL bind to specifically arranged mannose residues on the surface of a pathogen, MASP-2 is activated to cleave complement components C4 and C2 into C4a, C4b, C2a, and C2b.
The importance of SARS-CoV-2 coronavirus being able to directly activate MASP2also was indicated in studies of mice. They showed that the survival of infected mice, with 1 million copies per milliliter of the SARS-CoV-2 virus in their bloodstream, hinged on the presence or absence of complement.
Dr Lawrence said, “Knocking out the complement made the difference.”
It was observed that in severe cases of COVID-19, heparin (a blood thinner) often is administered either prophylactically or therapeutically, but it offers only one avenue of attack. MASP2 activation, however, affects complement and initiates anticoagulation and anti-inflammatory responses. To halt the cascade, Lawrence said, “You need to attack all the processes.”
The beneficial and therapeutic effects of interrupting the MASP2 cascade are evident in acute thrombotic microangiopathy (TMA). That condition correlates closely with COVID-19. In both conditions, MASP2 levels are very high.
In TMA studies, the drug narsoplimab was administered. Narsoplimab blocks the activation of caspase 8, the first thing activated when killing a macrovascular endothelial cell thus it has potential as a COVID-19 treatment by blocking the complement cascade.
Dr Miguel-Angel Perales, M.D., chief of the adult bone marrow transplantation service at Memorial Sloan Kettering Cancer Center, explained,“Narsoplimab is an investigational, fully human IgG4 monoclonal antibody (mAb) that binds to MASP2 (the effector enzyme of the lectin pathway of complement), leaves the classical pathway function fully intact, and blocks MASP-2-mediated coagulation.”
Dr Perales launched a Phase II trial of narsoplimab in TMA patients, which was converted to a pivotal trial after receiving FDA breakthrough therapy designation. Patients were treated once weekly for four weeks. Of the 28 patients in the study, 54% had a complete response rate. Of the 23 who were treated for four weeks or more, 65% (15 patients) had a complete response rate. Of those 15, 93% survived at least 100 days.
Dr Perales said, “These are high response rates and are supportive of COVID patients who also received narsoplimab.”
The study results underscore the importance of blocking the MASP2-mediated complement cascade. “Once the cascade is in motion, taking away the original insult doesn’t solve the problem,”Dr Perales said.
In Italy, Bergamo, Professor Dr Alessandro Rambaldi, Professor of hematology at the University of Milan and head of hematology and oncology at Papa Giovanni XXIII Hospital, found himself in the COVID-19 fight soon after the outbreak occurred.
Dr Rambaldi said, “My colleagues called from infectious disease, intensive care, and other departments, asking why their patients had thrombosis. This was unexpected.”
In a study, he found severe, extensive thrombotic events in the lungs, hearts, and brains of COVID-19 patients as endothelial cells were released into the bloodstream. He began searching for biological markers.
Dr Rambaldi added, “The parallels between COVID-19 and TMA were strikingly similar.”
It was observed that both involved endothelial damage that activated the lectin pathway, MASP2 activation, and multi-organ TMA.
Dr Rambaldi administered narsoplimab in a small trial, to six COVID-19 patients who had received continuous airway pressure for less than 48 hours.
Dr Rambaldi reported. “Their clinical condition improved rapidly. The levels of endothelial cells in the blood dropped after two, four, and six administrations of narsoplimab but in one patient rose again.”
Significantly one additional administration returned cell levels to normal. Serum levels of LDH, CRP, IL-6, and IL-8 also dropped throughout treatment. Ultimately, all six patients were discharged from the hospital. D-dimer also dropped during treatment and normalized after 25 days.
Dr Rambaldi said. “In all, we had clinical resolution of the dramatic respiratory failure and evidence that the hypercoagulation could be downregulated by the treatment with narsoplimab.”
The detailed but different research and studies of these three physicians suggests COVID-19 is an endothelial injury event and that narsoplimab, because of its ability to interrupt the MASP2-mediated cascade, may be an effective treatment for COVID-19. More extensive trials are needed, of course, before it can be authorized for use but, early results appear promising.
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