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New treatments of Covid-19: Monoclonal Antibody Therapy

As a Nephrologist I have been using Monoclonal antibodies therapy in kidney transplant patients as well as treating a number of kidney diseases for the last 20 years.

Post by on Saturday, June 5, 2021

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As a Nephrologist I have been using Monoclonal antibodies therapy in kidney transplant patients as well as treating a number of kidney diseases for the last 20 years.

Antibodies are naturally produced by the body’s immune system when it is exposed to foreign antigens present in bacteria, viruses, and unmatched blood products or in organ transplants. They are the most important part of the defense mechanism against infections. These then bind to antigen and trigger an immune response stimulating the specialized cells of the immune system to kill the invading pathogen.

 Most antibodies produced as part of the normal immune response are polyclonal, meaning that they are produced by a number of distinct B lymphocytes, and, as a result, they each have a slightly different specificity for the target antigen (eg, by binding different epitopes or binding the same epitope with different affinities). However, it is possible to produce large quantities of an antibody from a single B-cell clone.

Monoclonal antibody drugs are based on the natural antibodies that the body uses to fight infections. They work by binding to a specific target and then blocking its action or flagging it for destruction by other parts of the immune system.

Monoclonal antibodies are identical copies of an antibody that targets one specific antigen. Scientists can make monoclonal antibodies by exposing white blood cells to a particular antigen. They can then select a single white blood cell or clone and use this as the basis to produce many identical cells, making many identical copies of the monoclonal antibody.

In the last 3 decades more than 100 monoclonal antibodies (mAbs) have been designated as drugs; new approvals continue to accrue. Antibody treatments in themselves are not new. Available mAbs are directed against a large number of antigens and used for the treatment of immunologic diseases, organ transplantation , reversal of drug effects, and cancer therapy. They have also been used to treat viral infections such as Ebola and Ebstein bar virus in organ transplants. Each monoclonal antibody is specific to its matching antigen. The same principles have been used for COVID-19, and there are few authorized monoclonal antibody therapies.


Anti-SARS-CoV-2 monoclonal antibodies

The SARS-CoV-2 virus’ spike glycoprotein, which sits on its surface, functions to facilitate the virus’s entry into the body’s cells. Some SARS-CoV-2 antibodies bind to the spike protein and prevent the virus from entering the cell. The immune system of the majority of people who recover from COVID-19 produce antibodies to the SARS-CoV-2 virus. Research studies have shown that these antibodies persist for at least 6 months after the infection. In a major scientific breakthrough scientists have been able to produce these antibodies in a laboratory setting so that they can be infused into the blood of people who develop COVID infection.

Currently, all the monoclonal antibodies for COVID-19 for which the FDA have issued emergency use authorization target the spike protein.

More than 50 monoclonal antibody products that target SARS-CoV-2, the virus that causes COVID-19, are now in development. The US Food and Drug Administration (FDA) has already issued Emergency Use Authorization (EUA) for two such drugs on the basis of phase 2 trial data — Bamlanivimab Etesvimab made by Eli Lilly, and a cocktail of  Casirivimab plus Imdevimab, made by Regeneron .  These antibodies act like laser guided bombs and target the spike protein of the virus and stop it from attaching to and entering human cells. The antibody drugs covered by EUAs do not cure COVID-19, but they have been shown to reduce hospitalizations and visits to the emergency department for patients at high risk for disease progression. They are approved to treat patients older than 12 years with mild to moderate COVID-19 who are at high risk of progressing to severe disease or hospitalization. They are not authorized for use in patients who have been hospitalized or who are on ventilators. The hope is that antibody drugs will reduce the number of severe cases of COVID-19 and ease pressure on overstretched hospitals.

Antibodies are temperature-sensitive and need to be refrigerated during transport and storage, so a cold-chain-compliant supply chain is required. Fortunately, they can be kept at standard refrigerator temperatures, ranging from 2 °C to 8 °C

Another two-antibody cocktail from AstraZeneca, AZD7442, has been approved for phase 3 clinical trials.

Indications

They have been approved only for non-hospitalized COVID-19 patients with mild to moderate illness (eg, not requiring supplemental oxygen or, if on chronic supplemental oxygen, without an increased oxygen requirement) who have certain risk factors for severe disease : . These risk factors for adults (≥18 years) include any of the following:

•Older age (≥65 years)

•Body mass index (BMI) ≥25 kg/m²

•Pregnancy

•Chronic kidney disease

•Diabetes mellitus

•Immunosuppression (immunosuppressive disease or treatment)

•Cardiovascular disease (including congenital heart disease) or hypertension

•Chronic lung disease (eg, chronic obstructive pulmonary disease [COPD], asthma [moderate to severe], interstitial lung disease, cystic fibrosis, pulmonary hypertension)

•Sickle cell disease

•Neurodevelopmental disorders (eg, cerebral palsy) or other medically complex conditions (eg, genetic or metabolic syndromes and severe congenital anomalies)

•Dependence on a medical-related technology (eg, tracheostomy, gastrostomy, or positive pressure ventilation [unrelated to COVID-19])

 

(1) Bamlanivimab and Etesevimab

The Eli Lilly and Company developed two different antibody therapies for COVID

On February 9, 2021, the USFDA granted EUA to the emergency use of combined bamlanivimab and etesevimab for people with mild-to-moderate COVID-19. The EMA has also granted approval in May 2021 for its use in Europe. However this is not yet available in India.

The FDA also authorized  bamlanivimab monotherapy on November 10, 2020. However, on March 24, 2021, Eli Lilly and Company halted distribution of the bamlanivimab as a single agent  because of concerns of its reduced efficacy against SARS-CoV-2 variants. The FDA advised the use of alternative monoclonal treatments in light of the increase in the prevalence of which bamlanivimab has shown reduced efficacy.

Scientific studies have shown the combined bamlanivimab and etesevimab therapy reduced the risk of COVID-19 hospitalizations and death by 87% in people with mild-to-moderate symptoms at high risk of severe disease.

The recommended dose is for 700 mg of bamlanivimab and 1400 mg of etesevimab

Nausea and infusion-related adverse effects (pruritus, fever, rash) were reported with administration of monoclonal antibody therapy but were generally uncommon and mild.

(2) REGN-COV2: Casirivimab and imdevimab

Regeneron developed a “combination antibody cocktail” called REGN-COV2 which contains the antibodies casirivimab and imdevimab.

This has received approval both in the US ( by USFDA as well as in Europe ( by EMA) for treatment for COVID-19 patients at risk of developing severe disease but who do not require oxygen treatment.

According to Phase 3 clinical trials conducted by Regneron , the combined casirivimab and imdevimab antibodies reduced the risk of COVID-19 hospitalizations and death by 70% in people with mild-to-moderate symptoms. This was the antibody that was reportedly administered to Ex US President Trump which enabled him to have a quick recovery and return to work.

Like with bamlanivimab and etesevimab therapy, trials are being conducted to test the efficacy of these antibodies in hospitalised patients with severe disease who need oxygen or a mechanical ventilator as a result of COVID-19. This has just become available in India and the approximate cost is 60,000 INR. The side –effects are minimal and include infusion-related reaction events of moderate severity, including fever, chills, urticaria, pruritus, abdominal pain, and flushing. Rarely anaphylaxis was also reported.

The recommended dose   for the combined cocktail  is a single dose of 2400 mg . It should be given under medical supervision in  day care setting and not as a home based treatment

(3) Sotrovimab

This is the 3rd and the latest in the series of monoclonal antibodies. It is developed by Glaxo SmithKline and has received approval in Europe .

It targets a highly conserved epitope of the SARS-CoV-2 spike protein, which may make it more difficult for resistance to develop. It is given as a single intravenous infusion of 500 mg preferably given within 5 days of onset of COVID infection. It has not been found to be beneficial in hospitalised patients

Studies show that treatment with sotrovimab resulted in an 85% reduction in the risk of hospitalisation or death in high-risk adult outpatients . It maintains activity against all known variants of concern, including the variant from India

Anti-interleukin-6 receptor monoclonal antibodies

Interleukin 6 (IL-6) is a type of inflammatory cytokine. Antibodies that block this cytokine from binding to other cells may alleviate the danger of COVID-19-related inflammation.

It is believed that the immune system may overreact in response to COVID-19 and lead to a  cytokine storm, in which excessive amounts of inflammatory proteins called cytokines can cause life . This is not yet available in India.

(1) Tocilizumab

IL-6 is a pleiotropic pro-inflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. Tocilizumab is a recombinant humanised monoclonal antibody that inhibits binding of IL-6 to both membrane and soluble IL-6 receptors. This antibody has current approval from the FDA to treat rheumatologic disorders. It is given as a dose of 400 mg in 1-2 doses.

The NIH, USA has recommended these antibodies for hospitalized COVID-19 patients on the condition that healthcare professionals use them in conjunction with other treatments, such as dexamethasone and it has been shown to reduce mortality in hospitalized patients as well as resulting in an early discharge. However further studies in a larger number of patients are warranted.

This is available in India and and been used in ICUs during the current pandemic

(2) Levilimab (Ilsira)

The Russian biotechnology company BIOCAD developed the antibody Levilimab  (Ilsira) to prevent cytokine storm-related complications caused by COVID-19. The Russian Federation’s Ministry of Health has approved its use for COVID-19 treatment on June 5, 2020.

Preliminary studies demonstrate that Levilimab therapy can significantly reduce mortality among patients with COVID-19 and the burden on the health system.” However, the data supporting the use of levilimab have not been published. Thus these antibodies represent a major advance in the treatment of  COVID 19 . In the near  future more such drugs will go a great way in controlling this pandemic.

 

For more information please subscribe to my YouTube Channel TheKidney Klinic.



Dr Sanjeev Gulati
MD,DNB(CHD),DM,DNB(Nephrology).FISN,FIAP(Australia)FRCPC(Canada)FISOT. He is also Director, Nephrology and Kidney Transplant Fortis Gp of Hospitals, NCR. Adjunct Professor, Depptt Nephrology, Manipal University. Member Governing Body, ISN. Secretary, North Zone Chapter of ISN.





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