THE Q493R PROTEIN MUTATION OF THE SARS-CoV-2 EXHIBITING RESISTANCE AGAINST MONOCLONAL ANTIBODIES' TREATMENT

Edited by, JASPER VICTORIA

Amongst the various mutations of the SARS-Cov-2 variants, the q493r mutation is now of importance as it is known to exhibit resistance against the monoclonal antibodies used in the treatment of the SARS-CoV-2 infection, i.e, the covid-19.

The monoclonal antibodies were of much use in saving the lives of  covid-19 in patients who were moderately or severely ill, and also to drastically reduce their number of days of hospitalization and close monitoring.

The CDC reported of this development of resistance against the monoclonal antibodies and the reason or the cause behind as the q493r spike protein escape mutation. They observed this in a 73 year old immunocompromised patient in Italy, who had cholangiocarcinoma and developed sepsis  for which the patient had to take antimicrobials and steroids, though the patient tested negative for SARS-CoV-2 during admission. 

Three days later after the first SARS-CoV-2 test, and a day after from being resolved of the sepsis, the patient tested positive for SARS-CoV-2 infection, for which the patient had to take spike protein monoclonal antibodies for treatment of SARS-CoV-2 infection.

The viral load was still rising and the PCR tests for SARS-CoV-2 also were positive, even after administration of monoclonal antibodies such as etesevimab 400mg and bamlanivimab 700mg on a single infusion given intravenously. The patient later was dead even after ventilation when the monoclonal antibodies' treatment was not of use.

The new q493r mutation was on light in the patient's sample collected for a PCR test and traced back the spike protein genes to the alpha variant.

It was found that the q493r mutation developed due to selective pressure from bamlanivimab and etesevimab and the mutation to be capable of increasing the affinity for binding between the SARS-CoV-2 and the Angiotensin 2 Converting Enzyme (ACE2).

The q493r mutation rendered the monoclonal antibodies' treatment ineffective by preventiing the binding of the monoclonal antibodies to the SARS-CoV-2 spike protein.

The binding of bamlanivimab needs the following amino acid residues such as e484, f490, q493, s494, while etesevimab needs q494 for binding.

Additional to the resistance of q493r mutation to bamlanivimab and etesevimab, the mutation q494r also poses resistance against class 3 monoclonal antibodies, which do not hinder the direct binding of ACE2 at its binding site, but has seperate epitopes for binding.

The q494r mutation rendered the bamlanivimab ineffective by 6,666 fold and etesevimab by 232 fold.